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E-Clinical: High-impact Strategies - What You Need to Know: Definitions, Adoptions, Impact, Benefits, Maturity, Vendors

E-Clinical: High-impact Strategies - What You Need to Know: Definitions, Adoptions, Impact, Benefits, Maturity, Vendors

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Published by Emereo Publishing
The Knowledge Solution. Stop Searching, Stand Out and Pay Off. The #1 ALL ENCOMPASSING Guide to E-Clinical.An Important Message for ANYONE who wants to learn about E-Clinical Quickly and Easily...""Here's Your Chance To Skip The Struggle and Master E-Clinical, With the Least Amount of Effort, In 2 Days Or Less...""eClinical is a term used within the biopharmaceutical industry to refer to electronic systems for automating the management or conduct of clinical trials with the aim of replacing manual, ad hoc or paper-driven methods. Originally, ""eClinical"" was used to refer to any technology application in use within a clinical trial. Without a more specific definition, the industry used ""eClinical"" interchangeably to refer to number of different technologies, such as EDC solutions (Electronic Data Capture), CTMS (Clinical Trials Management System) or Randomization and Trial Supply Management systems, commonly using IVRS (Interactive Voice Response Systems), electronic patient diaries and other common types of electronic solutions widely used in clinical trials.Get the edge, learn EVERYTHING you need to know about E-Clinical, and ace any discussion, proposal and implementation with the ultimate book - guaranteed to give you the education that you need, faster than you ever dreamed possible!The information in this book can show you how to be an expert in the field of E-Clinical.Are you looking to learn more about E-Clinical? You're about to discover the most spectacular gold mine of E-Clinical materials ever created, this book is a unique collection to help you become a master of E-Clinical.This book is your ultimate resource for E-Clinical. Here you will find the most up-to-date information, analysis, background and everything you need to know.In easy to read chapters, with extensive references and links to get you to know all there is to know about E-Clinical right away. A quick look inside: EClinical trial technology, Accelrys, Case report form, ClearTrial, Clinical data acquisition, Clinical Data Interchange Standards Consortium, Clinical data management, Clinical data management system, Clinical Trial Management System, ClinLife, Common Technical Document, Data clarification form, Electronic Common Technical Document, Electronic patient-reported outcome, EudraCT, Mpro, Patient diary, Patient-reported outcome, Source document, Clinical trial, A1chieve, Age-Related Eye Disease Study, ALMANAC, Analysis of clinical trials, Assay sensitivity, ASTEROID trial, AURORA trial, Biological plausibility, British Doctors Study, CapOpus, CDR Computerized Assessment System, Censoring (clinical trials), Clinical significance, Clinical trial effect, Clinical trial protocol, Confirmatory trial, Consolidated Standards of Reporting Trials, Data confidentiality in clinical trials, Dose-ranging study, Dublin Molecular Medicine Centre, End point of clinical trials, European Clinical Research Infrastructures Network, European Forum for Good Clinical Practice, Jesse Gelsinger, Guatemala syphilis experiment, H5N1 clinical trials, Heart Protection Study, IFPMA Clinical Trials Portal, Imaging biomarker, INIT II, Intention to treat analysis, Interim analysis, International Studies of Infarct Survival, Intersalt study, Investigator's brochure, Jadad scale, JUPITER trial, Kano trovafloxacin trial litigation, Length time bias, Medical experimentation in Africa, MIDAS Trial, N of 1 trial, Natural history group, Patient recruitment, Per-protocol analysis, Potentially all pairwise rankings of all possible alternatives, Rule of three (medicine), Scandinavian Simvastatin Survival Study, SDTM...and Much, Much More!This book explains in-depth the real drivers and workings of E-Clinical. It reduces the risk of your technology, time and resources investment decisions by enabling you to compare your understanding of E-Clinical with the objectivity of experienced professionals - Grab your copy now, while you still can.
The Knowledge Solution. Stop Searching, Stand Out and Pay Off. The #1 ALL ENCOMPASSING Guide to E-Clinical.An Important Message for ANYONE who wants to learn about E-Clinical Quickly and Easily...""Here's Your Chance To Skip The Struggle and Master E-Clinical, With the Least Amount of Effort, In 2 Days Or Less...""eClinical is a term used within the biopharmaceutical industry to refer to electronic systems for automating the management or conduct of clinical trials with the aim of replacing manual, ad hoc or paper-driven methods. Originally, ""eClinical"" was used to refer to any technology application in use within a clinical trial. Without a more specific definition, the industry used ""eClinical"" interchangeably to refer to number of different technologies, such as EDC solutions (Electronic Data Capture), CTMS (Clinical Trials Management System) or Randomization and Trial Supply Management systems, commonly using IVRS (Interactive Voice Response Systems), electronic patient diaries and other common types of electronic solutions widely used in clinical trials.Get the edge, learn EVERYTHING you need to know about E-Clinical, and ace any discussion, proposal and implementation with the ultimate book - guaranteed to give you the education that you need, faster than you ever dreamed possible!The information in this book can show you how to be an expert in the field of E-Clinical.Are you looking to learn more about E-Clinical? You're about to discover the most spectacular gold mine of E-Clinical materials ever created, this book is a unique collection to help you become a master of E-Clinical.This book is your ultimate resource for E-Clinical. Here you will find the most up-to-date information, analysis, background and everything you need to know.In easy to read chapters, with extensive references and links to get you to know all there is to know about E-Clinical right away. A quick look inside: EClinical trial technology, Accelrys, Case report form, ClearTrial, Clinical data acquisition, Clinical Data Interchange Standards Consortium, Clinical data management, Clinical data management system, Clinical Trial Management System, ClinLife, Common Technical Document, Data clarification form, Electronic Common Technical Document, Electronic patient-reported outcome, EudraCT, Mpro, Patient diary, Patient-reported outcome, Source document, Clinical trial, A1chieve, Age-Related Eye Disease Study, ALMANAC, Analysis of clinical trials, Assay sensitivity, ASTEROID trial, AURORA trial, Biological plausibility, British Doctors Study, CapOpus, CDR Computerized Assessment System, Censoring (clinical trials), Clinical significance, Clinical trial effect, Clinical trial protocol, Confirmatory trial, Consolidated Standards of Reporting Trials, Data confidentiality in clinical trials, Dose-ranging study, Dublin Molecular Medicine Centre, End point of clinical trials, European Clinical Research Infrastructures Network, European Forum for Good Clinical Practice, Jesse Gelsinger, Guatemala syphilis experiment, H5N1 clinical trials, Heart Protection Study, IFPMA Clinical Trials Portal, Imaging biomarker, INIT II, Intention to treat analysis, Interim analysis, International Studies of Infarct Survival, Intersalt study, Investigator's brochure, Jadad scale, JUPITER trial, Kano trovafloxacin trial litigation, Length time bias, Medical experimentation in Africa, MIDAS Trial, N of 1 trial, Natural history group, Patient recruitment, Per-protocol analysis, Potentially all pairwise rankings of all possible alternatives, Rule of three (medicine), Scandinavian Simvastatin Survival Study, SDTM...and Much, Much More!This book explains in-depth the real drivers and workings of E-Clinical. It reduces the risk of your technology, time and resources investment decisions by enabling you to compare your understanding of E-Clinical with the objectivity of experienced professionals - Grab your copy now, while you still can.

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Published by: Emereo Publishing on Nov 05, 2012
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9781743387337

Sections

  • eClinical trial technology
  • Accelrys
  • Case report form
  • ClearTrial
  • Clinical data acquisition
  • Clinical Data Interchange Standards Consortium
  • Clinical data management
  • Clinical data management system
  • 'Clinical Data Management
  • Clinical Trial Management System
  • ClinLife
  • Common Technical Document
  • Data clarification form
  • Electronic Common Technical Document
  • Electronic patient-reported outcome
  • EudraCT
  • Mpro
  • Patient diary
  • Patient-reported outcome
  • Source document
  • Clinical trial
  • A1chieve
  • Age-Related Eye Disease Study
  • ALMANAC
  • Analysis of clinical trials
  • Assay sensitivity
  • ASTEROID trial
  • AURORA trial
  • Biological plausibility
  • British Doctors Study
  • CapOpus
  • CDR Computerized Assessment System
  • Censoring (clinical trials)
  • Clinical significance
  • Clinical trial effect
  • Clinical trial protocol
  • Confirmatory trial
  • Consolidated Standards of Reporting Trials
  • Data confidentiality in clinical trials
  • Dose-ranging study
  • Dublin Molecular Medicine Centre
  • End point of clinical trials
  • European Clinical Research Infrastructures Network
  • European Forum for Good Clinical Practice
  • •European Forum for Good Clinical Practices [1]
  • Jesse Gelsinger
  • Guatemala syphilis experiment
  • H5N1 clinical trials
  • Heart Protection Study
  • IFPMA Clinical Trials Portal
  • Imaging biomarker
  • INIT II
  • INIT I
  • Intention to treat analysis
  • Interim analysis
  • International Studies of Infarct Survival
  • Intersalt study
  • Investigator's brochure
  • Jadad scale
  • JUPITER trial
  • Kano trovafloxacin trial litigation
  • The Kano trovafloxacin trial litigation
  • Length time bias
  • Medical experimentation in Africa
  • MIDAS Trial
  • N of 1 trial
  • Natural history group
  • Patient recruitment
  • Per-protocol analysis
  • Potentially all pairwise rankings of all possible alternatives
  • Rule of three (medicine)
  • Scandinavian Simvastatin Survival Study
  • SDTM
  • Site management organization
  • Standard for Exchange of Non-clinical Data
  • Stateville Penitentiary Malaria Study

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Combine the advantages of up-to-date and in-depth knowledge with the convenience of printed books. A portion of the proceeds of each book will be donated to the Wikimedia Foundation to support their mission: to empower and engage people around the world to collect and develop educational content under a free license or in the public domain, and to disseminate it effectively and globally. The content within this book was generated collaboratively by volunteers. Please be advised that nothing found here has necessarily been reviewed by people with the expertise required to provide you with complete, accurate or reliable information. Some information in this book maybe misleading or simply wrong. The publisher does not guarantee the validity of the information found here. If you need specific advice (for example, medical, legal, financial, or risk management) please seek a professional who is licensed or knowledgeable in that area. Sources, licenses and contributors of the articles and images are listed in the section entitled “References”. Parts of the books may be licensed under the GNU Free Documentation License. A copy of this license is included in the section entitled “GNU Free Documentation License” All used third-party trademarks belong to their respective owners.

Contents
Articles
eClinical trial technology Accelrys Case report form ClearTrial Clinical data acquisition Clinical Data Interchange Standards Consortium Clinical data management Clinical data management system Clinical Trial Management System ClinLife Common Technical Document Data clarification form Electronic Common Technical Document Electronic patient-reported outcome EudraCT Mpro Patient diary Patient-reported outcome Source document Clinical trial A1chieve Age-Related Eye Disease Study ALMANAC Analysis of clinical trials Assay sensitivity ASTEROID trial AURORA trial Biological plausibility British Doctors Study CapOpus CDR Computerized Assessment System Censoring (clinical trials) Clinical significance Clinical trial effect 1 3 4 6 7 9 11 14 16 17 18 19 19 22 25 26 27 27 30 31 47 47 48 49 51 52 53 54 55 57 58 60 60 63

Clinical trial protocol Confirmatory trial Consolidated Standards of Reporting Trials Data confidentiality in clinical trials Dose-ranging study Dublin Molecular Medicine Centre End point of clinical trials European Clinical Research Infrastructures Network European Forum for Good Clinical Practice Jesse Gelsinger Guatemala syphilis experiment H5N1 clinical trials Heart Protection Study IFPMA Clinical Trials Portal Imaging biomarker INIT II Intention to treat analysis Interim analysis International Studies of Infarct Survival Intersalt study Investigator's brochure Jadad scale JUPITER trial Kano trovafloxacin trial litigation Length time bias Medical experimentation in Africa MIDAS Trial N of 1 trial Natural history group Patient recruitment Per-protocol analysis Potentially all pairwise rankings of all possible alternatives Rule of three (medicine) Scandinavian Simvastatin Survival Study SDTM Site management organization Standard for Exchange of Non-clinical Data Stateville Penitentiary Malaria Study

68 69 70 72 72 73 75 76 77 77 78 80 85 86 87 90 92 93 94 95 95 103 106 108 114 115 118 118 120 121 124 124 134 135 136 140 142 142

Stratify (clinical trials) Study of Tamoxifen and Raloxifene Surrogate endpoint Trials (journal) Tuskegee syphilis experiment Women's Health Initiative

144 144 144 145 147 157

References
Article Sources and Contributors Image Sources, Licenses and Contributors 161 164

Article Licenses
License 165

More recently. Therefore. Moreover. the pursuit of an integrated technology suite to streamline workflows and improve usability has become a key characteristic of the industry’s latest "eClinical" approach. electronic patient diaries and other common types of electronic solutions widely used in clinical trials. eliminating duplication of activities. the industry used "eClinical" interchangeably to refer to number of different technologies. this model of eClinical integration has become more difficult to maintain and support as it requires independent integrations between pairs of applications. The shift in the definition of "eClinical" has been a natural part of the industry’s evolution to seek better ways to utilize multiple technologies together within a clinical trial. and eliminating the need to enter data separately into both systems. generic connections between each application and the middleware make this a very repeatable and efficient method to implement.[5] This approach requires each technology application to be integrated only to the middleware (messaging hub).[1] Increasingly. These have been effective in enabling data to be shared between applications. "eClinical" was used to refer to any technology application in use within a clinical trial. The industry has found over time that eliminating data discrepancies between systems has reduced data reconciliation activities in addition to ensuring that those responsible for a clinical trial always have accurate and up-to-date information. has increased. More recently. both internal and externally-hosted. an example of an "eClinical solution" is the combination of EDC and IVR systems where common data are shared in a way that eliminates the need for users to enter the same data or perform the same action in both applications. Clinical Trials Technology Integration The eClinical concept has been brought to reality through technology integration. many of which require a specific build for each individual clinical trial. CTMS (Clinical Trials Management System) or Randomization and Trial Supply Management systems. sharing data. the problems of duplication of data and redundancy in process have increased. commonly using IVRS (Interactive Voice Response Systems). such as EDC solutions (Electronic Data Capture). ad hoc or paper-driven methods. the usage of the term "eClinical" has evolved from this earlier reference for any clinical trial technology to a more specific context focused more on business process than on individual technologies. maintaining multiple systems containing overlapping data and functionality has also brought significant inefficiencies for trial sponsors and technology users. integration messages are controlled by a single hub. This middleware then receives data and information from each application and determines which other applications require updating and in which way. the industry has migrated to a more efficient. As a consequence. Originally. Background While individual solutions have helped to automate or streamline their particular application areas of the clinical trial process. Without a more specific definition. and streamlining the use of multiple technologies for end users. and the resulting data reconciliation activities. As the number of applications.[2] [3] [4] As the number of relevant applications increases with greater adoption of EDC and other technologies. Initial system integrations have focused on secure data exchange between applications using point-to-point integrations. the term is being adopted to convey the concept of integrated technologies utilized in clinical trials technology products working together as solutions.eClinical trial technology 1 eClinical trial technology eClinical is a term used within the biopharmaceutical industry to refer to electronic systems for automating the management or conduct of clinical trials with the aim of replacing manual. scalable and supportable model by implementing integration middleware. As a result.[6] .

aspx) (eCF) • Clinpage (http://www. Forrester Research Market [6] S Shacter. Collectively.clinpage. October 2007 [5] L Ramos. June 2008 External links • eClinical Forum (http://www. References [1] ClinPage: 5 Definitions of "Eclinical" (http:/ / www. June 2007 [7] DataMonitor. The industry is now looking to provide significant workflow and process benefits for the end user – particularly the site and sponsor personnel – in the way that products are integrated. Applied Clinical Trials.com) . "The Promise of Next-Gen eClinical Trial Software".eClinical trial technology 2 Future of eClinical Both of the above point-to-point and middleware integration models are primarily focused on how the technologies can share information at the back-end. CTMS and RTSM (a. "In Search of the Holy Grail – Chasing ultimate clinical trial efficiency. com/ article/ 5_definitions_of_eclinical/ C10) [2] R Case.eclinicalforum. Data Warehouse and Enterprise Portal. “In Pursuit of the Paperless Clinical Trial: A look at EDC and CTMS . through another system. Applied Clinical Trials. IVRS) to be the key pieces of an eClinical foundation. one small step at a time". a site user is able to randomize and allocate medication to a subject from within their EDC solution without having to log out and enter a second solution. "A to Z Trial Integration". Pharmaceutical Executive. Current and future efforts focus around convergence – the ability to enable a user to access functionality normally contained discretely within one system. "Meshing EDC with CTMS". February 2007 [4] J Mcllwain. The resulting widespread adoption of these tools in the clinical trials space has made them the optimal central pieces for an eClinical suite. July 2005 [3] B Harper.org/main/default. clinpage. Bio-IT World. include ePRO. Safety. Other systems. This blurring of boundaries between IVR and EDC where the process of randomizing. end users are still required to access multiple applications and perform discrete activities within them.k. ECG. “Data Integration: Past & Future”.a. these tools enable sponsors to centralize and automate the data collection as well as study and logistics management of their clinical trials. In these situations. Although there are many different electronic tools to handle different aspects of the clinical trial process.Essential eClinical solutions to maximize efficiency in clinical trials”. A simple example entails enabling randomization functionality to be called directly from within a patient record of an EDC system – in that way. most [7] consider EDC. which do not feature as foundational pieces but still represent potentially relevant components of an eClinical suite. entering associated patient data and managing drug supplies happens all within a single interface helps to create a seamless and highly optimized end user experience. Medical Imaging. Submissions.

Accelrys 3 Accelrys Accelrys Type Traded as Industry Founded Public NASDAQ: ACCL [1] Life sciences. Polygen and. Oxford Molecular.accelrys. USA Key people Max Carnecchia. Accelrys started in 2001 from the fusion of five companies: Molecular Simulations Inc. an electronic lab notebook software firm. and Synomics Ltd. a suite of programs for life sciences.[4] Products • Pipeline Pilot. thus building a "pipeline". itself a result of the combination of Biodesign. the Genetics Computer Group (GCG). CFO David Mersten. • Symyx Notebook by Accelrys.com [2] Revenue Employees Website Accelrys (NASDAQ: ACCL [1]) is a software company headquartered in the US. It provides software for chemical research. later. In May of 2011 the company acquired Contur Software AB. an electronic laboratory notebook. Biocad and Biosym Technologies).Senior Vice President. UK Tokyo. In 2004. a program that serves as the connection of multiple pieces of software from different vendors. a suite of programs for material science. Commercial versions of otherwise academically licensed programs: • CHARMM • MODELLER . a cheminformatics platform. with representation in Europe and Japan. Accelrys acquired SciTegic. Japan Headquarters San Diego. California. • Materials Studio. Materials science 2001 Cambridge. • Accord. (MSI. Cambridge Molecular Design. Accelrys manages a Nanotechnology Consortium producing software tools for rational nanodesign. Synopsys Scientific Systems. Piraino. • Discovery Studio. especially in the areas of drug discovery and materials science.[3] In 2010 Symyx Technologies was merged with Accelrys. General Counsel and Secretary Frank Brown Chief Science Officer US$81 Million 700+ www. producer of the Pipeline Pilot software. President and CEO Michael A.

. because of human and machine error. The size of a CRF can range from a handwritten one-time 'snapshot' of a patient's physical condition to hundreds of pages of electronically captured data obtained over a period of weeks or months. html) External links • Accelrys official homepage (http://www. Depending on variables relating to the nature of the study. Examples of data that would lead to a query: a male patient being on female birth control medication or having had an abortion. the data entered in CRFs is rarely completely accurate or entirely readable. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site.accelrys.com/corporate_groupings/Accelrys) grouped at OpenCorporates Case report form A Case Report Form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. this data is usually de-identified (not traceable to the patient) by removing the patient's name. nasdaq. (It can also include required check-up visits months after the patient's treatment has stopped. Queries are non-sensible or questionable data that must be explained. (e. .com) • Accelrys companies (http://opencorporates. The sponsor of the clinical trial develops the CRF to collect the specific data they need in order to test their hypotheses or answer their research questions. All data on each patient participating in a clinical trial are held and/or documented in the CRF. the effectiveness of the study administrators in resolving these queries can significantly impact the cost of studies. com Accelrys company information (http:/ / accelrys. etc.g. The supervising Institutional Review Board (IRB) oversees the release of any personally identifiable data to the sponsor. From the sponsor's point of view. as well as managing its production. Before being sent to the sponsor. com/ company/ ) Nanotech Consortium (http:/ / accelrys. When the study administrators or automated mechanisms process the CRFs that were sent to the sponsor by local researchers. com/ asp/ SummaryQuote. com/ innovation/ consortia-special-interest-groups/ nanotechnology-consortium. Each query has to be resolved by the individual attention of a member of each local research team. these queries are usually addressed and resolved before the CRF data is included by the sponsor in the final clinical study report. asp?symbol=ACCL& selected=ACCL http:/ / www. including adverse events. Case report forms contain data obtained during the patient's participation in the clinical trial.Accelrys 4 References [1] [2] [3] [4] http:/ / quotes. However. medical record number. or a 15-year old participant having had hip replacement surgery. and giving the patient a unique study number.. the health of the study population).) The sponsor is responsible for designing a CRF that accurately represents the protocol of the clinical trial. as well as an individual in the study administration. To ensure quality control. they make a note of queries. the main logistic goal of a clinical trial is to obtain accurate CRFs. monitoring the data collection and auditing the content of the filled-in CRFs. accelrys.

gov/ workspaces/ CTMS/ Meetings/ SIGs/ Best_Practices/ SOPs/ CR003_SOP_Develop_Manage_CRF. htm . html [2] https:/ / cabig.Case Report Forms [4] References [1] http:/ / www. Canary Publications. icssc. nci.National Cancer Institute Standard Operating Procedure – Develop and Manage a Case Report Form [3] links to CRF information (PDF) Clinical Trials Software . ISBN 0-9531174-7-2 External links • • • • International Clinical Sciences Support Center (ICSSC) CRF Development [1] Standardized Case Report Form (CRF) Work Group [2] . com/ casereportforms. pdf#search=%22%22Case%20Report%20Form%22%20standardization%22 [4] http:/ / www. CRF Designer. nih. org/ services/ services-crfdevelopment. entrypointplus. gov/ workspaces/ CTMS/ CTWG_Implementation/ crf-standardization-sig [3] https:/ / cabig. nci. nih.Case report form 5 References • Debbie Kennedy.

VP of Worldwide Sales ClearTrial PLAN ClearTrial SOURCE ClearTrial TRACK Employees Website 50+ (August 1. CEO Michael Bruns. The level of effort is calculated based on an algorithm that has been derived from analysis of the cost and time drivers that affect each task. CMO Richard Zecca. COO Andrew Grygiel. 2011) cleartrial. Illinois. ClearTrial’s clinical trial subject matter experts (SMEs) have published peer-reviewed articles on functional service provider outsourcing in clinical trials[2] . Illinois 60661 USA Area served Key people Global Mike Soenen. as well as articles on clinical trial trends[5] . outsourcing. adaptive clinical trials[3] .com [1] Products ClearTrial is a multinational software developer headquartered in Chicago. and tracking of clinical trials.ClearTrial 6 ClearTrial ClearTrial Type Industry Founded Private Clinical trial software Chicago. which predicts the level of effort for a specific resource (person) to perform a given task (activity). Chicago. In April 2011. USA. The ClearTrial software architecture follows a project management methodology that includes activity-based costing. Illinois. ClearTrial was named one of five “Cool Vendors in Life Sciences”[6] by the research firm Gartner. The ClearTrial Work Breakdown Structure defines and groups the tasks and subtasks that comprise a clinical trial in a way that organizes and defines the total work scope of the clinical project. USA (2004) Headquarters 328 South Jefferson Street. and clinical trials for medical devices[4] . . The company develops and markets a software as a service (SaaS) system designed for biopharmaceutical and medical device manufacturers for the planning.

“Considerations for Medical Device Trials" (http:/ / appliedclinicaltrialsonline.. S. Hagemeyer. The ICH guidelines on Good clinical practice (GCP) use the term ‘Case report form’ or ‘CRF’ to refer to these systems 1 .. Applied Clinical Trials.ClearTrial 7 References [1] http:/ / www. The quality of the data collected relies first and foremost on the quality of that instrument. August 2008 [3] Blake-Michaels. development and quality assurance of the CRF such that the data collected will meet the highest standards. interactive voice response systems. com/ appliedclinicaltrials/ Rotating+ Feature+ Article/ Considerations-for-Medical-Device-Trials/ ArticleStandard/ Article/ detail/ 682817). Pharmaceutical Executive. see Data Collection Forms for Clinical Trials by Spilker 2 . K. Applied Clinical Trials. M. gartner. com/ appliedclinicaltrials/ Trial+ Design+ Articles/ Operation-Adaptive/ ArticleStandard/ Article/ detail/ 632985). No matter how much time and effort go into conducting the clinical trial.. K. therefore. if the correct data points were not collected. “Operation Adaptive” (http:/ / appliedclinicaltrialsonline. findpharma. paper forms completed at a site. development and quality assurance of such an instrument must be given the utmost attention. There is arguably no more important document than the instrument that is used to acquire the data from the clinical trial with the exception of the protocol. April 2011 External links Corporate website (http://www. “Steps to Functional Service Provider Success” (http:/ / appliedclinicaltrialsonline. • Document the process for CRF design.cleartrial. • Document training of clinical site personnel on the protocol. development. findpharma. . Soenen. For an extensive discussion regarding creation of CRFs and examples of actual data collection forms. pdf). “Cool Vendors in Life Sciences. Gartner. “Honing Reforms from Clinical Development” (http:/ / pharmexec. local electronic data capture systems. the quality and integrity of the data is of primary importance. approval and version control. It follows. that the design. findpharma. February 2011 [6] Lefebure.. M. Getz.. CRF completion instructions and data submittal procedures prior to enrollment of a subject. any of the following: paper or electronic medical records.. August 2010 [5] Stergiopoulos. D. or central web based systems. • Make the CRF available at the clinical site prior to enrollment of a subject. 2011” (http:/ / www. com [2] Lucas. October 2009 [4] Blake-Michaels. S.. Minimum standards • Design the CRF to collect the data specified by the protocol. a meaningful analysis may not be possible.. M.com) Clinical data acquisition Acquisition or collection of clinical trial data can be achieved through various methods that may include. but are not limited to. com/ appliedclinicaltrials/ Project+ Management/ Steps-to-Functional-Service-Provider-Success/ ArticleStandard/ Article/ detail/ 534273). com/ pharmexec/ Sales/ Honing-Reforms-from-Clinical-Development/ ArticleStandard/ Article/ detail/ 707517). The following is meant to highlight some of the most important points to consider during the design process. com/ resources/ 210900/ 210958/ cool_vendors_in_life_science_210958. No matter what CRF is utilized. cleartrial. Applied Clinical Trials. findpharma. which specifies the conduct of that clinical trial. The following recommendations are meant to assist in the design.

scdm. Canary Publications. the measurements should be obtained through independent means. If redundant data collection is used to assess data validity.L. • Establish and maintain a library of standard forms. External links • FDA Website: Clinical Data Management Regulations [1] • Association For Clinical Data Management [2] • Society For Clinical Data Management [3] References [1] http:/ / www. ISBN 0-9531174-7-2 • Rebecca Daniels Kush (2003). gov/ [2] http:/ / www. prompts and instructions clear and concise. References • Debbie Kennedy. • Make the CRF available for review at the clinical site prior to approval. ISBN 1-930624-28-X • Spilker B. • Use NCR (no carbon required) paper or other means to assure exact replicas of paper collection tools. • Design the CRF with the primary safety and efficacy endpoints in mind as the main goal of data collection. New York. CenterWatch / Thomson Healthcare. org. (1991). fda. • Design the CRF to follow the data flow from the perspective of the person completing it. • Avoid referential and redundant data points within the CRF whenever possible. eClinical Trials: Planning and Implementation. CRF Designer. uk/ [3] http:/ / www. Schoenfelder J. org/ . Data Collection Forms in Clinical Trials Raven Press.Clinical data acquisition 8 Best practices • Design the CRF along with protocol to assure collection of only the se data the protocol specifies. taking into account the flow of study procedures and typical organization of data in a medical record. acdm. • Keep questions.

• Standard for Exchange of Non-clinical Data (SEND) • The animal trial equivalent of SDTM. The objective is to establish a standardized data collection baseline across all submissions.Invited to form DIA SIAC Feb 2000 . storing of ODM is independent from hard. The data standards are defined as a series of Models.formed an Independent. . a machine readable version of the regulatory submission "define. • Clinical Data Acquisition Standards Harmonization (CDASH) • Defines a minimal data collection set for sixteen safety SDTM Domains.and human.Global participation CDISC standards • Study Data Tabulation Model (SDTM) • Highlights: recommended for FDA regulatory submissions since 2004. The preferred electronic format is XML. • Analysis Data Model (ADaM) • Designed to complement the SDTM submission by detailing the statistical analysis performed on the clinical trial results.Started as a Volunteer group Summer 1998 . non-profit organization Dec 2001 .and software. which can be expressed using an underlying electronic format. definitions and metadata. platform-independent data standards that enable information system interoperability to improve medical research and related areas of health-care". • Laboratory Data Model (LAB) • Case Report Tabulation Data Definition Specification (CRT-DDS) • Also referred to as "define. bears the same name. predefined collection of submission metadata "Domains" containing extensive variable collections. utilizes XML technology. machine.xml". harmonizing element names. provides extensible lists of controlled terms designed to harmonize data collected across submissions.readable.Clinical Data Interchange Standards Consortium 9 Clinical Data Interchange Standards Consortium Clinical Data Interchange Standards Consortium (CDISC) is a non-profit organization. • Operational Data Model (ODM) • The highlights of ODM: includes audit trail. using the Operational Data Model (ODM) as a base XML Schema. the described data standard. CDISC History • • • • Late 1997 . • Study Data Tabulation Model SDTM Implementation Guide (SDTM-IG) • Gives a standardized. whose mission is "to develop and support global. • CDISC Terminology • Defines controlled terminology for SDTM and CDASH. all information are independent from databases. Their main project.pdf".

'Introducing the CDISC Standards: New Efficiencies for Medical Research'. fda. cdisc. This is useful for setting up the EDC system to capture data. htm . References • Rebecca Daniels Kush (2003). MetaData only import allows only the importing of MetaData. html [4] http:/ / www. ODM Import Full import allows importing of ODM-formatted clinical data (MetaData and Data). variables etc. ODM Export The EDC system will generate ODM data files for further processing. eClinical Trials: Planning and Implementation. org/ [3] http:/ / www. ISBN 1-930624-28-X • A J de Montjoie (2009). subject matter experts and consultants deemed to have sufficient knowledge and experience implementing the various CDISC standards. ODM Import and ODM Export. CDISC Publications External links • Clinical Data Interchange Standards Consortium [2] • CDISC Standards [3] • Electronic Common Technical Document (eCTD) [4] (FDA) References [1] http:/ / www. This provides a EDC vendor-neutral system for defining a study. Basically allows third party software to define the forms.Clinical Data Interchange Standards Consortium 10 CDISC registered solutions providers CDISC maintains a list of solutions providers. gov/ cder/ regulatory/ ersr/ ectd. CDSIC registered solutions providers [1] ODM and EDC integration Electronic Data Capture (EDC) systems can be certified as compliant with the Operational Data Model (ODM) by CDISC. org/ standards/ index. There are two main types of integration. org/ rsp [2] http:/ / www. used in the EDC system. CenterWatch / Thomson Healthcare. cdisc. cdisc.

and Quality Control procedures to be applied. The data collected during a clinical trial will form the basis of subsequent safety and efficacy analysis which in turn drive decision making on product development in the pharmaceutical industry. data handling processes. At this stage the data will be declared final (terminology varies but common descriptions are Database Lock and Database Freeze) and the Clinical Data Manager will transfer data for statistical analysis. validation and quality control of data gathered during the conduct of a clinical trial. Paper CRFs will be printed. often using No Carbon Required paper. Electronic CRFs enable data to be typed directly into fields using a computer and transmitted electronically to Data Management. verification.Clinical data management 11 Clinical data management Clinical data management encompasses the entry. validated. standard CRF pages may be re-used for collection of data which is common across most clinical trials eg subject demographics. Design of CRFs needs to take into account the information required to be collected by the clinical trial protocol and intended to be included in statistical analysis. Where available. Case Report Form Design The Case Report Form (CRF) is the data collection tool for the clinical trial and can be paper or electronic. Key topics to cover will include the SOPs to be followed. and shipped to the investigative sites conducting the clinical trial for completion after which they are couriered back to Data Management. The Clincal Data Manager will be involved in early discussions about data collection options and will then oversee development of data collection tools based on the clinical trial protocol. . The Data Management Plan The Data Management Plan will describe the activities to be conducted in the course of processing data. complete and consistent. At the completion of the clinical trial the Clinical Data Manager will ensure that all data expected to be captured has been accounted for and that all data management activities are complete. Role of the Clinical Data Manager in a Clinical Trial The Clinical Data Manager plays a key role in the setup and conduct of a clinical trial. Clincal Data Management System to be used. description of data sources. Standard Operating Procedures Standard Operating Procedures (SOPs) describe the process to be followed in conducting data management activities and support the obligation to follow applicable laws and guidelines (eg ICH GCP [1] and 21CFR Part 11) in the conduct of data management activities. Once subject enrollment begins the Clinical Data Manager will ensure that data is collected. The Clinical Data Manager will liaise with other data providers (eg a central laboratory processing blood samples collected) and ensure that such data is transmitted securely and is consistent with other data collected in the clinical trial. data transfer formats and process.

When using a paper CRF the pages are entered by data entry operators. Validation Rules Validation rules are electronic checks defined in advance which ensure the completeness and consistency of the clinical trial data. For a clinical trial utilising a paper CRF the relational database will be built separately. system independent data standards which are now commonly used as the underlying data structures for clinical trial data. For electronic CRFs the validation rules may be applied in real time at the point of entry. Computer System Validation All computer systems used in the processing and management of clinical trial data must undergo validation testing to ensure that they perform as intended and that results are reproducible. In both cases the relational database will allow entry of all data captured on the CRF. Data Entry When an electronic CRF is in use data entry is carried out at the investigative site where the clinical trial is conducted by site staff who have been granted appropriate access to do so.Clinical data management 12 Database Design and Build For a clinical trial utilising an electronic CRF the database design and build and CRF design are closely linked. Best practice is for a first pass data entry to be completed followed by a second pass or verification step by an independent operator. Data queries must not be leading (ie they must not suggest the correction that should be made). Data Queries Where data entered does not pass validation rules then a data query may be issued to the investigative site where the clinical trial is conducted to request clarification of the entry. The electronic CRF will enable entry of data into an underlying relational database. Data Validation Data validation is the application of validation rules to the data. User Acceptance Testing Once an electronic CRF is built the clinical data manager (and other parties as appropriate) will conduct User Acceptance Testing (UAT). These describe parameters such as the name. Where the operator is unable to read the entry the clinical data manager should be notified so that the entry may be clarified with the person who completed the CRF. Offline validation may still be required (eg for cross checks between data types). Any discrepancies between the first and second pass may be resolved such that the data entered is a true reflection of that recorded on the CRF. CDISC The Clinical Data Interchange Standards Consortium [2] leads the development of global. For electronic CRFs only the site staff with appropriate access may modify data entries. For paper CRFs the Clinical Data Manager will apply the data query response to the database . The tester will enter data into the electronic CRF and record whether it functions as intended. length and format of each data field (variable) in the relational database.

Patient diaries may be developed in either paper or electronic (eDiary) formats. The Clinical Data Manager must ensure that data is reconciled between these processes. for example. all external data received and reconciled and all other data management activities complete the database may be finalised. The Clinical Data Manager will liaise with such data providers and agree data formats and transfer schedules. The Clinical Data Manager will liaise with the central laboratory and agree data formats and transfer schedules. 13 Central Laboratory Data Samples collected during a clinical trial may be sent to a single central laboratory for analysis. The sample collection date and time may be reconciled against the CRF to ensure that all samples collected have been analysed. it is generally not practical to raise data queries. Other External Data Analysis of clinical trail data may be carried out by laboratories. Serious Adverse Event Reconciliation The CRF will collect Adverse Events reported during the conduct of the clinical trial however there is a separate process which ensures that Serious Adverse Events are reported quickly. Patient Recorded Data Where the subject is required to record data (eg daily symptoms) then a diary will be provided for completion. image processing specialists or other third parties. Data management of this data requires a different approach to CRF data as. Database Finalisation and Extraction Once all expected data is accounted for. Such eDiaries generally take the form of a handheld device which enables the subject to enter the required data and transmits this data to a centralised server.Clinical data management and a copy of the data query is retained at the investigative site. Data may be reconciled against the CRF to ensure consistency. Metrics and Tracking Typical reports generated and used by the Clinical Data Manager will include: • • • • Status of page completion / missing pages Status of data queries Data queries not resolved within specified time limit Commonly raised data queries (to help identify areas where improvements can be made) . all data queries closed.

ich.Clinical data management 14 Quality Control Quality Control is applied at various stages in the Clincal Data Management process and is normally mandated by SOP. These errors are raised for review to determine if there is an error in the data or clarification from the investigator is required.The most popular method being double data entry where two different data entry operators enter the data in the system independently and both the entries are compared by the system. External links • Association for Clinical Data Management [2] A not-for-profit organisation that represents and supports professionals involved with managing clinical data from within the pharmaceutical. With the variance on the number of references that can be made for adverse event Terms or medication names. 'Classification The CDMS can be broadly divided into Paper based and electronic data capturing system. org/ Clinical data management system A clinical data management system or CDMS is a tool used in clinical research to manage the data of a clinical trial. the systems employ different means to verify the data. adverse event terms and medication names. Also. Electronic Data Capturing System In such CDMS the investigators directly uploads the data on CDMS and the data can then be viewed by the data validation staff. in these systems during validation the data clarification from sites are done through paper forms which are printed with the issue description and sent to the investigator site and site responds by answering on forms and mailing it back. Such systems nullifies the paper usage in Clinical trials validation of data. In case the entry of a value conflicts. • Society for Clinical Data Management [3] Dedicated to promoting quality and excellence in the field of clinical data management. The Data in CDMS is then transferred for the data validation. 'Clinical Data Management Once the data has been screened for typographical errors. Another method is Single Data Entry. Paper Based Systems Case report forms are manually filled at site and mailed to the company for which trial is being performed. The data items containing the adverse event terms or medication names can be linked to one of these . References [1] http:/ / www. data validation team can send the electronic alerts to sites if there is any issue. the coding is generally centered around two areas. Once the data is uploaded by site. Currently. Another function that the CDMS can perform is the coding of data. To reduce the possibility of errors due to human entry. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS. biotechnology and academic research fields. the data can be validated to check for logical errors. system alerts and a verification can be done manually. The data on forms is transferred to the CDMS tool through data entry. standard dictionaries of these terms can be loaded into the CDMS. An example is a check of the subject's age to ensure that they are within the inclusion criteria for the study.

The analysed data is compiled into clinical study report and sent to the regulatory authorities for approval. ISBN 1-4051-0740-5 • Tai BC. ASA could be mapped to Aspirin. 15 References • Stuart Summerhayes. At the end of the clinical trial the dataset in the CDMS is extracted and provided to statisticians for further analysis. External links • • • • Clinical Trial Management Systems [1] (caBIG) Association for Clinical Data Management [2] (ACDM) Society for Clinical Data Management [3] (SCDM) Data Quality Research Institute [2] (DQRI) References [1] https:/ / cabig. A review of software for data management. • Greenes RA. As an example. Barnett GO. Blackwell Publishing. CDM Regulations Procedures Manual. Popular adverse event dictionaries are MedDRA and WHOART and popular Medication dictionaries are COSTART and WHO Drug Dictionary. Comput Biomed Res.2(5):469-85. 1969 Oct..Clinical data management system dictionaries. Pappalardo AN. The system can check the data in the CDMS and compare it to the dictionaries. dqri. gov/ workspaces/ CTMS [2] http:/ / www. Ann Acad Med Singapore. 2000 Sep. Items that do not match can be flagged for further checking. nci. Marble CW.. Design and implementation of a clinical data management system.29(5):576-81. Seldrup J. nih. org/ . design and analysis of clinical trials. a common notation. Some systems allow for the storage of synonyms to allow the system to match common abbreviations and map them to the correct term.

. compliance with U. with emphasis on keeping up-to-date contact information for participants and tracking deadlines and milestones such as those for regulatory approval or the issue of progress reports. Lu C. electronic data capture. it would be impossible to create a complete list of CTMS requirements. feature-rich software provided by specialized vendors. As the amount of data grows. In the early phases of clinical trials.Clinical Trial Management System 16 Clinical Trial Management System A Clinical Trial Management System. Usability comparison of three clinical trial management systems. org/ / Business/ Biotechnology_and_Pharmaceuticals/ Pharmaceuticals/ Outsourcing/ Data_Management/ / . Each sponsor has different requirements that their CTMS must satisfy. and reporting of clinical trials. budgeting and financials. References • Choi B. EC/IRB approvals. and adverse event reporting systems. Despite differences. Each manager has different requirements that a system must satisfy. is a customizable software system used by the biotechnology and pharmaceutical industries to manage the large amounts of data involved with the operation of a clinical trial. when the number of patients and tests are small. which acts as a digital dashboard for trial managers. including: project management. patient management. CRC Clinical Trials Management System (CTMS): an integrated information management solution for collaborative clinical research. investigator management. and compatibility with other data management systems. External links • Some clinical trial management systems. most managers use an in-house or home-grown program to handle their data. though. preparation.. 2005. Clauw D. dmoz. Hunscher D.S. Drozdetski S. It maintains and manages the planning. compliance with government regulations. Rottenberg C. AMIA Annu Symp Proc. [1] at the Open Directory Project References [1] http:/ / www. Yu L. Greaves AW. and compatibility with other systems such as data management systems. 2003. Often. • Payne PR. performance. Kipps TJ. organizations increasingly look to replace their systems with more stable.:967. a clinical trial management system provides data to a business intelligence system. Food and Drug Administration (FDA) regulations. Some popular requirements include: budgeting. also known as CTMS. AMIA Annu Symp Proc. Hackett M. patient management.:921. several requirements are pervasive.

ClinLife is operated by Clariness.000 active members. 29. clinlife. CenterWatch Inc. 2001. and shortly thereafter. how they work. For the first time.org/professional/facts pat. Switzerland.html>.com/files/u9/Delays_in_Clinical_Trial_Completion.com. php/ solutions/ electronic-medical-records/ the-ehr-solution-to-clinical-trial-recruitment-in-physician-groups.com/2009/mar/14/science/sci-clinical-trials14>.volterys.[4] In December 2005 ClinLife was used for the first time in the Berlin district of Charlottenburg for a trial on diabetes. 27. France. Medical Clinical Research Slow for Lack of Patients.php>.2010 <http://www. explains what they are. their ethical considerations and why they are important. Times. It is the largest European portal of its kind and currently serves both Europe and North America. ClinLife. History The vast majority of clinical trials are delayed from the outset due to a lack of volunteers..com. <http://articles. ClinLife was also available in Austria and Switzerland. an independent company based in Zurich.2010 <http://www. the Czech Republic. More than 600 trials on over 60 illnesses have been published by ClinLife. and more than 30. Clariness: The Trial Network Company. 2009. clinlife. This results in sharp increases in the amount of time the public has to wait for new. effective treatments.com/index. healthmgttech. ClinLife was operational in a language other than German. .org/stats-de/>. Within a few months. References [1] Clariness. Healthmgttech.07. Poland and Portugal. See Volterys.07..ciscrp. An Industry in Evolution.de. Specific information about current trials is also given and a search option helps both healthy volunteers and patients with illnesses to find clinical studies on specific conditions in specific regions. 204.spinemark. ClinLife expanded its services to include all of Germany in 2006.[1] ClinLife’s website states that its mission is to assist clinical research centers in their patient recruitment efforts and to provide the public with easier. The portal provides general information about illnesses and about clinical trials.clariness. ClinLife. Italy.2010 < http:/ / www. A newsletter service also provides members with information via email about specific trials on specific illnesses. Many patients who received information at ClinLife went on to participate in the study. Clariness works and maintains contracts with research companies and institutes. com/ why_did_we_establish_clinlife>. By the end of 2008. SpineMark.com.000 patients have been put in contact with clinical trial centers. 27. 29.07..com. The second largest portal is Volterys with 40. Third Edition. L. the UK and the US.. Health Management Technology. Sahri. SpineMark: CRO Management Inc. also known as clinical sites. ClinLife is operated by Clariness.com.2010 < http:/ / www. com/ why_did_we_establish_clinlife>. 29. 27.2010 <http://www. more transparent access to clinical studies. The Center for Information & Study on Clinical Research Participation. this time to Belgium. Current status ClinLife is available in 11 languages in 16 countries and has 120. CISCRP.07. [4] Clinlife. com/ index.2010 <https://www. ClinLife had more than 1 million visitors. and with subsidiaries in Germany. San Diego: 2008.ClinLife 17 ClinLife ClinLife is an international patient portal for clinical trials.07. Volterys.A. the Netherlands. In 2007 ClinLife began publishing trials and assisting volunteers in the UK.com. in Hungary and Turkey.07.07.latimes. An online screener tests volunteers to see if they fulfill the trial criteria and they are then given the option to be automatically directed to a clinical trial center. [3] CenterWatch Staff. The site publishes trials. [2] ClinLife.[3] One aspect of this problem was that as of 2005 there wasn’t a single..pdf>. Roan. In 2009. comprehensive database that listed clinical studies in Germany. August 2009. pg.. In 2008 ClinLife expanded once again. March 14.[2] ClinLife maintains that all its services are free to the public and will always remain free. html>. 27. ClinLife travelled across the Atlantic and set up its platform in both Canada and the US.2010 < http:/ / www.000 members.

The Paper CTD is destined to be replaced by its electronic counterpart. Administrative and prescribing information Overview and summary of modules 3 to 5 Quality (pharmaceutical documentation) Safety (toxicology studies) Efficacy (clinical studies) Detailed subheadings for each Module are specified for all jurisdictions. fda. After the United States.com (http://www. gov/ cber/ gdlns/ m4ctd.clinlife. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) August 2001 [2] http:/ / www. It was developed by the European Medicines Agency (EMA. European Union and Japan. the eCTD. Europe). U.) and the Ministry of Health.S. pdf "Guidance for Industry. ICH M4: Organization of the CTD" U.S. ich. html . the CTD has been adopted by several other countries including Canada and Switzerland. Labour and Welfare (Japan).com/) Common Technical Document The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines and designed to be used across Europe. The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). based on national requirements. 5. The contents of Module 1 and certain subheadings of other Modules will differ. 2. 4.[1] The Common Technical Document is divided into five modules: 1. the Food and Drug Administration (FDA. org/ products/ ctd.ClinLife 18 External links • clinlife. External links • ICH [1] • Common Technical Document [2] References [1] http:/ / www. 3. Japan and the United States.

Handbook of SOPs for Good Clinical Practice. over 98. ISBN 0-8493-2181-6 External links • DCF entry in Clinical Research Dictionary [1] References [1] http:/ / www. As of January 1. htm Electronic Common Technical Document The electronic Common Technical Document (eCTD) is an interface for the pharmaceutical industry to agency transfer of regulatory information. Food and Drug Administration announced that the eCTD is the preferred format for electronic submissions. the data validation step and asking the investigator for clarification of discrepancies (data cleaning) is an important step towards creating a clean dataset suitable for statistical analysis of the clinical trial outcome. The DCF is part of the data validation process in a clinical trial. CRC.[3] .[2] Although the agency has not released an expected target date. In clinical trials. umich.Data clarification form 19 Data clarification form A Data Clarification Form (DCF) or Data Query Form (DQF) is a questionnaire specifically used in clinical research. 2008. It was developed by the International Conference on Harmonisation (ICH) Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). med.[1] To date. The DCF is the primary data clarification tool from the trial sponsor or Contract Research Organization (CRO) towards the investigator to clarify discrepancies and ask the investigator for clarification. the FDA revealed during the 2009 DIA Annual Meeting that it is looking at draft legislation to require eCTD. edu/ cacr/ dictionary/ D-F.000 eCTD sequences have been submitted to the FDA. The content is based on the Common Technical Document (CTD) format. the U. References • Celine Clive (2004).S.

There are two categories of modules: • Regional module: 1 (different for each region. Each submission message constitutes one "sequence". IT point of view eCTD (data structure) The eCTD is a message specification for the transfer of files and metadata from a submitter to a receiver.e.xml ctd-123456/0000/index-md5.Electronic Common Technical Document 20 Pharmaceutical point of view The eCTD has five modules • 1 Administrative Information and Prescribing Information • 2 Common Technical Document Summaries • 3 Quality • 4 Nonclinical Study Reports • 5 Clinical Study Reports A full table of contents [4] could be quite large. A cumulative eCTD consists of one or more sequences. Europe and Japan).txt ctd-123456/0000/m1 ctd-123456/0000/m2 ctd-123456/0000/m3 ctd-123456/0000/m4 ctd-123456/0000/m5 ctd-123456/0000/util The string ctd-123456/0000 is just an example. The primary technical components are: • A high level folder structure (required) • An XML "backbone" file which provides metadata about content files and lifecycle instructions for the receiving system • An optional lower level folder structure (recommended folder names are provided in Appendix 4 of the eCTD specification) • Associated Document Type Definitions (DTDs) and stylesheets. The contents of the Regional Module 1 are defined by each of the ICH regions (USA. country) • Common modules: 2-5 (common to all the regions) The CTD only defines the content of the common modules.. i. . While a single sequence may be viewed with web browser and the ICH stylesheet provided. viewing a cumulative eCTD requires specialized eCTD viewers. The top part of the directory structure is as follows: ctd-123456/0000/index.

[4] http:/ / www. It must be place in the above directory.ich. pdf External links • ICH eCTD Specification V 3. aspx?fileticket=VtDTs2A/ qZs=& tabid=37). They must be placed in the directory: ctd-123456/0000/util/style See entry 377 in Appendix 4.2 (http://estri.2. FDA Signals Intent to Reject eCTDs with Technical Issues" (http:/ / www. "DIA Update: News from the FDA" (http:/ / theectdsummit.europa. globalsubmit. com/ home/ LinkClick.htm) (FDA) • EUDRALEX Volume 2 .eu) . 21 Business process (protocol) The business process to be supported can be described as follows: Industry <-----> Message <-----> Agency The lifecycle management is composed at least of: • Initial submission: should be self-contained. com/ summit/ ?p=630). [3] Kathie Clark (June 30. [2] Kathie Clark (December 15. . Stylesheets Stylesheets should be included that support the presentation and navigation.eu/enterprise/ pharmaceuticals/eudralex/homev2. 2009).Electronic Common Technical Document Backbone (header) This is the file index.org) • Electronic Common Technical Document (eCTD) (http://www.ich. They must follow a naming convention.org/eCTD/eCTD_Specification_v3_2_2. gov/ downloads/ Drugs/ DevelopmentApprovalProcess/ FormsSubmissionRequirements/ ElectronicSubmissions/ UCM163175. • Incremental updates: with its sequence number. "Updates from the Regulators: FDA" (http:/ / theectdsummit.gov/Drugs/DevelopmentApprovalProcess/ FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.fda. fda. . The eCTD summit. com/ summit/ ?p=468). For example: ctd-123456/0000/index.xml The purpose of this file is twofold: • Manage meta-data for the entire submission • Constitute a comprehensive table of contents and provide corresponding navigation aid. . The eCTD summit.Pharmaceutical Legislation : Notice to Applicants (http://ec. DTDs DTDs must be placed in the directory: ctd-123456/0000/util/dtd See entry 371 to 376 in Appendix 4.it-validation. References [1] "U. February 2.htm) (EU legislation.pdf) (The specification) • ICH M2 ESTRI Main (http://estri. 2009. contains section on eCTD) • IT Pharma Validation Europe (Organization: CSV Validation Network) (http://www. The DTD of the backbone is in Appendix 8.xml in the submission sequence number folder. 2009).S.

exalon. and can be set up to only allow entry within specified time-windows.com (http://www. through tablet PCs. allowing tailored feedback to be . in-range entries to be made. and even in some cases of "forward filling".com/) • Regional file format requirements for eCTD (http://blog. with a set of possible response options. from home. then moves on to the next questions. with the patient phoning in e.html) • The eCTD summit blog (http://theectdsummit. and ensures that true compliance can be documented. it is not known when the ratings are actually made.html) 22 Electronic patient-reported outcome An electronic patient-reported outcome (ePRO) is a patient-reported outcome that is collected by electronic methods (ePRO).g. This improves compliance. The user taps on the appropriate response with finger or stylus. Research has shown substantial bias in such summary recall.[1] Diaries can overcome this problem by recording severity either on a momentary basis ("How bad is your pain right now?") or by recall over short periods ("How bad has your pain been today?"). Electronic diaries Diaries are used when it is desirable to obtain frequent assessments over a period of time.com/summit/) • eCTDBlog. with ratings unduly influenced by how the patient is feeling at the time of making the rating. and by maximum severity rather than average severity during the assessment interval. ePRO methods are most commonly used in clinical trials. often over 90%.ectdblog. ranging from small hand-helds such as the Palm Pilot.[4] [5] Electronic diaries also have benefits in that they only allow valid.[2] Electronic diaries automatically time-stamp all entries. The smaller devices are often used as electronic diaries. Documenting compliance is important if ePRO data are to be used to support regulatory applications. Computers generally run dedicated ePRO applications the use of the web for ePRO is not yet widespread. There are also a number of custom devices designed specifically for use as ePRO data collection devices. for example when a condition fluctuates in severity. Each response option is given a number.fxtrans. In one study. The study showed frequent cases of "back-filling". Telephones normally use an interactive voice response system (IVR). IVR systems are more often used for diaries. and the user presses the corresponding number key on the phone keypad to record the choice. but they can be used in a clinic setting.free and strictly neutral eCTD related news from regulators (http://www. Typically a single question at a time is presented on the screen. and the possible responses. Methods The two main methods currently used for ePRO are computers and telephone systems Computers are most often touch-screen devices. but they are also used elsewhere in health care. filling in a batch of entries some time.[3] ePRO applications typically achieve compliance rates of over 80%. designed to be used for symptom reporting on a daily basis. Larger devices are generally used in a clinic setting. and hears a spoken script which details the question. patients were given an instrumented paper diary that recorded covertly when it was opened.com/ ectd-news. often days. after they were due. Devices such as PDAs allow reminders to be given to patients when entries are due. The user calls into a dedicated phone line.Electronic Common Technical Document • Exalon eCTD News . Systems generally transfer data promptly to a central server. However when diary data is collected on paper.com/2009/11/ regional-file-format-requirements-for. completing entries before they were due. In such cases recall of severity over a period of time is unlikely to be accurate. and there is evidence that compliance may be quite poor.

Such branching logic can be handled automatically by the ePRO application. Electronic diaries also eliminate the need for manual editing and entry of data. They concluded that there was good agreement between paper and ePRO. The majority of patients preferred the computer to paper data collection. This general finding. in some detail. and no evidence of systematic bias. and depends on the establishing equivalence between modes of administration. At the lowest level. assessing quality of life and activities of daily living. such as paper. As with electronic diaries. The International Society for Pharmacoeconomomics and Outcomes Research (ISPOR) has issued guidelines on [13] Their approach is hierarchical. of course. Patient acceptability From the early days of ePRO there has been concern about whether all patients can cope with computer technology. does not guarantee that any specific migration will lead to equivalence.Electronic patient-reported outcome given to patients. Missing data within a questionnaire can be reduced or [6] eliminated. and this is important as missing data has been identified as a crucial quality issue in questionnaire data. and again often prefer it to paper. might be expected to have more problems. There is a great deal of evidence supporting the general equivalence of paper and ePRO methods. They more often include branching logic ("if YES continue with the next question.[10] [11] [12] Thus there seems to be no great barrier to recruiting representative patient samples in ePRPO studies. where most change has occurred. Validity and equivalence Establishing the validity of an ePRO instrument is in principle no different from that for other methods. and elimination of manual editing and data entry are important features of site-based ePRO. and each case must be reviewed and documented. Gwaltney and colleagues[14] have reported a meta-analysis in which they included 46 studies evaluating 278 scales. This can also improve compliance. where least change has been made. At the second level. At the third level.as if significant numbers of patients refuse to take part in clinical trials because of dislike of compluters then there will be bias in the study population. with questionnaires completed when patients come in for their scheduled visits.[8] [9] Elderly patients. goto question 34"). degree of change made during the process of migration from paper to electronic format. One of the earliest ePRO studies used a LINC-2 minicomputer to collect patient data. and complete psychometric validation carried out. This makes it easier for the patient to use. and those not familiar with computers. equivalence studies comparing the scores obtained from the two modes should be carried out. In this supervised situation.[7] Similar findings have been reported from many later studies. and we need to ask (1) whether the paper data can be used to establish validity of the electronic version. Three levels are suggested. the ePRO instrument must be treated as a new instrument. time-consuming and error-prone processes. . 23 Site-based The other main setting for ePRO is the clinic. and (2) whether data from paper and electronic versions can be used interchangeably. for example. This level includes both trivial changes (touch rather than circle a response choice) as well as changes that are supported by empirical findings in the literature. However most of the instruments in current use have been validated in paper form. cognitive interviewing of patients as a check that they construe ePRO and paper in the same way is sufficient. and it is often not necessary for the patient even to know that branching is taking place. The questionnaires used in site-based ePRO are often longer and more complex than those used in diaries. the prevention of out of range or inconsistent entries. if NO. This is important. But these groups also show high acceptance of ePRO. compliance is less of an issue.

[11] Allenby A. using handheld diaries.. [7] Slack WV. PMID 9549801. "Understanding recall of weekly pain from a momentary assessment perspective: absolute agreement. Goodman K. Reed CE. PMID 19412327. cfm?id=10549#nlm34076-0 [17] Kearney. [16] http:/ / dailymed. new instruments will be developed in parallel for paper and elctronic use. Dominitz J (2000). Sage. [6] Bernhard J. L. Nixdorf M.. L. Osoba D. PMID 14715390. Battersby C. Sohl SJ (2008). Cross-Over Evaluation of Mobile Phone vs Paper Diary in Subjects with Mild to Moderate Persistent Asthma". Beresford J.. Kleinman L. [15] Fries. McLachlan SA (2002). B. Monser R. Hovell MF (2008). M. and Bruce. "User preferences for computer administration of quality of life instruments". PMID 18647853.and within-person consistency. PMID 12492461.. [2] Stone AA. "Patient non-compliance with paper diaries". Simes J. D. nih.. Hicks GP. Specker C. "Randomized. Shiffman SS. McCann. Rose. Martin GJ (1996). Lundy JJ. gov/ downloads/ Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ UCM193282. Koch T. Basch E (2009). Drug Information Journal 34: 137–144. "Self-assessments of patients via Tablet PC in routine patient care: comparison with standardised paper questionnaires". Cella. [3] http:/ / www.[16] As well as clinical trial use. In some case an instrument may be developed and validated from the beginning in electronic form. PMID 18953579. PMID 8724947. The Journal of Rheumatology 36 (9): 2061–2066. [12] Tiplady B. milnacipran (for fibromyalgia).Electronic patient-reported outcome It is not always necessary to validate an ePRO measure against a pre-existing paper version. International Journal of Behavioral Medicine 15 (1): 29–33. European Journal of Cancer Care 11 (4): 245–253. PMID 19738214. Broderick JE. Stille FC. Stewart MJ. including ketorolac (for ocular pain). Lyle D. "Patient Reported Outcomes in Rheumatoid Arthritis: Assessing the equivalence of electronic and paper data collection". Supportive Care in Cancer 17 (4): 437–444. Fallowfield L. More commonly. The last example is particularly interesting in that detailed ePRO data on bleeding/spotting from a one-year clinical trial are presented in the patient information leaflet. advanced symptom management system (ASyMS-¬) in the management of chemotherapy-related toxicity". PMID 19900250. E. (1-4-2009). Miller. British Medical Journal 324 (7347): 1193–1194. . PMID 18444018. Pain 107 (1-2): 61–69. Cella DF. "Progress in Assessing Physical Function in Arthritis: PROMIS Short Forms and Computerized Adaptive Testing". between. Percept. New England Journal of Medicine 274 (4): 194–198. Value in Health 11 (2): 322–333. Mosconi P.[15] 24 In practice Several successful regulatory approvals have used ePRO data in recent years. and Maguire. and judged change in weekly pain". Shiffman S (2008). P. Norrie. Cella D. Schacher B. Schwartz JE (2004). Van Cura LJ (27-1-1966). [14] Gwaltney CJ. "Evaluation of a mobile phone-based. Cummings G. Coates AS. ePRO methods may be used to support patients in regular care.Respir. nlm. Krishnan. Gray. gov/ dailymed/ drugInfo. (2009). The Patient 3 (3): 133–143. Gee-Lennon. eszoplicone (for insomnia). and estradiol/levonorgestrel (for post-menopausal symptoms. An example of this is the collection of symptom data from patients undegoing chemotherapy. Open. [10] Yarnold PR. Ganz PA. N. This allows clinic staff to monitor outpatients. perhaps. pdf [4] Meltzer EO.. Broderick JE. [9] Richter JG.Med J 2: 72–79. J. "A computer-based medical-history system". Statistics in Medicine 17 (5-7): 517–532. M. "Missing quality of life data in cancer clinical trials: serious problems and challenges". Carrington R.. "Assessing functional status of elderly adults via microcomputer". Value in Health 12 (4): 419–429. Revicki DA... Hays RD. Kelley N. [13] Coons SJ. "Recommendations on Evidence Needed to Support Measurement Equivalence between Electronic and Paper-based Patient-Reported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report". Hufford MR (18-5-2002). PMID 18380645. Moinpour CM. Becker A. Alten R. J. Sloan JA. PMID 12016186. PMID 5902618. "Memory for Fatigue in Chronic Fatigue Syndrome: The Relation Between Weekly Recall and Momentary Ratings".. [8] Crawley JA. Shields AL.Mot. "The application of computer touch-screen technology in screening for psychosocial distress in an ambulatory oncology setting". Matthews J. R..[17] References [1] Stone AA.. [5] Friedberg F. Lenderking WR. M. Hurny C (15-3-1998). Schneider M (2008).Skills 82 (2): 689–690. Annals of the Rheumatic Diseases 67 (12): 1739–1741. M. Taylor. Schwartz JE. and to identify the occurrence of adverse reactions that may require intervention. "Equivalence of Electronic and Paper-and-Pencil Administration of Patient-Reported Outcome Measures: A Meta-Analytic Review". Ralston S (2010). fda. as is the case with the PROMIS (Patient-Reported Outcomes Measurement Information System) initiative. Shiffman S. Gwaltney CJ. Willers R.

europa. the EudraCT Number. The first step to apply for the EudraCT Number is to apply for a Security Code. Each clinical trial with at least one site in the European Union receives a unique number for identification.ispor.org/) • Patient-Reported Outcomes Measurement Information System (http://www. europa.org/default. europa. pdf [2] http:/ / eudract.nihpromis. References • Press Release EMEA EudraCT database [1] (PDF) External links • • • • EudraCT [2] EudraCT Supporting Documentation [3] EudraCT FAQ [4] International Standard Randomised Controlled Trial Number Register [5] (ISRCTN) References [1] http:/ / www. pdf [5] http:/ / www. The EudraCT Number must be included on all Clinical Trial applications within the European Community and as needed on other documents relating to the trials (e. html [4] http:/ / eudract. • NNNNNN is a six digit sequential number. controlled-trials.aspx) EudraCT EudraCT (European Union Drug Regulating Authorities Clinical Trials) is the European Clinical Trials Database of all clinical trials commencing in the European Union from 1 May 2004 onwards. html [3] http:/ / eudract. eu/ pdfs/ general/ direct/ pr/ 1258904en. SUSAR reports). europa. ema. In the second step the requestor can apply for theEudraCT Number itself. The EudraCT database has been established in accordance with Directive 2001/20/EC. ema. eu/ docs/ userGuides/ EudraCT_Public_FAQ. com/ isrctn/ . where: • YYYY is the year in which the number is issued. eu/ document.g. ema. The unique EudraCT number for each clinical trial has the format YYYY-NNNNNN-CC. ema. • CC is a check digit. eu/ index.Electronic patient-reported outcome 25 External links • International Society for Pharmacoeconomomics and Outcomes Research (http://www.

based on Series 40 Questionnaires may be generic (designed to be used in any disease population and cover a broad aspect of the construct measured) or condition-specific (developed speficially to measure those aspects of outcome that are of importance for a people with a particular medical condition). CRF Designer. PRO data may be collected via self-administered questionnaires completed by the patient or via interviewer-administered questionnaires. PC or mobile / cell phone.Mpro 26 Mpro PRO (Patient Reported Outcomes) is an umbrella term that covers a whole range of potential types of measurement but is used specifically to refer to questionnaires completed by the patient. The latter will only qualify as a PRO where the interviewer is gaining the patient’s views. com . ISBN 0-9531174-7-2 External links • mPRO from t+ Medical [1] • mobilePRO from Exco InTouch [2] References [1] http:/ / www. Thus. ePRO data is collected electronically via a range of devices including handheld PDA. mPRO is a product from OBS Medical and is a registered trademark of OBS Medical. References • Debbie Kennedy. The most commonly used PRO questionnaires assess one of the following constructs: • • • • Symptoms (impairments) Functioning (disability) Health related quality of life (HRQL) Quality of life (QoL). The term ePRO is used for electronic Patient Reported Outcomes. tplusclinical. not where the interviewer uses patient responses to make a professional assessment or judgment of the impact of the patient’s condition. Nokia 6300 . Canary Publications. PROs are a means of gathering patient rather than clinical or other views on the content covered by the questionnaire. com [2] http:/ / www. excointouch. The term mPRO refers specifically to the collection of PRO data on a mobile / cell phone.

Kasteleijn-Nolst Trenite DG. Frequent recording of symptoms using a diary helps to reduce recall bias. which is an important problem during clinical trials and the treatment of degenerative diseases with relatively few symptoms. Br J Clin Pharmacol. between.. Cohen AF. Ouwersloot-van der Meij MJ. quality of life) or to measure treatment compliance. 1995. Patient-reported outcome A patient-reported outcome or PRO is a questionnaire used in a clinical trial or a clinical setting. Pain. ibuprofen or placebo. PRO data may be collected via self-administered questionnaires completed by the patient themselves or via interviews. A patient diary as a tool to improve medicine compliance. 1996 Oct. home-monitored with an electronic patient diary. in a batch immediately before the clinic visit. and not.42(4):475-81. British Medical Journal. Overview PRO is an umbrella term that covers a whole range of potential types of measurement but is used specifically to refer to self-reports by the patient. 1999 Feb. Broderick JE. Hoedemaker HG. 310: 1469 • van Berge Henegouwen MT. Patient diaries are also way to find out if a patient takes the medication according to the treatment schedule.Patient diary 27 Patient diary A Patient Diary is a tool used during a clinical trial or a disease treatment to assess the patient's condition (e. where the responses are collected directly from the patient. Schwartz JE. Schoemaker RC. Shiffman SS.21(1):21-4..g. Pharm World Sci. Reints A. The latter will only qualify as a PRO where the interviewer is gaining the patient’s views.107 (1-2): 61-69 • Tiplady B. for example. not where the interviewer uses patient responses to make a professional assessment or judgment of the impact of the patient’s condition. Understanding recall of weekly pain from a momentary assessment perspective: absolute agreement. Electronic diaries ensure entries are made as scheduled. van Driel HF. PROs are a means of gathering patient rather than clinical or other views on outcomes. An Electronic Patient Diary registers the data in a storage device and allows for automatically monitoring the time the entry was made. 2004. References • Stone AA. Thus. Electronic diaries for asthma. Jacobs LD. and judged change in weekly pain. • van Gerven JM. symptom severity. .and within-person consistency. Self-medication of a single headache episode with ketoprofen. Brackenridge D. Crompton GK.

Questionnaires may be generic (designed to be used in any disease population and cover a broad aspect of the construct measured) or condition-targeted (developed specifically to measure those aspects of outcome that are of importance for a people with a particular medical condition). They should also be reliable and valid (including responsive to underlying change) and the structure of the scale (whether it possesses a single or multiple domains) should have been thoroughly tested using appropriate methodology in order to justify the use of scale or summary scores. SF-12 Health Survey (SF-12 Health Survey). These measurement “characteristics” are termed constructs and the questionnaires used to collect them. QoL goes beyond impairment and disability by asking about the patient’s ability to fulfill their needs and also about their emotional response to their restrictions. scales or tools. the Sickness Impact Profile. This must be demonstrated empirically (for example. measures should have a sound theoretical basis and should be relevant to the patient group with which they are to be used. each scale is scored and reported separately. psychometric and scaling standards if it is to provide useful information. the Health Utilities Index. it cannot be assumed that a questionnaire is unidimensional simply because the author intended it to be. However. In contrast. should be a number of scales that each address a single characteristic. A multi-dimensional questionnaire is used to provide a profile of scores. The most commonly used PRO questionnaires assess one of the following constructs: • • • • • • • Symptoms (impairments) and other aspects of well-being Functioning (disability) Health status General health perceptions Quality of life (QoL) Health related qualiy of life (HRQoL) Reports and Ratings of health care. A questionnaire that measures multiple constructs is termed multi-dimensional. A questionnaire that measures a single construct is described as unidimensional. . that is.Patient-reported outcome 28 Characteristics A well-designed PRO questionnaire should assess either a single underlying characteristic or. Health-related quality of life instruments are generally multi-dimensional questionnaires assessing a combination of aspects of impairments and/or disability and reflect a patient’s health status. Items (questions) in a unidimensional questionnaire can be added to provide a single scale score. Measures of functioning assess activities such as personal care. by confirmatory factor analysis or Rasch analysis). and the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey instruments are PRO instruments. where it addresses multiple characteristics. Specifically. termed instruments. Validation and quality assessment It is essential that a PRO instrument satisfy certain development. the Quality of Well-Being Scale. activities of daily living and locomotor activities. For example. the EuroQol (EQ-5D). the SF-36 Health Survey (SF-36 Health Survey). It is possible to create an overall (single summary) score from a multi-dimensional measure using factor analysis or preference-based methods but some may see this as akin to adding apples and oranges together. Examples Many of the common generic PRO tools assess health-related quality of life or patient evaluations of health care. the Nottingham Health Profile. measures. Measures of symptoms may focus on a range of impairments or on a specific impairment such as depression or pain.

29 Terminology The term PRO should not be confused with patient-based outcomes. 195-205). Killewo. McKenna SP. Quality of Life Research 2008. This information may. Value in Health 2004. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels. • Doward LC. Elsevier. CRF Designer. Alonso J. The term PROs is synonymous with the increasing use of the term patient reported outcome measures (PREMs). H. the Kidney Disease Quality of Life Instrument. patient-reported implies only that the patient provides the information. Assessment of patient-reported outcomes in clinical trials: the example of health-related quality of life. Quah (eds. Burke LB. depending on the purpose for which they were designed. Development of a new patient-based measure of pediatric ambulatory care. • Fayers P. Epidemiology and Demography in Public Health (pp. Integrating Patient-Reported Outcomes. to name a few. Br J Rheumatol 1995. • Gallagher P.. 2004 Dec. • Hays RD. Fundam Clin Pharmacol.).Patient-reported outcome Condition-targeted tools may capture any of the constructs listed above. • Wiklund I. Examples include the Adult Asthma Quality of Life Questionnaire (AQLQ). The latter implies that questionnaire covers issues of specific concern to the patient. 2004 Jun. or may not. 2010. (eds. Schor EL. 11: 165-83.34:899-900. ISBN 0-9531174-7-2 • McKenna SP. Epilepsy Surgery Inventory. 7(S1): S9-S12. • Valderas JM. 1990. Ding L. 357 (9249):7-8. National Eye Institute Visual Functioning Questionnaire. Measurement of Health Status in the 1990’s. Defining Patient-Reported Outcomes. Measurement and modeling of health-related quality of life. the Ankylosing Spondylititis Quality of Life questionnaire (ASQoL) and the Seattle Angina Questionnaire (SAQ). Erickson P. McKenna SP. Lancet 2001. 17: 1125-35. Conceptualising and defining outcome. • Patrick DL. Control Clin Trials. External links • • • • • • EuroQol Group (EQ-5D) [1] Patient Reported Outcomes Measurement Information System [2] Medical Outcomes Trust [3] Health Surveys [4] SF-36. Prospects and challenges in using patient-reported outcomes in clinical practice. • Willke RJ. 17: 1297-302. Hays RD. R. 124: 1348-1354. • Fung CH. Migraine Specific Quality of Life (MSQOL).18(3):351-63. Patient reported outcome measures: a model-based classification system for research and clinical practice. Qual Life Res. K. Hays RD. Cleary PD. • Kennedy D. However. Hays RD. Heggenhougen & S. In J. 2005. Oxford: Oxford University Press. 7(S1): S4-S8. Ham HP. Reeve BB. Pediatrics 2009. • Tennant A. Canary Publications. Value in Health 2004. Importance of differentiating health status from quality of life. Annu Rev Public Health.. References • Bradley C. Doward LC.) Assessing Quality of Life in Clinical Trials: Methods and Practice. be of concern to the patient. Bergner M.org [5] MAPI Institute (Linguistic validations of Patient-Reported Outcomes (PRO) instruments) [6] • MAPI Research Trust (non-profit organization involved in Patient-Reported Outcomes (PRO) instruments and Epidemiology [7] • ProQolid (Patient-Reported Outcome & Quality of Life Instruments Database) [8] • PROLabels(Database on Patient-Reported Outcome claims in marketing authorizations) [9] .25(6):535-52. 2008.

proqolid. euroqol. org/ [8] http:/ / www. mapivalues. org/ [10] http:/ / www. outcomes-trust. nihpromis. mapi-prolabels. org/ health/ surveys_tools. A source document is a document in which data collected for a clinical trial is first recorded. org/ [2] http:/ / www. mapi-institute. com/ Source document For use of this term in accounting. com/ [7] http:/ / www. mapi-trust. see Category:Accounting source documents. org/ [4] http:/ / www. org/ [3] http:/ / www. Examples of source documents include: • • • • • Medical records Lab reports Subject diaries X-rays ECG printouts . org/ [9] http:/ / www. These data are usually later entered in the case report form. rand.Patient-reported outcome • Mapi Values global PRO consultancy [10] 30 References [1] http:/ / www. html/ RAND [5] http:/ / www. org/ [6] http:/ / www. sf-36.

In early phases. devices.. In the U. followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment.S.[2] In coordination with a panel of expert investigators (usually physicians well known for their publications and clinical experience). the number of patients is typically increased. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries. If the sponsor cannot obtain enough patients with this specific disease or condition at one location. then investigators at other locations who can obtain the same kind of patients to receive the treatment would be recruited into the study.. drugs. and what kind of patients might benefit from the medication or device. the sponsor or investigator first identifies the medication or device to be tested. the elderly comprise only 14% of the population but they consume over one-third of drugs. investigators enroll healthy volunteers and/or patients into small pilot studies initially. and people with unrelated medical conditions are also frequently excluded. participants are healthy volunteers who receive financial incentives for their inconvenience. Due to the sizable cost a full series of clinical trials may incur. In planning a clinical trial..g. and whether the patient's health improves or not. Usually. These patients are volunteers and they are not paid for participating in clinical trials. they are often excluded from trials because their more frequent health issues and drug use produce unreliable data. information about adverse drug reactions and adverse effects of other treatments) and efficacy data to be collected for health interventions (e.[1] Despite this. As positive safety and efficacy data are gathered. In medical jargon. although this is not always required. the burden of paying for all the necessary people and services is usually borne by the sponsor who may be a governmental organization. These trials can take place only after satisfactory information has been gathered on the quality of the non-clinical safety. often a clinical trial is managed by an outsourced partner such as a contract research organization or a clinical trials unit in the academic sector.g. administer the treatment(s). 10 mg dose instead of 5 mg dose) .Clinical trial 31 Clinical trial Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety (or more specifically. effectiveness is how well a treatment works in practice and efficacy is how well it works in a clinical trial. patients who have been diagnosed with Alzheimer's disease) • Assess the safety and effectiveness of a different dose of a medication than is commonly used (e. one or more pilot experiments are conducted to gain insights for design of the clinical trial to follow. During the clinical trial. These data include measurements like vital signs. and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place. or biotechnology company. therapy protocols). diagnostics. concentration of the study drug in the blood. During dosing periods.g. Overview Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. and collect data on the patients' health for a defined time period. a pharmaceutical. Since the diversity of roles may exceed resources of the sponsor. children. occasionally longer. Women.. the investigators: recruit patients with the predetermined characteristics. The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests. Depending on the type of product and the stage of its development. the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo). study subjects typically remain on site at the unit for durations of anything from 1 to 30 nights. Some examples of what a clinical trial may be designed to do: • Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.

The time of action must be observed." He also founded "the Collective Investigation Record . The effect of the drug must be seen to occur constantly or in many cases.g. for testing a drug on a lion or a horse might not prove anything about its effect on man. and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days. The drug must be free from any extraneous accidental quality. a disease for which the drug is not specifically approved • Assess whether the new medication or device is more effective for the patient's condition than the already used. Persian physician and philosopher. 6. however. Avicenna. medical devices (like a new catheter). 32 History The history of clinical trials before 1750 is brief. Clinical trials may be required before the national regulatory [3] authority approves marketing of the drug or device.Clinical trial • Assess the safety and effectiveness of an already marketed medication or device for a new indication. One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvy. not a composite. there are some drugs whose heat is less than the coldness of certain diseases. Because the clinical trial is designed to test hypotheses and rigorously monitor and assess what happens. 5. The Book of Daniel verses 12 through 15. The experimentation must be done with the human body. biologics. ranging from vinegar to cider. Except for very small trials limited to a single location. Device B.[10] He compared the effects of various different acidic substances. The quality of the drug must correspond to the strength of the disease.e. Therapy B) Note that while most clinical trials compare two medications or devices. 2. so that they would have no effect on them. "the King's meat" over a trial period of ten days. where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. i. for use on patients. are ancient. some trials compare three or four medications. disease. gave such inquiries a more formal structure. because sometimes a drug cures one disease by its essential qualities and another by its accidental ones. The drug must be tested with two contrary types of diseases. clinical trials can be seen as the application of the scientific method. Frederick Akbar Mahomed (d. 4. describes a planned experiment with both baseline and follow-up observations of two groups who either partook of.) A protocol is always used in multicenter trials. Therapy A vs. the clinical trial design and objectives are written into a document called a clinical trial protocol. 1884). who worked at Guy's Hospital in London. psychological therapies. 7.[11] made substantial contributions to the process of clinical trials during his detailed clinical studies. it was an accidental effect. or a new dose of the drug.[6] In The Canon of Medicine in 1025 AD. (This uniformity is designed to allow the data to be pooled.. or did not partake of. for instance. The protocol is the 'operating manual' for the clinical trial and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics. on groups of afflicted sailors. or other interventions. for if this did not happen. The most commonly performed clinical trials evaluate new drugs.[4] [5] The concepts behind clinical trials. doses of medications. It must be used on a simple. or devices against each other. so that essence and accident are not confused. For example.[7] He laid out the following rules and principles for testing the effectiveness of new drugs and medications:[8] [9] 1. and specifically the experimental step. Device A vs. to understanding human or animal biology. 3. standard medication or device ("the gold standard" or "standard therapy") • Compare the effectiveness in patients with a specific disease of two or more already approved or common interventions for that disease (e. he laid down rules for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances.

all patients are given both . vaccines.Clinical trial for the British Medical Association. must be granted by both the FDA and the pharmaceutical company for such exceptions. new combinations of drugs.a. the investigators observe the subjects and measure their outcomes. Usually. or lifestyle changes. An example is the Nurses' Health Study. Currently. or a patient that has already attempted and failed all other standard treatments and whose health is [14] Usually. National Institutes of Health (NIH) organizes trials into five (5) different types:[13] • Prevention trials: look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. they compare the treated subjects to subjects who receive no treatment or standard treatment. The U. minerals. • Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition. since if a physician knew which patient was getting the study treatment and which patient was getting the placebo. The researchers do not actively manage the study. • In an interventional study. the researchers also do not know which treatment is being given to any given subject. • Compassionate use trials or expanded access: provide partially tested. a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. • Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Another way of classifying trials is by their purpose. This 'blinding' is to prevent biases. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. • Treatment trials: test experimental treatments. • Blind: The subjects involved in the study do not know which study treatment they receive."[12] 33 Types One way of classifying clinical trials is by the way the researchers behave. the investigators give the research subjects a particular medicine or other intervention. this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials. Usually. In this kind of study. • Quality of life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness (a. vitamins. case by case approval so poor that he does not qualify for participation in randomized clinical trials. In observational studies. • In an observational study. A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health.S. or new approaches to surgery or radiation therapy. Design A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. Then the researchers measure how the subjects' health changes. Supportive Care trials). unapproved therapeutics prior to a small number of patients that have no other realistic options. Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. and placebo-controlled. • Screening trials: test the best way to detect certain diseases or health conditions. These approaches may include medicines. the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. some Phase II and most Phase III drug trials are designed as randomized.k. he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. this involves a disease for which no effective therapy exists. If the study is double-blind. double blind. In addition.

The protocol contains a precise study plan for executing the clinical trial. . biotechnology or medical device companies in the United States. many clinical trials are small. The format and content of clinical trial protocols sponsored by pharmaceutical. even if conducted in various countries. during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). the alternate treatment would be a standard-of-care therapy. a well-established comparator sourcing agency can alleviate the problem of parallel importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence). Although the term "clinical trials" is most commonly associated with the large. a government health agency. Trials. encourage trialists to publish their protocols in the journal. A growing trend in the pharmacology field involves the use of third-party contractors to obtain the required comparator compounds. The protocol also gives the study administrators (often a contract research organization or CRO) as well as the site team of physicians. Such third parties provide expertise in the logistics of obtaining. e. and are designed to test simple questions. • Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment.[16] Regulatory authorities in Canada and Australia also follow ICH guidelines. not only to assure safety and health of the trial subjects. giving them the placebo). when a treatment exists that is clearly better than doing nothing for the subject (i. As an advantage to the manufacturer of the comparator compounds. and shipping the comparators. statistical considerations. 34 Active comparator studies Of note. and organization of the planned trial. methodology. but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. European Union. and the trial sponsor is a private company. storing. or Japan has been standardized to follow Good Clinical Practice [15] issued by the International Conference on Harmonization of Technical Requirements for Registration of guidance Pharmaceuticals for Human Use (ICH). This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together.e. The protocol describes the scientific rationale. Clinical trial protocol A clinical trial protocol is a document used to gain confirmation of the trial design by a panel of experts and adherence by all study investigators.Clinical trial placebo and active doses in alternating periods of time during the study. They may be "sponsored" by single physicians or a small group of physicians. design. nurses and clinic administrators a common reference document for site responsibilities during the trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time).g. or an academic research body such as a university. Some journals. objective(s). Details of the trial are also provided in other documents referenced in the protocol such as an Investigator's Brochure. The study would compare the 'test' treatment to standard-of-care therapy. randomized studies typical of Phase III. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. In other words.

To fully describe participation to a candidate subject. as the participant can withdraw at any time without penalty. Phases Clinical trials involving new drugs are commonly classified into four phases. .90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more. the doctors and nurses involved in the trial explain the details of the study using terms the person will understand. trials are also doubled-blinded so that the researchers do not know to which group a subject is assigned. Subjects in the treatment and placebo groups are assigned randomly and blinded as to which group they belong. but only have a power of . the greater the statistical power. in designing a clinical trial.Clinical trial 35 Design features Informed consent An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent". and these are controlled for by the inclusion of a placebo group. The Declaration of Helsinki provides guidelines on this issue. Each phase of the drug approval process is treated as a separate clinical trial. Statistical power The number of patients enrolled in a study has a large bearing on the ability of the study to reliably detect the size of the effect of the study intervention. potential benefits and key contacts. such as its purpose. Foreign language translation is provided if the participant's native language is not the same as the study protocol. The participant then decides whether or not to sign the document in agreement.[17] Informed consent is a legally-defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. Placebo groups Merely giving a treatment can have nonspecific effects. The power of a trial is not a single. The drug-development process will normally proceed through all four phases over many years. a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of . duration. and III. Phase IV are 'post-approval' studies. The research team provides an informed consent document that includes trial details. Informed consent is not an immutable contract. it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. risks. they conduct extensive pre-clinical studies. required procedures. The larger the sample size or number of participants in the trial. it will usually be approved by the national regulatory authority for use in the general population. If the drug successfully passes through Phases I. unique value. However.70 to detect a difference of 5 mg/dL. This is described as the "power" of the trial. this consideration must be balanced with the fact that more patients make for a more expensive trial. Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. II. By example. Since researchers can behave differently to subjects given treatments or placebos. Before pharmaceutical companies start clinical trials on a drug.

Clinical trial

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Pre-clinical studies
It involves in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.[18] Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[19] A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data. Questions have been raised by experts about whether Phase 0 trials are useful, ethically acceptable, feasible, speed up the drug development process or save money, and whether there is room for improvement.[20]

Phase I
Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging, also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing. Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. "The reason for conducting the trial is to discover the point at which a compound is too poisonous to administer."[21] Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay ranges from a small amount of money for a short period of residence, to a larger amount of up to approx $6000 depending on length of participation. There are different kinds of Phase I trial: SAD Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD)). MAD

Clinical trial Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.

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Phase II
Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB. • Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). • Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)). Some trials combine Phase I and Phase II, and test both efficacy and toxicity. Trial design Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.

Phase III
Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies."[22] [23] While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMA (European Union), for example. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[3] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug.

Clinical trial Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[24]

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Phase IV
Phase IV trial is also known as Postmarketing surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

Phase V
Phase V is a growing term used in the literature of translational research to refer to comparative effectiveness research and community-based research; it is used to signify the integration of a new clinical treatment into widespread public health practice. [25]

Length
Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, 6 years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about 8 years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines. Some reasons a clinical trial might last several years: • For chronic conditions like cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient. • For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe any effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years. • Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial. The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low.[26]

Clinical trial For clinical trials involving a seasonal indication (such as airborne allergies, Seasonal Affective Disorder, influenza, and others), the study can only be done during a limited part of the year (such as Spring for pollen allergies), when the drug can be tested. This can be an additional complication on the length of the study, yet proper planning and the use of trial sites in the southern as well as northern hemispheres allows for year-round trials can reduce the length of the studies.[27] [28] Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies like the Nurses' Health Study.)

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Administration
Clinical trials designed by a local investigator and (in the U.S.) federally funded clinical trials are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Phase III and Phase IV clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. (The sponsor provides the drug and medical oversight.) A CRO is a company that is contracted to perform all the administrative work on a clinical trial. It recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures that the sponsor receives 'clean' data from every site. Recently, site management organizations have also been hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local Institutional Review Board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.

Ethical conduct
Clinical trials are closely supervised by appropriate regulatory authorities. All studies that involve a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the U.S., this body is called the Institutional Review Board (IRB). Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is ensuring that potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California, the state has prioritized the individuals who can serve as the legally authorized representative.[29] In some U.S. locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. International Conference of Harmonisation Guidelines for Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected". The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary.

as for instance for questions of when to stop sequential treatments (see Odds algorithm)." If the participant's native language is not English. In larger clinical trials. device or other medical treatments to be tested. • The sponsor is responsible for monitoring the results of the study as they come in from the various sites. while at the same time presenting the material as briefly as possible and in ordinary language. as the trial proceeds. The DMC has the power to recommend termination of the study based on their review. • The sponsor is responsible for collecting adverse event reports from all site investigators in the study. The DMC meets periodically to review the unblinded data that the sponsor has received so far. the sponsor must translate the informed consent into the language of the participant. known in the U. FDA regulations and ICH guidelines both require that "the information that is given to the subject or the representative shall be in language understandable to the subject or the representative. it may be hard to turn this objective into a well-defined quantified objective function. In some cases this can be done. and (in some cases. 40 Safety Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor.Clinical trial Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. This is an area where sponsors can slant their judgment to favor the study treatment. Additional ethical concerns are present when conducting clinical trials on children (pediatrics). and/or women who become pregnant during the study. This allows the local investigators to make an informed judgment on whether to participate in the study or not. pregnant women. For safety reasons. and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. many clinical trials of drugs are designed to exclude women of childbearing age. if the study involves a marketable drug or device) the regulatory agency for the country where the drug or device will be sold. or seems to be causing unexpected and study-related serious adverse events. however. This is an independent group of clinicians and statisticians. as a Data Safety Monitoring Board). However.[30] . the various IRBs that supervise the study. for example if the study treatment is causing more deaths than the standard treatment. • The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study. the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug. a sponsor will use the services of a Data Monitoring Committee (DMC. and of any potential interactions of the study treatment(s) with already approved medical treatments. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. the local site investigators (if different from the sponsor). Sponsor • Throughout the clinical trial. and then quantified methods may play an important role.S. In some cases the male partners of these women are also excluded or required to take birth control measures.

before it allows the researcher to begin the study. and supporting documentation to the local IRB. or misrepresents data it has acquired from clinical trials. • In the U. • The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study. the consent(s). However. IRBs Approval by an IRB. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study. • When a local investigator is the sponsor. to see if they were correctly following study procedures.Clinical trial 41 Local site investigators • A physician's first duty is to his/her patients. This audit may be random. the FDA can audit the files of local site investigators after they have finished participating in a study. investigators often have a financial interest in recruiting subjects. Universities and most hospitals have in-house IRBs. On the other hand. • In commercial clinical trials. regarding the relationship of the adverse event to the study treatments). the data collection forms. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their . in other words. and where there is no independent sponsor. the study protocol and procedures have been tailored to fit generic IRB submission requirements. It may require changes in study procedures or in the explanations given to the patient. In this case. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred. and if a physician investigator believes that the study treatment may be harming subjects in the study. • The local investigators are responsible for conducting the study according to the study protocol. but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. central and south America. Other researchers (such as in walk-in clinics) use independent IRBs. the investigator can stop participating at any time. • The local investigator is responsible for being truthful to the local IRB in all communications relating to the study. "An estimated 40 percent of all clinical trials now take place in Asia. However. the regulatory agency may make the wrong decision. there may not be formal adverse event reports. and promptly informing the local IRB of all serious and study-treatment-related adverse events. Eastern Europe..S. and supervising the study staff throughout the duration of the study. Different countries have different regulatory requirements and enforcement abilities. or for cause (because the investigator is suspected of fraudulent data). that they (or their legally authorized representatives) give truly informed consent. and the sponsor. Avoiding an audit is an incentive for investigators to follow study procedures. The local investigators are responsible for making an independent judgment of these reports. Regulatory agencies • If a clinical trial concerns a new regulated drug or medical device (or an existing drug for a new purpose). the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. or to be marketed. each local site investigator submits the study protocol. or ethics board. if the sponsor withholds negative data. is necessary before all but the most informal medical research can begin. • The local investigator or his/her study staff are responsible for ensuring that potential subjects in the study understand the risks and potential benefits of participating in the study. the appropriate regulatory agency for each country where the sponsor wishes to sell the drug or device is supposed to review all study data before allowing the drug/device to proceed to the next phase. and can act unethically in order to obtain and maintain their participation. • The local investigators are responsible for reviewing all adverse event reports sent by the sponsor.

Clinical trials are traditionally expensive and difficult to undertake. among others: • manufacturing the drug(s)/device(s) tested • staff salaries for the designers and administrators of the trial • payments to the contract research organization. coordination between Europe. Clinical trials follow a standardized process. Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [32] Currently. including onsite monitoring by the CRO before and (in some cases) multiple times during the study • one or more investigator training meetings • costs incurred by the local researchers such as pharmacy fees. National Institutes of Health offer grants to investigators who design clinical trials that attempt to answer research questions that interest the agency. Jacob Sijtsma of the Netherlands-based WEMOS. depending on the amount of the grant and the amount of effort expected from them. Using internet resources can." [31] Beginning in the 1980s. [34] National health agencies such as the U. These other sites may or may not be paid for participating in the study. the number of patients required. These activities are pursued in the interest of the consumer and public health.S. safe and effective medicines are developed and registered in the most efficient and cost-effective manner. The costs to a pharmaceutical company of administering a Phase III or IV clinical trial may include. there is a 50% tax credit for sponsors of certain clinical trials. most clinical trial programs follow ICH guidelines."[33] 42 Economics Sponsor The cost of a study depends on many factors. At the same time.[35] . • any payments to patients enrolled in the trial (all payments are strictly overseen by the IRBs to ensure that patients do not feel coerced to take part in the trial by overly attractive payments) These costs are incurred over several years.Clinical trial operations". in some cases. and whether the study treatment is already approved for medical use. harmonization of clinical trial protocols was shown as feasible across countries of the European Union. and coordinates data collection from any other sites. the site management organization (if used) and any outside consultants • payments to local researchers (and their staffs) for their time and effort in recruiting patients and collecting data for the sponsor • study materials and shipping • communication with the local researchers. aimed at "ensuring that good quality. an advocacy health organisation tracking clinical trials in developing countries. the investigator who writes the grant and administers the study acts as the sponsor. to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness.S. In the U. IRB fees and postage. says Dr. In these cases. especially the number of sites that are conducting the study. reduce the economic burden.

additional online resources to help them locate clinical trials.[37] Volunteers may search directly on ClinicalTrials. many clinical trials will not accept participants who contact them directly to volunteer as it is believed this may bias the characteristics of the population being studied. Volunteers with specific conditions or diseases have Newspaper advertisements seeking patients and healthy volunteers to participate in clinical trials. flyers. posters in places the patients might go (such as doctor's offices). in order to ensure that their motivation for participating is the hope of getting better or contributing to medical knowledge. Locating trials Depending on the kind of participants required. These amounts can be small. trial type. and Canada.S. sponsors of clinical trials use various recruitment strategies.Clinical trial 43 Investigators Many clinical trials do not involve any money.S. participants are paid because they give up their time (sometimes away from their homes) and are exposed to unknown risks. However. Patients In Phase I drug trials. and search for specific Parkinson's clinical trials using criteria such as location. However. including patient databases. when the sponsor is a private company or a national health agency. investigators are almost always paid to participate. Such trials typically recruit via networks of medical professionals who ask their individual patients to consider enrollment. patients are not paid. without the expectation of any benefit. Most other clinical trials seek patients who have a specific disease or medical condition. just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies).gov to locate trials using a registry run by the U. National Institutes of Health and National Library of Medicine. and personal recruitment of patients by investigators. . people with Parkinson's disease can use PDtrials to find up-to-date information on Parkinson's disease trials currently enrolling participants in the U. they are often given small payments for study-related expenses like travel or as compensation for their time in providing follow-up information about their health after they are discharged from medical care. and symptom. However. or be substantial and include 'overhead' that allows the investigator to pay the research staff during times in between clinical trials. without their judgment being skewed by financial considerations. newspaper and radio advertisements. however. In most other trials. Participating in a clinical trial Phase 0 and Phase I drug trials seek healthy volunteers.[36] Other disease-specific services exist for volunteers to find trials related to their condition. For example.

accessing the raw data.S. Statistical software is used to analyze the collected data and prepare it for regulatory submission. particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. particularly with respect to investigational sites. Clinical trial management systems (CTMS) are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial. heart rate and temperature Blood sampling Urine sampling Weight and height measurement Drugs abuse testing Pregnancy testing (females only) Information technology The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Researchers may be restricted from contributing to the trial design. manage its quality and prepare it for analysis. Access to many of these applications are increasingly aggregated in web-based clinical trial portals.[42] . Controversy In 2001.[41] Seeding trials are particularly controversial. Interactive voice response systems (IVRS) are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). and interpreting the results. and others who have participated in trials in the past.Clinical trial 44 Steps for volunteers Before participating in a clinical trial. interested volunteers should speak with their doctors.[38] All volunteers being considered for a trial are required to undertake a medical screen. on the control over clinical trials exerted by sponsors. family members. They strengthened editorial restrictions to counter the effect. by 2000. After receiving consent from their doctors. volunteers then arrange an appointment for a screening visit with the trial coordinator. After locating a trial. The editorial noted that contract research organizations had. Patient-reported outcome measures are being increasingly collected using hand-held. volunteers will often have the opportunity to speak or e-mail the clinical trial coordinator for more information and to answer any questions. the editors of 12 major journals issued a joint editorial. Web-based electronic data capture (EDC) and clinical data management systems (CDMS) are used in a majority of clinical trials[40] to collect case report data from sites. published in each journal. received 60% of the grants from pharmaceutical companies in the U. There are different requirements for different trials. but typically volunteers will have the following tests:[39] • • • • • • • Measurement of the electrical activity of the heart (ECG) Measurement of blood pressure. sometimes wireless ePRO (or eDiary) devices.

asp). Retrieved 2007-03-27. "Clinical Trials . html). com/ ?id=i1oAxuE29MUC& pg=PA3& lpg=PA3& q). in the European Union. commondreams. Crossley. Hypertension (American Heart Association) 19: 212–217 [213] [12] O'Rourke. pdf) (Japanese) [33] ICH (http:/ / www. and the West. info/ Nautica/ Medicine/ Lind(1753). (1992). P. Clinical Pharmacology & Therapeutics 67 (5). com/ books?id=d8GxG0d9rpgC& pg=PA118& dq& hl=en#v=onepage& q=& f=false)". [28] Yamin Khan and Sarah Tilly. Thordarson. [11] O'Rourke. Hypertension (American Heart Association) 19: 212–217 [212] [13] Glossary of Clinical Trial Terms. "Frederick Akbar Mahomed". ISBN 0-471-21388-8 [6] Curtis L.1. com/ medicaltranslationpaper. (1992). Daly (2000). NIH Clinicaltrials. doi:10. gov/ ct2/ info/ understand) [18] "Guidance for Industry. asha. php). asp?postId=27). com/ pdf/ POI-Seasonality. org) [17] What is informed consent? US National Institutes of Health. Virginia Poole. p. [2] Van Spall HG. Jacqueline Benedetti. 1999-03-16. Michael F. ich. edu/ ab_2328_bill_20020826_enrolled. pdf) [16] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (http:/ / www. [25] http:/ / www. Pharm-Olam International (POI) (http:/ / www. [7] Toby E. 2001. and in Japan. pdf) [30] Back Translation for Quality Control of Informed Consent Forms (http:/ / www. com/ blog. findpharma. [3] The regulatory authority in the USA is the Food and Drug Administration.1001/jama. html) [31] Common Dreams (http:/ / www. Retrieved 2007-09-09. . (2004). Applied Clinical Trials Online. Stephanie Green. Turner. . p. 4. . Kiss A. ISBN 1-58488-302-2 [5] " Clinical Trials Handbook (http:/ / books. . Meinert.. Knopf.297. google. ecancermedicalscience. [27] Yamin Khan and Sarah Tilly. ISBN 978-0195035681. Retrieved 26 April 2010. org/ LOB/ media/ MEDIA482. MJ. html). . the Ministry of Health. p. Retrieved 26 February 2010. [8] Tschanz. Food and Drug Administration. . John Wiley and Sons. ucsd. pdf). 2005. . David W. p.gov (http:/ / clinicaltrials. 2328 (http:/ / irb. "Flu. ich. Season. CRC Press. pharm-olam. 129-133. 3. com/ books?id=Zke8ocubNXAC& pg=PA1& dq& hl=en#v=onepage& q=& f=false)". Peterson (2005). in Canada. 218. Covance Inc. Michael F. Shayne Cox Gad (2009). com/ appliedclinicaltrials/ Drug+ Development/ Flu-Season-Diseases-Affect-Trials/ ArticleStandard/ Article/ detail/ 652128). [29] Assembly Bill No.go. [10] "James Lind: A Treatise of the Scurvy (1754)" (http:/ / www. "Clinical pharmacology in the Middle Ages: Principles that presage the 21st century". Susan Tonascia (1986). Health Canada.1021/ja0713781. ISBN 0-521-52994-8. ISBN 0781757843. pp. "Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review". ich. google. com/ periapproval/ svc_phase3b. [20] Silvia Camporesi (October 2008). PMID 19616703. pdf) [32] Pmda.jp 独 立 行 政 法 人 医 薬品 医 療 機 器 総 合 機 構 (http:/ / www. 447-450 [448]. go. PMID 17374817. Diseases Affect Trials" (http:/ / appliedclinicaltrialsonline. Pharm Med 24 (4): 223–229. gov/ oc/ ohrt/ irbs/ drugsbiologics. JAMA 297 (11): 1233–40.11. jp/ ich/ s/ s1b_98_7_9e. China. Clinical trials: design. doi:10. com/ viewarticle/ 582554_2 [22] "Guidance for Institutional Review Boards and Clinical Investigators" (http:/ / www. (May/June 1997).118.1016/S0140-6736(09)61309-X. PMID 17497782. Labour and Welfare [4] " Clinical trials in oncology (http:/ / books. cancer. com). Pharmacotherapeutics for Advanced Practice: A Practical Approach. Lancet 374 (9685): 176. org/ cache/ compo/ 276-254-1. com/ pharmaceuticalmedicine/ Fulltext/ 2010/ 24040/ EU_Compassionate_Use_Programmes__CUPs___Regulatory. gts-translation.1233. and analysis (http:/ / books. gov/ downloads/ Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ ucm078933. Retrieved 2010-06-15. aspx). Fowler RA (March 2007). Huff (2003). "Seasonality: The Clinical Trial Manager's Logistical Challenge" (http:/ / www. p. Lippincott Williams & Wilkins. "The Arab Roots of European Medicine". "Phase 0 trials: a platform for drug development?".gov (http:/ / clinicaltrials. [24] Arcangelo. Saudi Aramco World 48 (3): 20–31. and Reviewers" (http:/ / www. medscape. "Frederick Akbar Mahomed". . Geneva" (http:/ / www. google. Alfred A. Powerful Medicines. Investigators. January 2006. org/ archive/ 2007/ 12/ 14/ 5838/ ) . fda. pdf). P (2007). Craig Brater and Walter J. org/ academic/ questions/ PhasesClinicalResearch/ [26] Web Site Editor. doi:10. [23] "Periapproval Services (Phase IIIb and IV programs)" (http:/ / www. fda. Toren A. John Crowley (2003). Retrieved 2008-11-07. gov/ ct2/ info/ glossary) [14] Helene S (2010). "Phase 0 workshop at the 20th EORT-NCI-AARC symposium. [9] D. Food and Drug Administration. American Cancer Society 129 (22): 7155. [21] http:/ / www. . The Rise of Early Modern Science: Islam. bruzelius. ecancermedicalscience. Andrew M. the European Medicines Agency. Oxford University Press. USA. Retrieved 2007-03-27.What Your Need to Know" (http:/ / www. Cambridge University Press. conduct. pmda. pharm-olam. "EU Compassionate Use Programmes (CUPs): Regulatory Framework and Points to Consider before CUP Implementation" (http:/ / adisonline. [19] The Lancet (2009). Clinicaltrials. org/ docroot/ ETO/ content/ ETO_6_3_Clinical_Trials_-_Patient_Participation. [15] ICH Guideline for Good Clinical Practice: Consolidated Guidance (http:/ / www. .Clinical trial 45 References [1] Avorn J. covance.

PMC 81460. PMC 1550630.int/trialsearch) • IFPMA Clinical Trials Portal (IFPMA CTP) (http://clinicaltrials. org/ resources/ hlth_tutorial/ mod4c. org/ en/ participate_clinicalresearch_how [39] Life on a Trial . Moore PK (2003). ISBN 1-56592-566-1 • Chow S-C and Liu JP (2004). cmaj.. 2001-04-17. htm). John Wiley & Sons.gov) • Clinical Trials for cancer research (http://www. Med. php?option=com_content& view=article& id=25& Itemid=21) [40] Life Sciences Strategy Group. pdtrials. fda. "Seeding trials: just say "no"" (http:/ / www. T. [42] Sox HC. . J.cancer. Seib. jmir. org/ 2005/ 1/ e5/ ) (Free full text). PMID 15829477.. "Clinical Trial Technology Utilization. "The Internet and clinical trials: background. Dale MM. Ritter JM. Cancer Clinical Trials: Experimental Treatments and How They Can Help You. Retrieved 2008-08-21.who. Drazen JM. online resources. ISBN 0-443-07145-4 • Finn R. 149 (4): 279–80. DeAngelis CD. (1999). . Clinical Trials: A Practical Approach. [35] Paul. CMAJ 165 (6): 786–8. Design and Analysis of Clinical Trials : Concepts and Methodologies. Prescott.gov/clinicaltrials) .2196/jmir. (Mar 2005). authorship and accountability" (http:/ / www. ca/ cgi/ pmidlookup?view=long& pmid=11584570).National Cancer Institute .org) • The International Clinical Trials Registry Platform (ICTRP) (http://www. . et al (September 2001).ifpma. [36] http:/ / www.7. Rennie D (August 2008). PMID 11584570.org) to Find Ongoing & Completed Trials of New Medicines • ClinicalTrials.gov (http://clinicaltrials.Clinical trial [34] "Tax Credit for Testing Expenses for Drugs for Rare Diseases or Conditions" (http:/ / www. Journal of medical Internet research 7 (1): e5. examples and issues" (http:/ / www. co.What to Expect (http:/ / www.e5. R. Pharmacology 5 ed. May. "Sponsorship. Purchasing Preferences & Growth Outlook" Syndicated Publication. . beavolunteer. ISBN 0-471-90155-5 External links • The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (http://www. Edinburgh: Churchill Livingstone. org/ en/ about_PDtrials_what [37] http:/ / www. ISBN 0-471-24985-8 • Pocock SJ (2004). org/ cgi/ pmidlookup?view=long& pmid=18711161). Food and Drug Administration. pdtrials. doi:10. Ann. mlanet. Sebastopol: O'Reilly & Associates. 46 • Rang HP. html [38] http:/ / www. Intern. Retrieved 2007-03-27..ich. .1. . 2009 [41] Davidoff F. . annals. uk/ index. PMID 18711161. gov/ orphan/ taxcred.

including rates of hypoglycemia. prospective.000 international units of vitamin A). Bausch & Lomb was a collaborator in the study and provides vitamins pre-packaged with this formulation. 400 international units of vitamin E. Praful N. and • evaluate the effects of high doses of antioxidants and zinc on the progression of the two conditions in those with AMD The study of 3600 individuals for an average of 6. clinicaltrials. global. basal (insulin detemir [Levemir]). Chakkarwar. The A1chieve study will evaluate adverse events and effectiveness of premix (biphasic insulin aspart 30 [NovoMix 30]). added to prevent copper deficiency anemia. Hajjaji. PMID 20466163. León. The study was designed to • investigate the natural history and risk factors of age-related macular degeneration (AMD) and cataracts.gov NCT00771680 Observational Study to Evaluate the Effectiveness and Safety of Levemir®. observational study of basal. and biphasic insulin analogs in daily clinical practice run by Novo Nordisk. A1chieve should provide important [3] information about how insulin analogs perform in daily clinical practice. meal-time. and biphasic insulin analogs in daily clinical practice". Jihad. non-interventional. and meal-time (insulin aspart [NovoRapid]) insulin analogs in people with type 2 diabetes in near-routine clinical practice. South America.3 years concluded that high levels of antioxidants and zinc can reduce some people's risk of developing advanced AMD by about 25 percent. Thus. The primary aim of the study is to assess the adverse event profile of the study insulins in routine clinical practice. Issam (2010). and measures of current standards of care. in the form of zinc oxide. The results were reported in the October 2001 issue of Archives of Ophthalmology. com/ id/ 38303754 [3] Shah. cnbc. effectiveness (HbA(1c). Siddharth N. one of the National Institutes of Health in the United States. Diabetes Research and Clinical Practice 88: S11–6. and postprandial plasma glucose) and patient quality of life outcomes will be measured. including recent plasma glucose results and hypoglycemic episodes.A1chieve 47 A1chieve A1chieve[1] is a 60 000-person. sold commercially as Ocuvite PreserVision antioxidant vitamin and mineral supplement. Age-Related Eye Disease Study The Age-Related Eye Disease Study was a clinical trial sponsored by the National Eye Institute. A1chieve is an international. Haddad. The supplements had no significant effect on the development or progression of cataracts. for . "The A1chieve study: A 60 000-person. gov/ show/ NCT00771680) [2] http:/ / www. doi:10. and two milligrams of copper as cupric oxide. open-label. prospective. prospective. prevalence of diabetes-related complications. Comprehensive epidemiological data will be collected at baseline. multi-center. 24-week study of people with type 2 diabetes using an insulin analog. NovoMix® 30 and NovoRapid® in Insulin naïve Subjects With Type 2 Diabetes (http:/ / www. observational study of basal. The study recruited 60 000 people[2] from 28 countries across four continents (Asia.1016/S0168-8227(10)70003-6. and Europe). "High levels" in this case were defined to be: • • • • • 500 milligrams of vitamin C. Reference [1] ClinicalTrials. Litwak. 15 milligrams of beta-carotene (or 25. In addition. fasting plasma glucose... Those that benefited from the dietary supplements included those with intermediate-stage AMD and those with advanced AMD in one eye only. a condition associated with high levels of zinc intake. global. 80 milligrams of the dietary mineral zinc. as do other suppliers. Africa. meal-time.

ISBN 1841840343. . google.[1] Compared to standard axillary management. can be used with low failed localization and false negative rates. provided both radioisotope and blue dye are used to locate the sentinel nodes.Age-Related Eye Disease Study example. used to stage axillary spread of disease. com/ books?id=gzE1STlawtUC& pg=PA237& ots=LRfU-laUCF& dq="Axillary+ Lymphatic+ Mapping+ Against+ Nodal+ Axillary+ Clearance"& ie=ISO-8859-1& output=html& sig=IYwGmDfjzrhI02v65-djSogoe2g). clinicaltrials. 48 External links • NEI's website [1] about the study • Summary of the study [2] References [1] http:/ / www. Sentinel Lymph Node Biopsy (http:/ / books. without any increase in cancer-related anxiety." This major randomized trial performed in several centres in the UK produced clear evidence that sentinel node biopsy (SNB). gov/ amd/ [2] http:/ / www. (2003). Viteyes AREDS formula eye vitamins. nei. SNB results in greatly decreased arm problems and increased quality of life. There is no evidence of a difference in local recurrence rates. 237. p. . The acronym stands for "Axillary Lymphatic Mapping Against Nodal Axillary Clearance. gov/ ct/ show/ NCT00000145 ALMANAC ALMANAC is the name of a major breast cancer trial. though longer-term evidence on this is awaited from other studies. Informa Health Care. nih. References [1] Hiram S Cody.

compliance. Although the statistical techniques employed in the clinical trials are often quite simple. who should be kept in their original group for the analysis. we must either find out whether the outcome data are available for them by contacting the trial lists. They may die. This involves making assumptions about the outcomes in the 'lost' participants. none of the patients is excluded and the patients are analyzed according to the randomization scheme. they may withdraw themselves or be withdrawn by their clinician. An extreme variation of this is the participants who receive the treatment from the group they were not allocated to. not the effects in the subgroup of the participants who adhere to it. Some patients drop out from the study. as a systematic reviewer. or Some patients are not compliant. Ø The rationale for this approach is that. Most trials do not yield perfect data. If the participants are lost to follow-up then the outcome may not be measured on them. you can extract the appropriate data from the trial reports. A patient is randomized to the Treatment A but has been treated with the Treatment B. or by being withdrawn from active treatment) should still be kept in the analysis.we often do not have the data that we need for these participants. in the first instance. we want to estimate the effects of allocating an intervention in practice. and so on. Although the medical investigators have often difficulties in accepting the ITT analysis. The basic ITT principle is that participants in the trials should be analysed in the groups to which they were randomized. when the patients drop out before a response can be obtained they cannot be included in the analysis. Since it came up in the 1960s. This issue causes no problems provided that. that is. In the ITT population. however. But the strict ITT principle suggests that they should still be included in the analysis. The first issue is that the participants who strayed from the protocol (for example by not adhering to the prescribed intervention. For instance. recent statistical research tackled specific and difficult the clinical trial issue. perhaps due to the adverse effects of the intervention being studied. or move away. such as when the patients do not receive the full intervention or the correct intervention or a few ineligible patients are randomly allocated in error. regardless of whether they received or adhered to the allocated intervention. As treated The as-treated analysis has the general idea to compare the subjects with their treatment regimen that they received. do not take their medication as instructed.e. There is an obvious problem . Probably the most important problem is the occurrence of the dropout in a clinical trial. or we must impute (i. Intention to treat The randomized clinical trials analyzed by the intention-to-treat (ITT) approach provide the unbiased comparisons among the treatment groups. it is the pivotal analysis for the FDA and EMEA. make up) their outcomes. Some examples are as follows: • • • • The patients who do not satisfy the inclusion and/or exclusion criteria are included in the trial.Analysis of clinical trials 49 Analysis of clinical trials Failure to include all participants in the analysis may bias the trial results. Ø The second issue in the ITT analyses is the problem of loss to follow-up. the principle of the ITT has become widely accepted for the analysis of the controlled clinical trials. The ITT analysis is not appropriate for examining the adverse effects. The ITT analysis is generally favoured because it avoids the bias associated with the non-random loss of the participants. like the dropouts. non-inferiority studies. The people are lost from the clinical trials for many reasons. Two issues are involved here. It does not consider the fact which treatment they were assigned for the treatment. and so on. even not in an ITT analysis. Despite the fact that the most clinical trials are carefully planned. "Protocol violations" may occur. In order to include such participants in an analysis. many problems can occur during the conduct of the study. .

so that carrying forward an intermediate value is a conservative estimate of how well the person would have done had he or she remained in the study. that is. when the patients drop out before a response can be obtained they cannot be included in the analysis. If a patient drops out of the study after the third week. ISBN 9783940934000 . This population is classically called the per-protocol population and the analysis is called the per-protocol-analysis. rather than focusing simply on the endpoint. and • It allows the analysis to examine the trends over time. and outcome assessment. The assumption is that the patients improve gradually from the start of the study until the end. This analysis is known as an "on-treatment" or "per protocol" analysis. the measurements obtained before the patient dropped out can be used to establish the unknown measurement at the end of the study. it does not show the practical value of the new drug. even not in an ITT analysis. The advantages to this approach are that • It minimises the number of the subjects who are eliminated from the analysis. the per-protocol restricts the comparison of the treatments to the ideal patients. Conducting clinical trials. Also. The Last-Observation-Carried-Forward (LOCF) method allows for the analysis of the data. When the patients are examined on a regular basis. References AR Waladkhani. (2008). For instance. In that case. by restricting the analysis to a selected patient population.Analysis of clinical trials 50 Per protocol The analysis can only be restricted to the participants who fulfil the protocol in the terms of the eligibility. But. However. a series of the measurements is obtained. then this value is "carried forward" and assumed to be his or her score for the 5 missing data points. interventions. the recent research shows that this method gives a biased estimate of the treatment effect and underestimates the variability of the estimated result. Last observation carried forward The most important problem during the performance of the clinical trial is the occurrence of the dropout. Let's assume that there are 8 weekly assessments after the baseline observation. A per-protocol analysis envisages determining the biological effect of the new drug. those who adhered perfectly to the clinical trial instructions as stipulated in the protocol. A theoretical and practical guide.

that is.[2] The choice of the margin is sometimes problematic in non-inferiority trials. Non-inferiority trials attempt to rule out some margin of inferiority between a test and control intervention i.. etc. non-inferiority trials have a feature in common with external (historically) controlled trials. usage of concomitant medications. Importance Lack of assay sensitivity has different implications for trials intended to show a difference greater than zero between interventions (superiority trials) and trials intended to show non-inferiority. In addition. since this trial would not ensure that the test intervention is any more effective than a placebo given that the effect ruled out is larger than the effect of the control compared to placebo. For instance. when one intervention is superior). if there is reliable and reproducible evidence from previous superiority trials of an effect size of 10% for a control intervention compared to placebo. a noninferiority trial designed to rule out that the test intervention may be as much as 15% less effective than the control may not have assay sensitivity. generally does not contain such direct evidence of assay sensitivity. In contrast.e rule out that the test intervention is no worse than the control intervention by a chosen amount. a valid noninferiority trial is not possible in situations in which there is a lack of data demonstrating a reliable and reproducible effect of the control compared to placebo. This also means that non-inferiority trials are subject to some of the same biases as historically controlled trials. The chosen margin of inferiority in a non-inferiority trial cannot be larger than the largest effect size which the control intervention reliably and reproducibly demonstrates compared to placebo or no treatment in past superiority trials. differences in disease definitions or changes in the natural history of a disease.Assay sensitivity 51 Assay sensitivity Assay sensitivity is a property of a clinical trial defined as the ability of a trial to distinguish an effective treatment from a less effective or ineffective intervention. If a trial intended to demonstrate efficacy by showing superiority of a test intervention to control lacks assay sensitivity.[3] The finding of "difference" or "no difference" between two interventions is not a direct demonstration of the internal validity of the trial unless another internal control confirms that the study methods have the ability to show a . the effect of a drug in a past trial may not be the same in a current trial given changes in medical practice. When two interventions within a trial are shown to have different efficacy (i. an appropriately designed non-inferiorty trial designed to rule out that the test intervention may be as much as 5% less effective than the control would have assay sensitivity. a trial that demonstrates non-inferiority between two interventions. and the design of the planned non-inferiority trial. or an unsuccessful superiority trial. Differences in sensitivity Assay sensitivity for a non-inferiority trial may depend upon the chosen margin of inferiority ruled out by the trial. with this same data. On the other hand. the chosen margin is sometimes larger than the effect size of the control compared to placebo." In this way. In addition to choosing a margin based upon credible past evidence. the planned non-inferiority trial must be designed in a way similar to the past trials which demonstrated the effectiveness of the control compared to placebo. to have assay sensitivity. it will fail to show that the test intervention is superior and will fail to lead to a conclusion of efficacy. the trial may find an ineffective intervention to be non-inferior and could lead to an [1] erroneous conclusion of efficacy. the so-called "constancy assumption.e. In contrast. if a trial intended to demonstrate efficacy by showing a test intervention is non-inferior to an active control lacks assay sensitivity. Without assay sensitivity. differences in outcome timing and definitions. a trial is not internally valid and is not capable of comparing the efficacy of two interventions. that finding itself directly demonstrates that the trial had assay sensitivity (assuming the finding is not related to random or systematic error). Given investigators desire to choose larger margins to decrease the sample size needed to perform a trial.

Assay Sensitivity. org/ MediaServer. [3] International Conference on Harmonization Guidance E-10 (2000). Tuzcu EM. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006. Erbel R. Ballantyne CM. .Assay sensitivity difference. . Tardif JC. Retrieved 2007-09-16. Davignon J.gov/) from US National Library of Medicine • FDA Website (http://www. Crowe T.295:1556-65. PMID 11714400. . a placebo group) to internally validate the trial. doi:10.gov/) ASTEROID trial The ASTEROID trial was a clinical trial published in 2006 that shows the effects of statins (drugs that inhibit the enzyme HMG-CoA reductase) on atherosclerosis. jser?@_ID=486& @_MODE=GLB). Choice of Margin" (http:/ / www. [2] Temple.e.clinicaltrials.jpc60002 PMID 16533939. "Active Control Non-Inferiority Studies: Theory. the trial contains a third group receiving placebo). Since most clinical trials do not contain an internal "negative" control (i.". fda. they showed regression of the atherosclerotic plaques in response to a high dose of rosuvastatin[1] References [1] Nissen SE. Robert J (2002-02-19). SM (2000). over the range of interest (i. Cain V. if one exists. 52 References [1] Snapinn. ASTEROID Investigators. Raichlen JS. ich. Wolski K. Nicholls SJ. Retrieved 2007-10-21.gov (http://www. "Choice of Control Group and Related Issues in Clinical Trials" (http:/ / www.1001/jama. "Noninferiority trials. Goormastic M. ppt). Current controlled trials in cardiovascular medicine 1 (1): 19-21. the data to evaluate the validity of the trial comes from past trials external to the current trial. gov/ ohrms/ dockets/ ac/ 02/ slides/ 3837s1_02_Temple. External links • ClinicalTrials.e. Employing intravascular ultrasound (IVUS).13.295.fda. Sipahi I. Schoenhagen P. Fruchart JC. Libby P.

Group (2005). PMC 1175096. double-blind. One group received rosuvastatin 10 mg daily and the other group received a placebo. References [1] Fellstrom BC. nonfatal myocardial infarction. placebo-controlled study investigating the use of rosuvastatin in the prevention of cardiovascular disease among patients undergoing chronic hemodialysis. Aurora Study.gov entry (http://clinicaltrials.1186/1468-6708-6-9. W. org/ cgi/ content/ short/ 360/ 14/ 1395?query=TOC). "Effect of rosuvastatin on outcomes in chronic haemodialysis patients – design and rationale of the AURORA study".1056/NEJMoa0810177. doi:10. Zannad. A. doi:10. Jardine AG. Schmieder. J. the marketer of Crestor. aged 50–80 years and undergoing maintenance hemodialysis. Although the mean LDL cholesterol was reduced by 43% in the rosuvastatin arm of the study at three months.[2] The trial was conducted across 280 medical centers in 25 countries. Holdaas. Jardine. nejm. The combined primary end point was death from cardiovascular causes. H. Wilpshaar. et al (April 2009). F.8 years. in part. R. The AURORA trial sought to fill this gap. 360 (14): 1395–1407.gov/show/NCT00240331) . Rose. PMID 19332456. by AstraZeneca. H. no difference in the primary end point was demonstrated at an average follow-up of 3. PMID 15910680.AURORA trial 53 AURORA trial The AURORA trial (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) was a randomized. External links • Clinicaltrials. [2] Fellstrom BC. to one of two groups. Engl. The study randomized 2776 patients. Curr Control Trials Cardiovasc Med 6 (1): 9.[1] The trial was sponsored. .[1] The trial was undertaken because although patients with end-stage renal disease (ESRD) are at high risk of adverse cardiovascular events. "Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis" (http:/ / content. N. no large clinical trial had confirmed the benefit of lipid lowering agents. or nonfatal stroke. Med.

that 'it could be no more ridiculous for the strange who passed the night in the steerage of an emigrant ship to ascribe the typhus. But this is a feature I am convinced we cannot demand. Other important criteria in evaluations of disease and adverse event causality include consistency. Since large. surgical procedure.Biological plausibility 54 Biological plausibility In epidemiology and biomedicine. amongst other “absurd” associations. it should be plausible and explicable biologically according to the known facts of the natural history and biology of the disease in question. It is also an important part of the process of evaluating whether a proposed therapy (drug. specificity and a meaningful temporal relationship. there was "…no biological knowledge to support (or to refute) Pott’s observation in the 18th century of the excess of cancer in chimney sweeps. Watson. vaccine. Biological plausibility is one component of a method of reasoning that can establish a cause-and-effect relationship between a biological factor and a particular disease or adverse event."[1] Treatment outcomes The preliminary research leading up to a randomized clinical trial (RCT) of a drug or biologic has been termed "plausibility building". . in the 20th century there was no biological knowledge to support the evidence against rubella. the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd." In short. after the great English epidemiologist who proposed them in 1965. These are known collectively as the Bradford-Hill criteria. strength of association. to the vermin with which bodies of the sick might be infected. Biological plausibility is an essential element of the intellectual background of epidemiology. definitive RCTs are extremely expensive and labor intensive. which he there contracted. tissue or animal data which are eventually found to point to a mechanism of action or to demonstrate the desired biological effect. This involves the gathering and analysis of biochemical. only sufficiently promising therapies are thought to merit the attention and effort of final confirmation (or refutation) in them. the association between a biological factor and a disease (or other bad outcome) should be biologically coherent. To quote again from my Alfred Watson Memorial Lecture [1962]. This concept has application to many controversial public affairs debates. Austin Bradford Hill himself de-emphasized "plausibility" among the other criteria: It will be helpful if the causation we suspect is biologically plausible. As Sherlock Holmes advised Dr. whatever remains. However.) has a real benefit to a patient. That is to say. What is biologically plausible depends upon the biological knowledge of the day. Applications Disease and adverse event causality It is generally agreed that to be considered “causal”. "when you have eliminated the impossible. This process is said to confer biological plausibility. such as that over the causes of adverse vaccination outcomes.' And coming to nearer times. The term originated in the seminal work of determining the causality of smoking-related disease (The Surgeon General’s Advisory Committee on Smoking and Health [1964]). the term biological plausibility refers to the proposal of a causal association — a relationship between a putative cause and an outcome — that is consistent with existing biological and medical knowledge. It was lack of biological knowledge in the 19th that led to a prize essayist writing on the value and the fallacy of statistics to conclude. must be the truth. etc. however improbable.

the evidence for this link had been largely circumstantial. followed up in further questionnaires in 1957. sex. ca/ cgi/ content/ full/ 168/ 2/ 180). British Doctors Study The British doctors study is the generally accepted name of a prospective cohort study which ran from 1951 to 2001. despite its importance. Canadian Medical Association Journal. 58.[2] It has been observed that. The study. Because of the limited sample size females were excluded from most analyses and publications focused on the male physicians. L. clinical data from epidemiological studies. 295-300. [2] Hoffer. formal open or controlled clinical trials may confer clinical plausibility. 1991.[2] would herald a new type of scientific research. 1966. Austin Bradford (1965). and vitally linked tobacco smoking to a number of serious diseases. when it was published in 1956. and their cause-specific mortality. and obtained responses in two-thirds. 1978. as well as general physical health and current smoking habits. No further cohorts were recruited. [3] Hoffer. “The Environment and Disease: Association or Causation?” (http:/ / www. biological plausibility is lacking for most complementary and alternative medicine therapies. case series and small. According to the strictest criteria. cit. the researchers wrote to all registered physicians in the United Kingdom.[3] 55 References [1] Hill. To further investigate the link. the researchers felt it necessary to offer a definition of the prospective principle. In fact. smoking had been advertised as "healthy" for many years. Op. The study In October 1951. and in 1956 provided convincing statistical proof that tobacco smoking increased the risk of lung cancer. The respondents were stratified into decade of birth.701 of them. and finally in 2001. Context Although there had been suspicions of a link between smoking and various diseases. case reports. a therapy is sufficiently scientifically plausible to merit the time and expense of definitive testing only if it is either biologically or clinically plausible. 168 (2) [January 21 issue]. com/ tufte/ hill). 40. edwardtufte. . cmaj.Biological plausibility In distinction to biological plausibility. Proceedings of the Royal Society of Medicine. “Complementary or alternative medicine: the need for plausibility” (http:/ / www. This approach to medical [1] questions was fairly new: in the 1954 "Preliminary report". and there had been no clear explanation why rates of lung cancer had soared. 1971. the Medical Research Council (MRC) instructed its Statistical Research Unit (later the Oxford-based Clinical Trial Service Unit) to conduct a prospective study into the link. showed to relevance of epidemiology and medical statistics in questions of public health. John (2003).

and the appreciation of the problem would only grow in the ensuing decades. prepare all subsequent reports for publication. published every ten years (see the 2004 article for a summary) more information became available. and those who smoke until age 60 lose 7 years. specifically. The original study was run by Richard Doll and Austin Bradford Hill. for example the more recent Heart Protection Study. Hill AB (November 1956). Boreham J. doi:10. R. with Doll.2. for example. making appropriate statistical analyses possible. those who smoke until age 30 have no excess mortality. on average. Richard Peto joined the team in 1971 and would. "Mortality in relation to smoking: 50 years' observation on male British doctors". Peto R. and that more than 50% of all smokers die of a disease known to be smoking-related. although the excess mortality depends on amount of smoking. myocardial infarction. BMJ 328 (7455): 1529. Doll and Peto are both celebrated epidemiologists.1529.1136/bmj. those who smoke until age 40 lose 1 year. that smoking decreases life span up to 10 years.1136/bmj.328. PMID 15213107. (2004).7455. [3] In the follow-up reports. PMC 437139. "Lung cancer and other causes of death in relation to smoking. [2] Doll. PMC 437141.[3] Impact and personalities The true impact of the study is difficult to gauge. now commonly referred to as "heart attack") occurred markedly more often in smokers. doi:10. Nevertheless. A major conclusion of the study is. PMID 15217868. References [1] Doll R. PMC 2035864. the British doctors study was to provide conclusive evidence of linkage between smoking and lung cancer.38142. that both lung cancer and "coronary thrombosis" (the then-prevalent term for myocardial infarction. "The mortality of doctors in relation to their smoking habits".554479. Hill AB.1136/bmj. respiratory disease and other smoking-related illnesses.1071. Sutherland I. a second report on the mortality of British doctors". British Medical Journal 2 (5001): 1071–1081.British Doctors Study 56 Statistical analysis Response rates were quite high. The result was. (1954). BMJ 328 (7455): 1519.AE. as smoking was not considered a public health problem in the 1950s. . doi:10. those who smoke until 50 lose 4 years. [3] Doll R.5001. and their fame is largely based on their pioneering work in the study mentioned. PMID 13364389. They would continue their work on other cardiovascular studies.

or harmful use is established using the SCAN interview's chapters 11 and 12. The Lancet 370 (9584): 293–4. doi:10. PMID 17662860. doi:10. The aim of the RCT is to compare an approach using motivational interviewing. observer-blinded clinical trial of specialized addiction treatment versus treatment as usual for young patients with cannabis abuse and psychosis" [2]. parallel-group. com/ content/ pdf/ 1745-6215-9-42. pdf . abuse. The trial is. among the only trials aimed at this particular group of comorbid substance abusers with schizophrenia.1016/S0140-6736(07)61135-0. Nordentoft M (2008). PhD. the trial measures level of psychopathology in terms of positive and negative symptoms with the PANSS instrument. It is an intervention aimed at reducing cannabis consumption in young persons with comorbid severe mental illness such as schizophrenia or schizotypal personality disorder. dk [2] http:/ / www. • Nordentoft M. and quality of life and related life-areas measured with the Manchester Short Assessment of Quality of Life instrument and the World Health Organisation's Disability Assessment Schedule. trialsjournal.1186/1745-6215-9-42. cognitive behaviour therapy. External links • CapOpus . capopus. The presence of mental illness and cannabis dependency. Larsen AM. psychiatrist Merete Nordentoft. the Municipality of Copenhagen. It is run by professor. Trials 9: 42. cognitive function using a set of validated tests. PMC 2475529. Among the trial's funders are the Lundbeck foundation.in both Danish and English [1] • Hjorthøj C.CapOpus 57 CapOpus CapOpus is the name of a randomized controlled trial (RCT) running in Denmark at Psychiatric Center Bispebjerg (part of Region Hovedstadens Psykiatri) and physically located at Bispebjerg Hospital in Copenhagen. "Design paper: The CapOpus trial: A randomized. MD. Madsen MT. Hjorthøj C (2007). PMID 18620563. Arendt MC. References [1] http:/ / www. Fohlmann A. along with the English MIDAS Trial. and the stages of change model compared with standard treatment. "Cannabis use and risk of psychosis in later life". Vesterager L. Gluud C. Retrieved 2008-08-06. As secondary outcomes. and Sygekassernes Helsefond. The primary outcome of the trial is reduction in number of days using cannabis. and cannabis dependency. as measured by the timeline followback instrument.

T. In September.CDR Computerized Assessment System 58 CDR Computerized Assessment System The CDR Computerized Assessment System (CDR System) is a computerized battery of cognitive tests designed in the late 1970s by Professor Keith Wesnes at the University of Reading in Berkshire.Ferrara. stress. Quantifying fluctuation in dementia with Lewy bodies. for repeated testing in clinical trails. Del Serf. PhD. et al. Emree. Issue 9247.Spano. P. Spiegelg [1] 2. placebo-controlled international study The Lancet. Walker. L. The cognitive drug research computerized assessment system in the evaluation of early dementia-is speed of the essence [2] 4. Manktelow TC (2002) Cognitive deficits in recently diagnosed untreated patients with Parkinson’s disease Journal of Psychopharmacology 16 (Suppl. A. Ballard. M. R. simple reaction time. Cognitive Performance in Hypertensive and Normotensive Older Subjects [4] 8. The standard battery of tests lasts 18 minutes. and Vascular Dementia M. McKeith. word recognition. England. M. sensitivity and specificity makes it acceptable to be used in clinical trials with either healthy subjects or diseased patient populations. episodic secondary memory. R. Ancillary equipment is used for specific cognitive tests such as a postural stability (sway) meter. Task stimuli are presented in a laptop computer and participants respond via ‘YES’ and ‘NO’ buttons on a two-button response box. and spatial working memory. a critical flicker fusion device or joysticks for CDR’s tracking test. Effects of Rivastigmine on Cognitive Function in Dementia with Lewy Bodies: A Randomised Placebo-Controlled International Study Using the Cognitive Drug Research Computerised Assessment System I.Spiegel [3] 6. The CDR System’s simplicity. R. A. The CDR System is a series of brief neuropsychological tests that assess major aspects of cognitive function known to be influenced by a wide variety of factors including trauma. fatigue. R. medicines and drugs. The standard battery of cognitive tests in The CDR System includes immediate/delayed word recall. (1994). R. T. mood states.F.Del Ser. Ferrarac. digit vigilance. working memory. J. K. 2009. Examples of tests that can be added include measurements of executive function. R. disease (both physical and mental). Individual tests can be added to or removed from the battery to target specific cognitive domains. I. G.Emre. Ayre. PhD. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised. social cognition. choice reaction time. Cummings. developed to assess both enhancement and impairment of human cognitive performance. Simpson.G. Neuman E. DM and C. Journal of Psychopharmacology 18 (Suppl): A48 7. Volume 356. which records both the accuracy and reaction time. and motor skill. MD . ageing. McKeithb. G.Wesnes. T.McKeith. The CDR System is a computer based cognitive testing tool. numeric working memory. P. J. P. P. nutrition. Referenced publications/abstracts 1. The CDR System tasks have proven validity in definitively measuring cognitive function in a variety of domains including attention. executive function.Cicin-Sain. double-blind. MD. A. Alzheimer’s disease. picture recognition.M. Pages 2031-2036 I. motor function and postural stability. Spanod. Pharmacodynamic effects of a repeated oral administration of 4 dose levels of S 12024-2 in 36 elderly volunteers. Moon G. G. J.): A31 5. An internet version of The CDR System is available using keyboard commands to measure responses. Cicin-Saing. Cognitive Drug Research was acquired by United BioSource Corporation. Neurobiology of Aging 15: S100 9.Anand. O’Brien. The CDR System software is loaded onto laptop computers for testing in medical clinics. Macher J-P (2004) Modafinil reverses the marked attentional deficits produced by acute sleep deprivation in healthy volunteers. Anandh.Surmonk (1991) The Cognitive Drug Research Computerized Assessment System for Demented Patients: A Validated Study 3. MD.

com/ ProdukteDB/ produkte. com/ journal/ 109705834/ abstract [3] http:/ / linkinghub. Journal of Psychopharmacology 8 (Suppl). The value of assessing cognitive function in drug development: Dialogues in Clinical Neuroscience 2: 183-202. Simpson PM (1994) The construct validity of the cognitive drug research computerised assessment system. L. Nandy P. (Lib: 86) External links • Assessing Change in Cognitive Function in Dementia [6] • Alzheimer's Clinical Dementia Rating [7] References [1] http:/ / content. Simpson P. org/ cgi/ content/ abstract/ 54/ 8/ 1616 [6] http:/ / content. interscience. elsevier. com/ ProdukteDB/ produkte. Herting R. Mayleben D. Clinical Research (2000).: A21 13. K. wiley. asp?Aktion=ShowAbstract& ArtikelNr=000048651& Ausgabe=227588& ProduktNr=224226 [2] http:/ / www3. Perhach J (2004) Dose and time dependent discrimination of daytime sleepiness measured by multiple sleep latency tests (MSLT). Psychomotor performance tests (PPT) and Stanford Sleepiness Scale (SSS) after a single AM administration of a sedative hypnotic drug Sleep 27: A49 11. wustl. asp?Aktion=ShowPDF& ArtikelNr=113719& ProduktNr=229093& filename=113719. org/ cgi/ content/ abstract/ 36/ 6/ 1079 [5] http:/ / neurology. pdf [7] http:/ / alzheimer. karger. Corser B. htm .CDR Computerized Assessment System [5] 59 10. Roth A. edu/ cdr/ AboutCDR/ aboutcdr. karger. Harris S. ahajournals. White.: A20. 12. Schwartz P (1994) Further evaluations of the criterion validity of the CDR computerised assessment system Journal of Psychopharmacology 8 (Suppl). com/ retrieve/ pii/ S0140673600033997 [4] http:/ / hyper.

Many clinical trials are designed with a minimum follow-up time. that it is related to probability of replication. Conducting clinical trials. . clinical significance refers to either of two related but slightly dissimilar concepts whereby certain findings or differences. Practical significance may also convey semi-quantitative. addresses whether an intervention or treatment may or may not fully correct the finding. even if measurable or statistically confirmed.[2] NHST only yields information about whether results are statistically likely given some assumption about the population. or feasibility assessments of utility. more restrictive usage designate the broader usage as linguistically imprecise and thus erroneous. practical significance optimally yields quantified information about the importance of a finding. Commentators who utilize the second.[3] In terms of testing clinical treatments. ISBN 978-3-940934-00-0 Clinical significance In medicine and psychology. This means that the results aren't reported until that amount of the time after the last patient signed up for the trial.Censoring (clinical trials) 60 Censoring (clinical trials) The term censoring is used in clinical trials to refer to mathematically removing a patient from the survival curve at the end of their follow-up time. how effective is the intervention or treatment. the "practical clinical significance" answers the question. statistical significance does not yield information about magnitude of effect. how likely it is that the statistical test of the treatment would erroneously indicate that the treatment is effective? Practical significance In broad usage. References • AR Waladkhani. NHST answers the question. what is the probability of obtaining data that indicate the effect is not zero?[1] NHST is often misunderstood in several ways: that the p-value is the probability that the null hypothesis is false. Types of significance Statistical significance Statistical significance tends to be used in the context of null hypothesis significance testing (NHST). number needed to treat (NNT). practical significance. using metrics such as effect size. either by (1) being of a magnitude that conveys practical relevance (a usage that conflates practical and clinical significance interchangeably). or (2) more technically and restrictively. the proposed alternative hypothesis should be accepted. comparative. Often reports of the preliminary results don't include any minimum follow-up time and include the patients with very short follow-up time which definitely affects the reliability of the result. if a hypothesis that an effect is zero in the population is true (the null hypothesis). either may or may not have additional significance. and that if the null hypothesis is rejected. and its common misuse. nor clinical significance. and preventive fraction. (2008). so the more patients are censored and the earlier they are censored the more unreliable the results are. Given the nature of NHST. or how much change does the treatment cause? In terms of testing clinical treatments. A theoretical and practical guide. Censoring a patient will reduce the sample size for analyzing after the time of the censorship. statistical significance can only indicate an answer to this question: if a treatment is actually ineffective. Reducing the sample size always reduces reliability.

a more technical restrictive usage denotes this as erroneous. improved.[4] This technical use within psychology and psychotherapy not only results from a carefully drawn precision and particularity of language. because they may simply reflect a level of normal human variation. to establish the connection between performance on the specific test and the individual's more general functioning. It is very possible to have a treatment that yields a significant difference and medium or large effect sizes. and are recommended for inclusion in addition to statistical significance. in that they do not either explain existing information about the client. the Hageman-Arrindell method. but does not move a patient from dysfunctional to functional. clinicians look for information in the assessment data and the client's history that corroborates the relevance of the statistical difference. It involves calculating a Reliability Change Index (RCI).depending on the directionality of the RCI and whether the cutoff score was met. and “how much change has occurred during the course of therapy. 61 Specific usage In contrast.[5] Effect size can provide important information about the results of a study. Five common methods are the Jacobson-Truax method. when used as a technical term within psychology and psychotherapy.[10] [11] Calculation of clinical significance Just as there are many ways to calculate statistical significance and practical significance. there will be a difference of scores or subscores that is statistically significant. is a treatment effective enough to cause the patient to be normal? For example.effect size). not all of those statistically significant differences are clinically significant.[9] The RCI equals the difference between a participant’s pre-test and post-test scores. In terms of clinical treatment studies. Cutoff scores are established for placing participants into one of four categoriesrecovered. the change could be a large decrease in depressive symptoms (practical significance. Differences that are common in the population are also unlikely to be clinically significant. and [8] Revenstorf as a way to answer the question. the Gulliksen-Lord-Novick method. is a therapy or treatment effective enough such that a client does not meet the criteria for a diagnosis? Jacobson and Truax later defined clinical significance as “the extent to which therapy moves someone outside the range of the dysfunctional population or within the range of the functional population. . divided by the standard error of the difference. the Edwards-Nunnally method. not individual changes. Differences that are small in magnitude typically lack practical relevance and are unlikely to be clinically significant. clinical significance answers the question. are subject to change based on population variability of the dependent variable.” [9] Clinical significance is also a consideration when interpreting the results of the psychological assessment of an individual. clinical significance was first proposed by Jacobson. Follette.[4] Jacobson-Truax Jacobson-Truax is common method of calculating clinical significance. Effect sizes have their own sources of bias. and tend to focus on group effects. a treatment might significantly change depressive symptoms (statistical significance).Clinical significance Effect size is one type of practical significance. unchanged. Frequently. but it enables a shift in perspective from group effects to the specifics of change(s) within an individual. and 40% of the patients no longer met the diagnostic criteria for depression (clinical significance). or provide useful direction for intervention. clinical significance yields information on whether a treatment was effective enough to change a patient’s diagnostic label. or deteriorated. and hierarchical linear modeling.”[9] They proposed two components of this index of change: the status of a patient or client after therapy has been completed.[4] It quantifies the extent to which a sample diverges from expectations. unlikely to have occurred purely by chance. there are a variety of ways to calculate clinical significance. Additionally. However. Within psychology and psychotherapy.[6] [7] [4] Although clinical significance and practical significance are often used synonymously.

1044-1048.. such as Hierarchical each patient. 37. or deteriorated. Assessing Adolescent and Adult Intelligence (3rd ed. E. 2008). Alan S.. the clinical significance of change. 12-19. D. B. L. Reetz.E. instead of only two data points (pre-test and post-test).. and dividing by the standard deviation of the population. The American Psychologist. Feb 7. compared to the Jacobson-Truax method. html) (22 August 2010). 997-1003. Hierarchical Linear Modeling (HLM) HLM involves growth curve analysis instead of pre-test post-test comparisons. (1997). 511-516. San Diego: Sattler Publications. T. Establishing clinically significant change: increment of precision and the distinction between individual and group level of analysis. N. L. Paper presented at the Annual Meeting of the Southwest Educational Research Association (New Orleans. [8] Jacobson. M.. ISBN 978-0-9702671-6-0 [11] Kaufman. indicates four categories similar to those used by Jacobson-Truax: deteriorated. Online Submission.. American Psychologist. 2008).Multiple Criteria for Evaluating the Magnitude of Experimental Effects. [6] Wilkinson. com/ WileyCDA/ WileyTitle/ productCd-0471735531. Paper presented at the Annual Meeting of the Southwest Educational Research. A comparison of three methods of identifying reliable and clinically significant client changes: commentary on Hageman and Arrindell. improved but not recovered. & Greenbaum.. N. The reliability of change indicates whether a patient has improved. Behavior Therapy. (1984). 1195-1202. Ellis. Clinical significance: A statistical approach to defining meaningful change in psychotherapy research. 59(1). The earth is round (p < . (1999). Lay summary (http:/ / www.604. (2008). Journal of Consulting and Clinical Psychology. The earth is round (p < . (1999). [13] Speer. 997-1003. This is done by subtracting the pre-test and post-test scores from a population mean. LA. Journal of Counseling Psychology. HLM also allows for analysis of growth curve models of dyads and groups.Clinical significance Gulliksen-Lord-Novick [12] is similar to Jacobson-Truax. Journal of Consulting and Clinical Psychology.S..05). 37. W. so three data points are needed from [14] A computer program. Lichtenberger. Elizabeth (2006). stayed the same. 10. W. L. (1999). & Thompson. & Arrindell. 1169-1193. Feb 7.. [10] Sattler JM (2008). . 54. J.. Behaviour Research and Therapy. Reporting practices and APA editorial policies regarding statistical significance and effect size. Confidence intervals are used when calculating the change from pre-test to post-test. Hageman-Arrindel The Hageman-Arrindel[15] calculation of clinical significance involves indices of group change and of individual change. References [1] Cohen. Reliability scores are used to bring the pre-test scores closer to the mean. Ladany. [16] Linear and Nonlinear Modeling is used to calculate change estimates for each participant. C. J. (1991). (2000). Behaviour Research and Therapy. P.. The American Psychologist. and recovered. Nilsson. Psychotherapy outcome research: Methods for reporting variability and evaluating clinical significance. Hoboken (NJ): Wiley. (1997). 49 (12). T.. [12] Hsu. D. J. [2] Haase. & Truax.C. and Revenstorf. [7] Cohen. A. "Clinical" Significance: "Clinical" Significance and "Practical" Significance are NOT the Same Things. Online Submission. so greater actual change in scores is necessary to show clinical significance. wiley.. 36(4).V. (1995).[4] 62 Edwards-Nunnally [13] of calculating clinical significance is a more stringent alternative to the The Edwards-Nunnally method [14] Jacobson-Truax method. LA. and then a confidence interval is developed for this adjusted pre-test score. Online Submission. (1989). & APA Task Force on Statistical Inference. R. [5] Vacha-Hasse.05).. A second index. Lance. P. Follette. D. Five methods for computing significant individual client change and improvement rates: Support for an individual growth curve approach. except that it takes into account regression to The Gulliksen-Lord-Novick method the mean.). N.F. ISBN 978-0-471-73553-3. not reliably changed. W. 15(4). L. Paper presented at the Annual Meeting of the Southwest Educational Research Association (New Orleans. [3] "Clinical" Significance: "Clinical" Significance and "Practical" Significance are NOT the Same Things. 63. "Clinical" Significance: "Clinical" Significance and "Practical" Significance are NOT the Same Things. 413-425. M. [15] Hageman. (2008). [14] Peterson. 594. 49 (12). [9] Jacobson. [4] Peterson. Assessment of children: Cognitive foundations (5/e). J.R.S. Statistical methods in psychology journals: Guidelines and explanations. Theory & Psychology.

shortening it more (output per hour went up. Researchers concluded that the workers worked harder because . In the experiment room.[10] In the lighting studies. This measuring began in secret two weeks before moving the women to an experiment room and continued throughout the study. Evaluation of the Hawthorne effect continues in the present day. Only occasionally are the rest of the studies mentioned. Some of the variables were: • giving two 5-minute breaks (after a discussion with them on the best length of time). com/ hlm/ index. The term was coined in 1950 by Henry A. Landsberger[3] when analysing older experiments from 1924-1932 at the Hawthorne Works (a Western Electric factory outside Chicago). Although illumination research of workplace lighting formed the basis of the Hawthorne effect. but when they received six 5-minute rests. Relay assembly experiments In one of the studies. but overall output decreased). Output was measured mechanically by counting how many finished relays each worker dropped down a chute. Thus the term is used to identify any type of short-lived increase in productivity. and then changing to two 10-minute breaks (not their preference). they had a supervisor who discussed changes with them and at times used their suggestions. However it is said that this is the natural process of the human being to adapt to the environment without knowing the objective of the experiment occurring. and even relocating workstations resulted in increased productivity for short periods. It was suggested that the productivity gain occurred because the workers were impacted by the motivational effect of the interest being shown in them.[3] [4] [5] Historia The term gets its name from a factory called the Hawthorne Works. ssicentral.Clinical significance [16] http:/ / www. • providing food during the breaks • shortening the day by 30 minutes (output went up). Then the researchers spent five years measuring how different variables impacted the group's and individuals' productivity.[6] where a series of experiments on factory workers was carried out between 1924 and 1932. experimenters chose two women as test subjects and asked them to choose four other workers to join the test group. Together the women worked in a separate room over the course of five years (1927–1932) assembling telephone relays. Hawthorne Works had commissioned a study to see if its workers would become more productive in higher or lower levels of light. Changing a variable usually increased productivity. The workers' productivity seemed to improve when changes were made and slumped when the study was concluded. they disliked it and reduced output. light intensity was altered to examine its effect on worker productivity.[1] [2] not in response to any particular experimental manipulation. html 63 Clinical trial effect The Hawthorne effect is a form of reactivity whereby subjects improve or modify an aspect of their behavior being experimentally measured simply in response to the fact that they are being studied. clearing floors of obstacles. even if the variable was just a change back to the original condition.[7] [8] [9] Most industrial/occupational psychology and organizational behavior textbooks refer to the illumination studies. returning to the first condition (where output peaked). This effect was observed for minute increases in illumination. Productivity increased. other changes such as maintaining clean work stations.

The cliques served to control group members and to manage bosses. when bosses asked questions. not testing factors separately. A lot to do with feeling free. The experimental manipulations were important in convincing the workers to feel this way: that conditions were really different.[11] The study was conducted by Elton Mayo and W. and having a sympathetic supervisor were the real reasons for the productivity increase. on the grounds that they have not been properly published and so he cannot get at details. McIlvaine Parsons (1974) argues that in the studies where subjects received feedback on their work rates. The researchers found that although the workers were paid according to individual productivity. In more detail: 50% of a SD for up to 4 weeks. was that "the six individuals became a team and the team gave itself wholeheartedly and spontaneously to cooperation in the experiment. being treated as special (as evidenced by working in a separate room). Workers apparently had become suspicious that their productivity may have been boosted to justify firing some of the workers later on. p. Richard E. 30% of SD for 5–8 weeks. Sugrue (1991. and 20% of SD for > 8 weeks.e. productivity decreased because the men were afraid that the company would lower the base rate. learning effects." (There was a second relay assembly test room study whose results were not as significant as the first experiment. He also argues that the rest periods involved possible learning effects. clique members gave the same responses. . These results show that workers were more responsive to the social force of their peer groups than to the control and incentives of management. Researchers hypothesized that choosing one's own coworkers. He does say that this experiment is about testing overall effect.Clinical trial effect they thought that they were being monitored individually. (which is < 1% of the variance). because of the sympathy and interest of the observers. the results should be considered biased by the feedback compared to the manipulation studies. and the fear that the workers had about the intent of the studies may have biased the results. One interpretation. The experiment was repeated with similar effects on mica splitting workers. But Mayo says it is to do with the fact that the workers felt better in the situation. His key argument is that in the studies where workers dropped their finished goods down chutes. 50%-63% score rise). not feeling supervised but more in control as a group. both permanent skill improvement and feedback-enabled adjustments to suit current goals]. mainly due to Elton Mayo. He also discusses it not really as an experimenter effect but as a management effect: how management can make workers perform differently because they feel differently. even if they were untrue.e. Detailed observation between the men revealed the existence of informal groups or "cliques" within the formal groups. which decays to small level after 8 weeks. working as a group. 333) in a review of educational research say that uncontrolled novelty effects cause on average 30% of a standard deviation (SD) rise (i. Lloyd Warner between 1931 and 1932 on a group of fourteen men who put together telephone switching equipment. Parsons defines the Hawthorne effect as "the confounding that occurs if experimenters fail to realise how the consequences of subjects' performance affect what subjects do" [i. These cliques developed informal rules of behavior as well as mechanisms to enforce them. whereas he had extensive personal communication with Roethlisberger and Dickson. Clark and Timothy F. It is notable however that Parsons refuses to analyse the illumination experiments.) 64 Bank wiring room experiments The purpose of the next study was to find out how payment incentives would affect productivity. the "girls" had access to the counters of their work rate. It is possible that the illumination experiments were explained by a longitudinal learning effect. Interpretation and criticism H. The surprising result was that productivity actually decreased.

Dr..[13] The Hawthorne effect has been well established in the empirical literature beyond the original studies.".1186/1471-2288-7-30. and an experiment may give them this for the first time. com/ 1471-2288/ 7/ 30). Fisher P (2007). economists Steven Levitt and John A.[14] but also.[15] In a 2011 paper. assemblymag. if they act on it or do not see it as in their interest. doi:10. journals. elsevier. This can affect whether participants believe something.[16] If so. There is less certainty about the nature of the surprise factor. 141 (2): 111–4. nlm. Landsberger. Chasen ST (December 2008). as in the interpretation of Mayo and his followers but rather a system of power. Rosenthal and Jacobson (1992) ch. PMID 18771841. improving their performance by improving their skill will be dependent on getting feedback on their performance. The experiments stand as a warning about simple experiments on human participants viewed as if they were only material systems. webpage: Arnewood-motivation2 (http:/ / www.' he said. J. nor a system of informal group relations. [2] Fox NS.ejogrb. Obstet. So he thinks it is not awareness per se. Dr. org& rfr_dat=cr_pub=ncbi. of class antagonisms". So for Adair. "Clinical estimation of fetal weight and the Hawthorne effect" (http:/ / linkinghub. [6] "The Hawthorne Works" from Assembly Magazine (http:/ / www. com/ retrieve/ pii/ S0301-2115(08)00300-X). other than it certainly depended on the mental states of the participants: their knowledge. The output ("dependent") variables were human work. van Haselen R. "Variability in the Hawthorne effect with regard to hand hygiene performance in high. 1086/ 595692?url_ver=Z39. So you often will not see any Hawthorne effect—only when it turns out that with the attention came either usable feedback or a change in motivation. calls the Hawthorne effect 'a glorified anecdote.Clinical trial effect A psychology professor at the University of Michigan. edu/ doi/ abs/ 10. Angela M. "The Hawthorne Effect: a randomised. 88-2003& rfr_id=ori:rid:crossref. This discovery was a blow to those hoping to apply the behavioral sciences to manipulate workers in the interest of management. etc. nor special attention per se.11 also reviews and discusses the Hawthorne effect.[17] [18] 65 References [1] McCarney R. this confirms the analysis of SRG Jones's 1992 article examining the relay experiments. Talbot EA. Hawthorne Revisited. beliefs.07. Gynecol. The Hawthorne study showed "that the performance of workers had little relation to ability and in fact often bore an inverse relation to test scores.. Brennan JS. etc.023. the issue is that an experimental effect depends on the participants' interpretation of the situation. htm).' 'Once you have got the anecdote. and the educational effects can be expected to be similar (but it is not so obvious that medical effects would be). [5] "MOTIVATION AT WORK: a key issue in remuneration". controlled trial" (http:/ / www. BMC Med Res Methodol 7: 30. Infect Control Hosp Epidemiol 30 (3): . 1958. Research on the demand effect also suggests that people might take on pleasing the experimenter as a goal. biomedcentral.2008. at least if it does not conflict with any other motive. Ithaca. PMID 17608932. Reprod.1016/j. Smith R. but participants' interpretation must be investigated in order to discover if/how the experimental conditions interact with the participants' goals. 'you can throw away the data. [3] Henry A. Griffin M. Braverman argues that the studies really showed that the workplace was not "a system of bureaucratic formal organisation on the Weberian model. nih. The Social Problems of an Industrial Civilisation.'"[12] Harry Braverman points out in Labor and Monopoly Capital: The Degradation of Work in the Twentieth Century that the Hawthorne tests were based on industrial psychology and were investigating whether workers' performance could be predicted by pre-hire testing. Biol. He argues that it should be viewed as a variant of Orne's (1973) experimental demand effect. Iliffe S. net/ studentzone/ subjects/ business/ motivate/ motivation2.and low-performing inpatient care units" (http:/ / www. Taylor E. Kirkland KB (March 2009). 1949. Warner J. . PMC 1936999. [4] Elton Mayo. gov). Routledge. Bowey. Richard Nisbett. and so the original conclusions were overstated. com/ CDA/ Archives/ 0cdaaa2e0d5c9010VgnVCM100000f932a8c0____) [7] Kohli E. Hawthorne and the Western Electric Company. List claim that in the illumination experiments the variance in productivity is partly accounted for by other factors such as the weekly cycle of work or the seasonal temperature. doi:10. that this is why manipulation checks are important in social sciences experiments. Adair (1984): warns of gross factual inaccuracy in most secondary publications on Hawthorne effect and that many studies failed to find it. Eur. uchicago. . Ptak J. arnewood.

"Communication by the total experimental situation: Why is it important. . B. H.1. James M. • Mayo. "Was There Really a Hawthorne Effect at the Hawthorne Plant? An Analysis of the Original Illumination Experiments". W. Social Science and Medicine 69 (9): 2330–2340. doi:10. doi:10. elsevier. [18] Jones. In Pliner. (1987). R. doi:10.1016/j. Ithaca.1257/app. • Clark. Manufacturing knowledge: a history of the Hawthorne experiments. (1968. • Jastrow (1900). G.] • Bramel. . asp?typ=fulltext& file=000147951).1257/app. • Jones. Elton (1933). jstor. present. • Levitt. American Psychologist 36 (8): 867–878. 724-7238 [15] Rosenthal. doi:10. Instructional technology: past. Sociology: a down to earth approach (9th ed. economist.224. L. D. • Leonard.867.Clinical trial effect 222–5. (1984).. 140. "Hawthorne. (20 March 2004). American Journal of Sociology 98 (3): 451–468. New Scientist 181 (2439): 42–45. (1973). J. T. nytimes. . siop. American Journal of Sociology 98 (3): 451–468. (2011).8. Monthly Review Press. (1981). com/ finance/ displaystory. "The Hawthorne effect: A reconsideration of the methodological artifact". Stephen R.06. and future. "Erectile dysfunction after therapy with metoprolol: the hawthorne effect" (http:/ / content. doi:10.3. • Landsberger.334. • Orne.004. "Was there a Hawthorne effect?" (http://www. & Sugrue. M. [17] Light work (http:/ / www. 327–343. L. doi:10.). and its significance for the ecological validity of findings". John A. T. [8] Cocco G (2009). Elton (1949). NY.jhealeco.2006. G. ed. G. Anglin. PMID 19199530. affect. The Journal of Applied Psychology 85(5).69. M. ISBN 0521403588. Labor and Monopoly Capitalism. Journal of Applied Psychology 69 (2): 334–345. New York Times.1016/j. . Fact and fable in psychology. . December 6. Gael Elton (1984). E. 66 Further reading • Adair. • Gillespie.1159/000147951. Harry. com/ 1998/ 12/ 06/ weekinreview/ scientific-myths-that-are-too-good-to-die. (2000) "Goal orientation and task demand effects on motivation. M. • Mayo. and performance". "Was There Really a Hawthorne Effect at the Hawthorne Plant? An Analysis of the Original Illumination Experiments". (2011).2007. Krames.3. Hawthorne Revisited. C.1037/0021-9010. p. methodological issues..1016/0883-0355(87)90001-2. K. [16] Levitt. Richard (1991). John A. ISBN 0704323605. p. New York: MacMillan.. • Lovett. List.1086/595692. Henry A. ISBN 0872878201.36. 1974.. (2008).socscimed. R. R. ISBN 978-0-205-57023-2..1037/0003-066X. (1992). 80. 1992) Pygmalion in the classroom: Teacher expectation and pupils' intellectual development. (1958). R.2. J Health Econ 27 (2): 444–59. cfm?story_id=13788427). G. pdf) [11] Henslin.224. Alloway. [12] Kolata. G. The Economist.. doi:10. "Running on empty".. "Outpatient process quality evaluation and the Hawthorne effect". (1992).. html) [13] Braverman. Englewood. [14] Steele-Johnson.jstor. • Marsh. Cambridge: Cambridge University Press. American Economic Journal: Applied Economics 3 (1): 224–238. London: Quartet. American Economic Journal: Applied Economics 3 (1): 224–238. and class bias in psychology". the myth of the docile worker. Colorado: Libraries unlimited. List. PMID 18654082. & Jacobson. Masatu. June 6th 2009. • Mayo. Steven D. (1991).1. Routledge. PMID 18192043. P. "Was there a Hawthorne effect?" (http:/ / www. Steven D. International Journal of Educational Research 11 (3): 253–388. Pearson Education. The human problems of an industrial civilisation. Irvington publishers: New York.003. [9] Leonard KL (March 2008). pp. org/ stable/ 2781455). The Mad Mosaic: A Life Story. (2006). doi:10. com/ retrieve/ pii/ S0167-6296(07)00095-1). Stephen R. doi:10. how it is evaluated. (1998) "Scientific Myths That Are Too Good to Die". pp144-5. "Is patient satisfaction sensitive to changes in the quality of care? An exploitation of the Hawthorne effect" (http:/ / linkinghub. com/ produktedb/ produkte.org/stable/2781455). Boston: Houghton Mifflin. Hawthorne and the Western Electric Company. and directions for future research". "Student's evaluations of university teaching: research findings. (http:/ / www. karger. L. [10] What We Teach Students About the Hawthorne Studies: A Review of Content Within a Sample of Introductory I-O and OB Textbooks (http:/ / www. Friend. The Social Problems of an Industrial Civilisation. D.07. org/ tip/ backissues/ Jan 04/ pdf/ 413_023to039. [Reviews references to Hawthorne in the psychology methodology literature. Cardiology 112 (3): 174–7.

Science 183 (4128): 922–932.922..html). J. 157–191. M. P. by Stephen W.4128. A. . • BBC Radio 4: Mind Changers: The Hawthorne Effect (http://www. • Schön. Pygmalion.edu/hc/ hawthorne/intro. New York: Academic Press. pp.hbs. in a more accessible source. MA: Harvard University Press. • Zdep. London: Routledge.183. M.. (1983). Draper. London: Weidenfeld & Nicolson.library. Shayer. Abraham (2005). J. "A reverse Hawthorne effect in educational evaluation". "What happened at Hawthorne?: New evidence suggests the Hawthorne effect resulted from operant reinforcement contingencies". Harvard Business School.psy. R. • Parsons. (1970). "Problems and issues in intervention studies".html). Cambridge. (1992).1016/0022-4405(70)90025-7. A. The reflective practitioner: How professionals think in action. Fritz J. D. S. Experimenter effects in behavioral research.uk/iplayer/episode/b00lv0wx/ Mind_Changers_Series_4_The_Hawthorne_Effect/) • Harvard Business School and the Hawthorne Experiments (1924-1933) (http://www.] • Roethlisberger. D. (1939). ISBN 0415054710. Journal of School Psychology 8 (2): 89–95. In Demetriou. S. ISBN 0297842552. doi:10.. doi:10. University of Glasgow.co. New York: Appleton. The national teaching and learning forum 8 (2): 1–4. 67 External links • The Hawthorne. 107–121. & Zaleznik. Richard C. (1999). London: Temple Smith. "Pygmalion in the classroom". (1966). used to argue that the effect was due to feedback-promoted learning. • Trahair. ISBN 0851172318. pp. Irvine.Clinical trial effect Communication and affect. H. ISBN 0120530503. [A very detailed description. Neo-Piagetian theories of cognitive development: implications and applications for education.. (1974).uk/ ~steve/hawth. S. Efklides. • Wall. W. Department of Psychology. Elton Mayo: The Humanist Temper. • Rhem. ISBN 1412805244. placebo and other expectancy effects: some notes (http://www. of some of the experiments. A.. London: Transaction Publishers.ac. M. (1999).bbc. • Rosenthal. Pain: the science of suffering. Dickson. Management and the Worker. H. • Shayer. M.1126/science.gla.

what types of people may participate in the trial. The format and content of clinical trial protocols sponsored by pharmaceutical. Regulatory authorities in Canada and Australia also follow the ICH guidance. procedures. fda. European Union. design. The existence of a clinical trial protocol allows researchers at multiple locations (in a multicenter trial) to perform the study in exactly the same way. The plan is designed to safeguard the health of the participants (while limiting their financial liability) as well as answer specific research questions. html#1 [2] http:/ / www. methodology. the schedule of tests. The protocol also gives the study administrators (often a contract research organization) as well as the local researchers a common reference document for the researchers' duties and responsibilities during the trial. or Japan has been standardized: they are written to follow the [1] issued by the International Conference on Harmonization of Technical Good clinical practice guidance Requirements for Registration of Pharmaceuticals for Human Use (ICH) [2]. purposefully publish trial protocols. study participants are seen regularly by the research staff (usually medical doctors and/or nurses) to monitor their health and to determine the safety and effectiveness of the treatment(s) they are receiving. Clinical trial protocols for other clinical trials do not necessarily follow the standard format. and dosages. The protocol usually also gives the background and reason the trial is being conducted. so that their data can be combined as though they were all working together. but these could be provided in other documents referenced in the protocol (such as an Investigator's Brochure). org . The protocol describes. ich. References [1] http:/ / www. statistical considerations. The protocol contains a study plan on which the clinical trial is based. and organization of a clinical trial. medications. Some journals. and the length of the study. While in a clinical trial. gov/ cdrh/ guidance-about. such as Trials.Clinical trial protocol 68 Clinical trial protocol A clinical trial protocol is a document that describes the objective(s). biotechnology or medical device companies in the United States. among other things.

Ungerleider. . "Assessing Whether to Perform a Confirmatory Randomized Clinical Trial" (http://jnci. pdf) (PDF)." Basic outline of the process of a Confirmatory Trial 1. The target patient population segmented for the trial is clearly outlined.org/cgi/reprint/88/22/1645. 4. Mahesh K.. Retrieved 2010-02-26 Further reading • Parmar. 2. understood and defined as this may influence the test sites and scientists (practitioners. Retrieved 2010-02-26. the quantity of effects and relating these effects to their clinical significance. 1998-02-05.B. ich.1645. . is established as part of the initial protocol. According to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: "Confirmatory Trials are intended to provide firm evidence in support of claims and hence adherence to protocols and standard operating procedures is particularly important. 3. doi:10. unavoidable changes [1] should be explained and documented. specialists.) involved. The Confirmatory Trial should clarify key clinical questions relevant to efficacy an/or safety clearly and definitively.1093/jnci/88. References [1] "Statistical Principles for Clinical Trials" (http:/ / www. A design justification and statistical aspects such as the principal features of the planned analysis. and their effect examined.oxfordjournals. org/ LOB/ media/ MEDIA485. PMID 8931608.pdf) (PDF). etc. Journal of the National Cancer Institute 88 (22): 1645–51. Richard S. This type of trial may be implemented when it is necessary to provide additional or firm evidence of efficacy or safety. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The mechanism of the trail implements a key hypothesis of interest which is rigorously tested at the end of the Confirmatory Trial and directly follows the predefined primary objective of the trial.22.Confirmatory trial 69 Confirmatory trial A Confirmatory Trial can be defined as an adequately controlled trial where hypotheses are stated in advance and evaluated according to a protocol. The Confirmatory Trial should be concise in addressing only a specific number of questions. ICH. Of importance in a Confirmatory Trial is the process of estimating with due precision potential effects attributable to the treatment. Richard Simon (1996-11-20).

g. epidemiologists. This meeting resulted in the Standardized Reporting of Trials (SORT) statement. Canada to discuss ways of improving the reporting of randomized trials. This group also published recommendations for authors reporting randomized trials. along with some brief descriptive text. [10] acupuncture [11] ).[14] in 1995 representatives from both these groups met in Chicago. a third CONSORT Group meeting was held in 2007 resulting in publication of a newly revised CONSORT Statement [2] and explanatory document [3] in 2010. Drummond Rennie. clinical trialists. and work is ongoing. and aiding their critical appraisal and interpretation.[2] Considered an evolving document[3] . The CONSORT Statement The main product of the CONSORT Group is the CONSORT Statement [1]. another group of experts. herbals.consists of a 25-item checklist and a participant flow diagram.medical journal editors. the Asilomar Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature. minimum set of recommendations for reporting randomized trials. and independently.Consolidated Standards of Reporting Trials 70 Consolidated Standards of Reporting Trials CONSORT (Consolidated Standards Of Reporting Trials) encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials.[4] noninferiority and equivalence trials. 30 experts . the flow diagram displays the progress of all participants through the trial.[16] Since the revision in 2001. coherent evidence-based recommendation..g. from JAMA. It offers a standard way for authors to prepare reports of trial findings. facilitating their complete and transparent reporting. This list is.[2] which is an evidence-based. reducing the influence of bias on their results.. the evidence base to inform CONSORT has grown considerably.[7] abstracts[8] ).g. and methodologists . the CONSORT Statement is subject to periodic changes as new evidence emerges. analyzed. data (e. cluster randomized trials.[12] a 32-item checklist and flow diagram in which investigators were encouraged to report on how randomized trials were conducted. and were working on a similar mandate. The most recent version of the Statement .[9] non-pharmacologic treatments. Users of the guideline are strongly recommended to refer to the most up-to-date version while .the CONSORT 2010 Statement . Extensions of the CONSORT Statement have been developed to give additional guidance for randomized trials with specific designs (e. The Statement has been translated into several languages.[6] ). The checklist items focus on reporting how the trial was designed. and interventions (e. empirical data highlighting new concerns regarding the reporting of randomized trials. with the aim of merging the best of the SORT and Asilomar proposals into a single. USA.[15] Further meetings of the CONSORT Group in 1999 and 2000 led to the publication of the revised CONSORT Statement in 2001. which was first published in 1996. Concurrently. [3] The CONSORT ‘Explanation and Elaboration’ document explains and illustrates the principles underlying the CONSORT Statement. by no means.[13] At the suggestion of Dr. Therefore. Extensions of the CONSORT Statement The main CONSORT Statement is based on the 'standard' two-group parallel design. exhaustive. It is strongly recommended that it is used in conjunction with the CONSORT Statement. History In 1993. and interpreted. convened in California.[5] pragmatic trials. USA.. This resulted in the Consolidated Standards of Reporting Trials (CONSORT) Statement. The current definitive version of the CONSORT Statement and up-to-date information on extensions are placed on the CONSORT website [1]. harms.met in Ottawa. the most recent update was published in March 2010.

BMJ 2008. Haynes B. 2010 Jun 8. Another indication of CONSORT’s impact is reflected in the approximately 17. consort-statement. org/ mod_product/ uploads/ 3559_STRICTA AIM 2010. JAMA 1996. Reporting randomized. New England Journal of Medicine. [13] Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature. org/ mod_product/ uploads/ CONSORT Extension for Non-inferiority and Equivalence Trials 2006. Simel D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. pdf) [5] Piaggio G. org [2] Schulz KF. STRICTA Revision Group. consort-statement. [15] Begg C. Moher D. Extending the CONSORT Statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Treweek S. Cho M. JAMA 2006. consort-statement. (http:/ / www. CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. org/ mod_product/ uploads/ CONSORT Extension for Cluster Trials 2004. Ann Intern Med 2008: 148(4):295-309. (http:/ / www. The Standards of Reporting Trials Group. Youping L. JAMA. Call for comments on a proposal to improve reporting of clinical trials in the biomedical literature. Barnes J. 273(13):1054-1055. BMJ. Moher D. Hopewell S. conducting and interpretation of clinical trials. Moher D. Hammerschlag R. pdf) [10] Boutron I. 134(8):657-662.200 times and the accompanying explanatory document over 500 times. Elbourne DR. Schulz K. Altman DG. PLoS Med. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. org/ mod_product/ uploads/ CONSORT Extension for Non-Pharmacologic Treatements 2008 . Moher D for the CONSORT and Pragmatic Trials in Healthcare (Practihc) group. Moher D. (http:/ / www. (http:/ / www. Oxman AD. 121(11):894-895. 2010 Mar23. org/ mod_product/ uploads/ CONSORT Statement 2001 (Ann Intern Med). pdf) [6] Zwarenstein M. Evans SJ. Elbourne DR. Altman DG. Altman DG. An experiment and a call for responses from readers. Tunis S. consort-statement.[17] Results from a recent systematic review suggest that use of the CONSORT checklist is associated with improved reporting of randomized trials. (http:/ / www. 141(10):781-788. Devereaux PJ. 1994. org/ mod_product/ uploads/ CONSORT Extension for Harms 2004.340:c869 [4] Campbell MK.Explanatory document. [14] Rennie D. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. O'Neill RT. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. 328(7441):702-708. Ravaud P. Bombardier C. Altman DG. Horton R. Egger M. consort-statement. (http:/ / www. Altman DG. pdf) . Schulz KF. and International Committee of Medical Journal Editors. Moher D. consort-statement.Explanatory document. Rennie D. BMJ. consort-statement. CONSORT Group. 276(8):637-639. Gagnier JJ. 71 Impact The CONSORT Statement has gained considerable support since its inception in 1996.[18] References [1] http:/ / www. (http:/ / www. Boon H. Schulz K. pdf) [7] Ioannidis JP. Schulz KF and the CONSORT Group. including The Lancet. The 2001 revised Statement has been cited over 1. 295:1152-1160. org/ mod_product/ uploads/ CONSORT Extension for Herbal Interventions 2006 (Ann Intern Med). CONSORT statement: extension to cluster randomised trials. BMJ 2004. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. org/ mod_product/ uploads/ CONSORT Extension for Pragmatic trials 2008. Gotzsche PC. A proposal for structured reporting of randomized controlled trials. Reporting of noninferiority and equivalence randomized trials: An extension of the CONSORT statement. Schulz KF. controlled trials of herbal interventions: an elaborated CONSORT statement. World Association of Medical Editors. for the CONSORT Group. Altman DG. 1994. Stroup DF. pdf) [8] Hopewell S. pdf) [9] Gagnier JJ. Middleton P. BMJ. Eastwood S. Schulz KF. Olkin I. [16] Moher D.a2390. Moher D. Rochon P. JAMA 1995.7(6):e1000261 (http:/ / www. Reporting randomized controlled trials.500 hits per month that the CONSORT website has received. Altman DG. 2010. Ann Intern Med 2004. White A. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials . Wager E. Pocock SJ. PLoS Med 2008 5(1): e20. consort-statement. Altman DG. Taixiang W. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. Altman DG. pdf) [11] MacPherson H. Pitkin R. 272(24):1926-1931. Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature. Altman DG. consort-statement. Ann Intern Med 2001. org/ mod_product/ uploads/ CONSORT Extension for Abstracts 2008 . Clarke M. 337. It has also recently been published as a book for those involved in the planning.Consolidated Standards of Reporting Trials writing or interpreting reports of clinical trials. consort-statement. pdf) [12] The Standards of Reporting Trials Group. Ann Intern Med 2006. Moher D. JAMA. Gøtzsche PC. (http:/ / www. Elbourne D. over 600 journals and editorial groups worldwide now endorse it.340:c332 [3] Moher D. Evans SJW. Montori V. 144(5):364-367.

The main reasons for this is to avoid trials in the later phases using doses that are significantly different from those that will subsequently be recommended for clinical use and also to avoid the need for modification of dosing schedules at later stages where a large amount of data has already been accumulated for a different dose range. so as to analyze the efficacy and safety of the drug.Consolidated Standards of Reporting Trials [17] Keech A. Does the CONSORT checklist improve the quality of reports of randomised controlled trials? A systematic review. Hill C. and to provide it to the health authorities. Dose Finding in Drug Development. . a drug) are tested against each other to establish which dose works best and/or is least harmful. low-dose group. Schulz K. Moher D.g. Med J Aust 2006. 2007: Australasian Medical Publishing: NSW. dose given. A theoretical and practical guide. ISBN 0849321859. For these purposes the sponsor has to protect my personal information even in countries whose data privacy laws are less strict than those of this country. medium-dose group and a high-dose group.[2] References [1] Ting. Although such a response will nevertheless be available from phase III or phase IV trials. I will not be referred to by my name in any report of the study. The maximum tolerable dose (MTD) information is necessary to be able to design such groups and therefore dose-ranging studies are usually designed after the availability of MTD information. 185(5):263-267. My identity will not be disclosed to any person. except for the purposes described above and in the event of a medical emergency or if required by the law. Altman DG. [2] Lee. [18] Plint AC. A typical patient declaration might read: “ I have been informed of the benefit that I gain from the protection and the rights granted by the European Union Data Protection Directive and other national laws on the protection of my personal data. Gebski VJ. Gaboury I. Dose-ranging is usually a phase I or early phase II clinical trial. ISBN 0387290745.[1] The main goal of a dose-ranging study is to estimate the response vs. a typical dose-ranging study may include four groups: a placebo group. Pike R. ISBN 978-3-940934-00-0 Dose-ranging study A dose-ranging study is a clinical trial where different doses of an agent (e.My data will be processed electronically to determine the outcome of this study. A guide to the CONSORT Statement and the principles of randomised controlled trials. For instance. Chi-Jen (2005).I agree that the representatives of the sponsor or possibly the health authorities can have access to my medical records. Interpreting and reporting clinical trials. Clinical Trials Of Drugs And Biopharmaceuticals. Conducting clinical trials. and a few groups that receive different doses of the test drug. (2008). Morrison A. it is important to carry out dose-ranging studies in the earlier phase I or phase II stages. Naitee (2006). My participation in the study will be treated as confidential. Australia. 72 Data confidentiality in clinical trials Due to the EU Directive 2001/20/EC the inspectors appointed by the Member States have to maintain the confidentiality whenever they gain access to the confidential information as a result of the good clinical practice inspections in the accordance with the applicable national and international requirements. Springer-Verlag. CRC Press. Typically a dose ranging study will include a placebo group of subjects. ” References AR Waladkhani. My data may be transferred to other countries (such as the USA).

Dublin Molecular Medicine Centre 73 Dublin Molecular Medicine Centre Dublin Molecular Medicine Centre (DMMC) was set up in 2002. to create critical mass in molecular medicine research in Dublin. The objective of this initiative is to create an internationally recognised centre of research excellence by 2010. • A network of new clinical research facilities linking the proposed new centre to existing centres at Beaumont [6] Hospital. haematological. cervical. neuropsychiatric genetics and nutrigenomics. as a registed charity. New Clinical Research Centre DMMC has successfully secured funding from the Wellcome Trust for a major clinical research centre to be led by Professor Dermot P. St. • TCD Institute of Molecular Medicine[4] focuses on cancer (prostate. A transgenic facility to create disease models using transgene single-cell microinjection and knockout technologies is in place. Vincent’s University Hospital Dublin • Establishment of trans-institutional research consortium in prostate cancer. cell signalling. molecular histopathology. advanced drug delivery. Resources The academic resources supporting the teaching hospitals include: • UCD Conway Institute of Biomolecular & Biomedical Research[2] which is organised into 3 interactive multi-disciplinary centres : synthesis and chemical biology. esophageal. • Comprehensive and flexible cross-institution education and training programmes in molecular medicine • New technology cores in transcriptomics. Funding was provided by the Higher Education Authority[1] . James's Hospital. . proteomics and pharmacy. cell imaging and bioinformatics. Ireland. the Royal College of Surgeons in Ireland (RCSI) and Trinity College. • National Biocollection Resource for study of psychosis. Galway to create a nationwide platform as the European Union launches the Seventh Framework Programme. Strategic links are likely to be fostered with University College Cork and National University of Ireland. Dublin . genomic research into inflammatory disease. Dublin (TCD). DMMC is owned jointly by the city's three premier biomedical research institutions : University College Dublin (UCD). integrative biology and molecular medicine. Kelleher for Dublin comprising two elements: • A new centre will be built at St. [3] • RCSI Research Institute whose portfolio included cellular neuroscience. Dublin[5] . proteomics. Vincent’s University Hospital Dublin and Mater Misericordiae University Hospital Other Accomplishments • New laboratory facilities in each of the Dublin colleges • Genome Research Units at the Mater Misericordiae University Hospital and St. thoracic). infection and immunity (tuberculosis). molecular research.

ie/ [12] http:/ / www. ie/ documents/ DMMC%20Annual%20Report%202005. Kelleher. ucd. Dublin [14] • Higher Education Authority of Ireland [15] References [1] Home Page | Higher Education Authority | An tÚdarás um Ard-Oideachas (http:/ / www. Dublin William G Powderly MD. ie/ conway/ ) [3] (http:/ / www. ie/ research2/ index. beaumont. tcd. mater. ie/ IMM/ [11] http:/ / www. ie/ [6] Beaumont Hospital. stjames. ucd. Head of Medical School. htm/ [10] http:/ / www. beaumont. Director of RCSI Institute Externals links • • • • • • • • DMMC 2005 Annual Report [7] UCD Conway Institute of Biomedical Research [8] RCSI Research Institute [9] TCD Institute of Molecular Medicine [10] St. rcsi. ie/ [14] http:/ / www. stjames. Chief Executive DMMC Dermot P. ie/ [15] http:/ / hea.Home Page (http:/ / www. stvincents. Dublin [12] St James Hospital. rcsi. UCD Brian Harvey PhD. Vincent's University Hospital. ie/ research2/ index. dmmc. ie) [2] UCD Conway Institute – Scientific Research. hea. ie/ conway/ [9] http:/ / www.Dublin Molecular Medicine Centre 74 Key Personnel • • • • • Michael Kamarck PhD. Dublin [13] Beaumont Hospital. Dublin [11] Mater Misericordiae University Hospital. ie/ ) [7] http:/ / www. Trinity College. Chair of the DMMC Board. ie/ [13] http:/ / www. Ireland . tcd. pdf/ [8] http:/ / www. ie/ . htm) [4] (http:/ / www. Innovation & Outreach (http:/ / www. Dublin. ie/ IMM/ ) [5] http:/ / www. Postgraduate Education. Head of School of Medicine and Medical Science. Senior VP Wyeth Biopharma Pierre Meulien PhD.

Just as in the survival curves not all patients die. thus it picks up death from side effects of the treatment. and effects on survival after relapse. in justifying a marketing approval).findpharma. The people who relapse are still surviving but they are no longer disease-free. The patients who don't respond aren't included. A trial might also define one or more secondary endpoints such as median progression-free-survival (PFS) that will be measured and are expected to be met. This endpoint involves selecting a subgroup of the patients. In the disease free survival. (2008).org/endpoints. the curve for the actual survival would look better than disease free survival curve. Overall survival Overall survival is based on death from any cause. It measures the length of the response in those patients who responded. not just the condition being treated. Response duration The response duration is occasionally used to analyze the results of the treatment for the advanced disease. A trial might also define exploratory endpoints that are less likely to be met. Because the patients survive for at least some time after the relapse. Measuring the selected endpoints is the goal of a trial. The event for the progression free survival is that the disease gets worse or progresses. Progression free survival The Progression Free Survival is usually used in analysing the results of the treatment for the advanced disease.com/pharmrep/Clinical+Selling/ The-Clinical-Side-Clinical-trial-endpoints/ArticleStandard/Article/detail/108378) • Endpoints: How the Results of Clinical Trials are Measured (http://cancerguide. The event is progression of the disease (relapse). such as surgery or surgery plus adjuvant therapy. in "disease free survival curves" not all patients relapse and the curve may have a final plateau representing the patients who didn't relapse after the study's maximum follow-up. The response rate and survival are examples of the endpoints. A clinical trial will usually define or specify a primary endpoint as a measure that will be considered success of the therapy being trialled (eg. A theoretical and practical guide. Typical cancer trial endpoints Disease free survival The disease free survival is usually used to analyse the results of the treatment for the localized disease which renders the patient apparently disease free.html) . the event is relapse rather than death. The primary endpoint might be a statistically significant improvement in median overall survival (OS).End point of clinical trials 75 End point of clinical trials An endpoint is something which is measured in a clinical trial or study. ISBN 978-3-940934-00-0 External links • Clinical trial endpoints (http://pharmrep. Conducting clinical trials. References AR Waladkhani.

ensuring adequate quality standards through audit procedures and an ability to conducts cross-border projects that comply with good clinical practice. France. If ECRIN succeeds in helping to create a Europe-wide network of centres sufficient scale will evolve to facilitate EU standards in clinical research and appropriate training. • Support industry and academic multinational clinical studies in Europe.org/) (ECRIN) • European Forum for Good Clinical Practice (http://www. data management and monitoring Quality assurance.500 clinical studies. regulation and insurance Adverse event reporting Methodology. • Promote specialty or disease-specific networks. Germany. to connect national networks of clinical research infrastructures throughout the European Union. These collectively represent 112 medical centres and hospitals that conduct in the region of 1. Denmark.[1] Six European countries participate in ECRIN : (Sweden.europa.European Clinical Research Infrastructures Network 76 European Clinical Research Infrastructures Network The European Clinical Research Infrastructures Network (ECRIN) was established in 2004 with funding from Sixth Framework Programme as a reciprocal knowledge programme. The national participants work in a network together with the European Forum for Good Clinical Practice. standard operating procedure and audits Communication with participants. investigators and sponsors Transparency and clinical trial registries • Education and careers References [1] :: Efgcp Online :: (http:/ / www. Spain and Italy) and the have a transatlantic link with Canada. partnerships Sponsors and funding Ethics and informed consent Legislation. Objectives ECRIN intends to meet the expectations of the EU and the pharmaceutical industry through a harmonisation process. fostering enrolment to same. tools and practices. working multinationally and using cohorts and registries of patients. Removing Bottlenecks A ten-point set of initiatives is being developed across participating member countries to stramline clinical research: • • • • • • • • • Compatible structuring of centres.eu/research/fp6/index_en.ecrin. efgcp.cfm?p=0/) • European Clinical Research Infrastructures Network (http://www. be/ ) External links • Sixth Framework Programme (http://ec.efgcp.be/) . • Improve the quality of clinical research through the compatibility of procedures.

1999) was the first person publicly identified as having died in a clinical trial for gene therapy. both in Europe and abroad. The disease is usually fatal at birth. be/ Jesse Gelsinger Jesse Gelsinger (June 18. broke several rules of conduct: • Inclusion of Gelsinger as a substitute for another volunteer who dropped out. Wilson (U Penn). despite having high ammonia levels that should have led to his exclusion from the trial • Failure by the university to report that two patients had experienced serious side effects from the gene therapy • Failure to disclose. in the informed-consent documentation. but Gelsinger had not inherited the disease.[2] [3] The Gelsinger case was a severe setback for scientists working in the field. September 17. On September 13. The University of Pennsylvania later issued a rebuttal[1] but paid the parents an undisclosed amount in settlement. External links • European Forum for Good Clinical Practices [1] References [1] http:/ / www. efgcp. He was 18 years old. James M.European Forum for Good Clinical Practice 77 European Forum for Good Clinical Practice The European Forum for Good Clinical Practices (EFGCP) is a European think tank which works on the ethical. and scientific framework of clinical research in Europe.September 17. the symptoms of which include an inability to metabolize ammonia . the deaths of monkeys given a similar treatment. leading to multiple organ failure and brain death.a byproduct of protein breakdown. Gelsinger was injected with an adenoviral vector carrying a corrected gene to test the safety of the procedure. Both Wilson and the University are reported to have had financial stakes in the research. at 2:30 pm. 1999. regulatory. Gelsinger suffered from ornithine transcarbamylase deficiency. A Food and Drug Administration (FDA) investigation concluded that the scientists involved in the trial. The EFGCP is committed to the development of the standards for the protection of human subjects and data quality in clinical trials. an X-linked genetic disease of the liver. 1981 . . including the lead researcher Dr. He died four days later. in his case it was the result of a genetic mutation and as such was not as severe .some of his cells were normal which enabled him to survive on a restricted diet and special medications. apparently having suffered a massive immune response triggered by the use of the viral vector used to transport the gene into his cells. Gelsinger joined a clinical trial run by the University of Pennsylvania that aimed at developing a treatment for infants born with severe disease.

uk/science/horizon/ 2003/trialerror. Retrieved 2010-11-16. without the Guatemala informed consent of the subjects. [3] "Don't Compromise Ethics in Human Experiments. Rewards. during the administration of President Truman and President Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials. [2] Greenberg. prostitutes. This resulted [2] in at least 83 deaths . upenn. the U.[1] Information about these experiments was uncovered by Professor Susan Mokotoff Reverby of Wellesley College. "Science for Sale.[1] A total of about 1500 study subjects were involved although the findings were never published. virginia.31613. acknowledged that the Guatemalan work could not be done domestically. Reverby found the documents in 2005 while researching the Tuskegee syphilis study.. Retrieved 2010-11-16. and Delusions of Campus Capitalism". Experiments The experiments were led by United States Public Health Service physician John Charles Cutler.wired. formally apologized to Guatemala for conducting these experiments.guineapigzero. in Cutler's archived papers. Chicago: U.. pages 104-106.the rise and fall of genome therapy: http://www. The Perils.[3] In archived documents.[4] [1] . Thomas Parran.com/news/technology/0.net/2008/01/ on-gene-therapy-and-informed-consent/#comments • BBC Horizon Trial and error . and treated most subjects with antibiotics. Dr. . Jesse's father.co. and details were hidden from Guatemalan officials. who later took part in the late stages of the Tuskegee syphilis experiment. htm). In October 2010.00. law. prisoners and mental patients with syphilis and other sexually transmitted diseases.bioethics.Almanac Between Issues" (http:/ / www.shtml Guatemala syphilis experiment The syphilis experiments in Guatemala were United States-led human experiments conducted in Guatemala from 1946 to 1948. Law.com/jesse. 2008-04-18.S. [4] [5] The experiments were funded by a grant from the National Institutes of Health to the Pan American Sanitary Bureau and involved multiple Guatemalan government ministries. 2007. the U. Bioethics Expert Says" (http:/ / www. Chicago Press. Upenn.html • On gene therapy and informed consent (2008 debate): http://blog. .edu.S. edu/ almanac/ between/ FDAresponse. html).Jesse Gelsinger 78 Notes [1] "Institute for Human Gene Therapy Responds to FDA . edu/ html/ news/ 2008_spr/ milstein. External links • Another Chance For Gene Therapy?: http://www.[1] Doctors infected soldiers. 2/14/2000. Daniel S. tells of Jesse's death: http://www. Jr.bbc. and shared her findings with United States government officials. Surgeon General at the time of the experiments.virginia.edu.html • Paul Gelsinger.1282. 324pp.

. government asked the Institute of Medicine to conduct a review of these experiments. prisoners. and partly because penicillin was costly and in short supply during the war.Guatemala syphilis experiment While the Tuskegee experiment followed the natural progression of syphilis in those already infected. called the experiments "a dark chapter in history of medicine" and commented that modern rules absolutely prohibit conducting human subject research without informed consent. soldiers.[8] [9] In a joint statement. Although some follow-up laboratory testing and patient observation continued until the early 1950s. hhs.[1] When the subjects contracted the disease they were given antibiotics. co. co. uk/ world/ 2010/ oct/ 01/ us-apology-guatemala-syphilis-tests). uk/ news/ world-latin-america-14712089). The researchers paid prostitutes infected with syphilis to have sex with prisoners and some subjects were infected by directly inoculating them with the bacterium. in Guatemala doctors deliberately infected healthy people with the diseases some of which are fatal if untreated. Retrieved 29 August 2011. The subjects for all of the STD experiments consisted of female sex workers. com/ news/ local/ massachusetts/ articles/ 2010/ 10/ 02/ wellesley_professor_unearths_a_horror_syphilis_experiments_in_guatemala/ ).[6] The study appears to have ended in 1948. government formally apologized and announced that there was no statute of limitations for the violation of human rights in that medical research. the U.S. who had called these experiments "a crime against humanity". BBC News. boston. html).[3] President Barack Obama apologized to President Álvaro Colom. Also. Additionally. Public Health Service Sexually Transmitted Diseases (STD) Inoculation Study" (http:/ / www. [3] Chris McGreal (1 October 2010).S. 1 October 2010. the experiments were led by John Cutler.[11] In addition. . or our commitment to human dignity [10] and great respect for the people of Guatemala". gov/ 1946inoculationstudy/ factsheet. partly because of medical “gossip” about the work. and we apologize to all the individuals who were affected by such abhorrent research practices.[1] References [1] "Fact Sheet on the 1946-1948 U." [4] "Wellesley professor unearths a horror: Syphilis experiments in Guatemala" (http:/ / www. Francis Collins. lack of knowledge of and consent for experimental procedures by study subjects. the Presidential Commission for the Study of Bioethical Issues will ask a panel of international experts to review the current state of medical research on humans around the world and ensure that such incidents cannot be repeated.S. Hillary Clinton and Kathleen Sebelius said: "Although these events occurred more than 64 years ago."[7] 79 Apology In October 2010. Democracy Now!. org/ 2010/ 10/ 5/ exposed_us_doctors_secretly_infected_hundreds). Retrieved 12 July 2011. . bbc. "Conducted between 1946 and 1948. The Guardian. the U. 5 October 2010. the Centers for Disease Control and Prevention acknowledges that "the design and conduct of the studies was unethical in many respects. U. a US health service physician who would later be part of the notorious Tuskegee syphilis study in Alabama in the 1960s. The goal of the study seems to have been to determine the effect of penicillin in the prevention and treatment of venereal diseases. although adequate penicillin therapy was prescribed for 76% of subjects. we are outraged that such reprehensible research could have occurred under the guise of public health. guardian. the current Director of National Institutes of Health.S. Boston Globe. Retrieved 2 October 2010. similar research was also conducted on the transmission and prophylaxis of gonorrhea and [7] chancroid. and mental hospital patients. Human rights activists called for subjects' families to be compensated. Retrieved 2 October 2010. 29 August 2011. The conduct exhibited during the study does not represent the values of the US. We deeply regret that it happened. including deliberate exposure of subjects to known serious health threats. Department of Health & Human Services [2] "Guatemalans 'died' in 1940s US syphilis study" (http:/ / www. and the use of highly vulnerable populations. . democracynow. .completion of therapy was documented for only 26%. "US says sorry for "outrageous and abhorrent" Guatemalan syphilis tests" (http:/ / www. [5] "Exposed: US Doctors Secretly Infected Hundreds of Guatemalans with Syphilis in the 1940s" (http:/ / www.

The New York Times. . uk/ news/ world-us-canada-11457552). html).S. Department of Health & Human Services. and to Chiron Corporation of Emeryville. 30 September. Still. npr. . 2010 (http://www.S. (1 October 2010). apologizes for newly revealed syphilis experiments done in Guatemala" (http:/ / www. WHO changed the prototype strains and now offers three new prototype strains which represent three of the six subclades of the clade 2 virus which have been responsible for many of the human cases that have occurred since 2005. com/ wp-dyn/ content/ article/ 2010/ 10/ 01/ AR2010100104457.S. html). "The United States issued an unusual apology Friday to Guatemala for conducting experiments in the 1940s in which doctors infected soldiers. which does not change. co. In April 2004.[1] Current status of H5N1 candidate vaccines Candidate vaccines were developed in the United States and the United Kingdom during 2003 for protection against the strain that was isolated from humans in Hong Kong in February 2003 but the 2003 strain died out in 2004 making the vaccine of little use. [9] "U. 1 October 2010. gov/ 1946inoculationstudy/ findings. nytimes. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans.S. html). The vaccine focuses on the M2 viral protein. gov/ news/ press/ 2010pres/ 10/ 20101001a. Apologizes For Syphilis Experiments In Guatemala" (http:/ / www. October 1. Acambis announced in early August 2005 that it has had successful results in animal testing. such a vaccine is years away . 1946-48 (http://www. BBC News." [10] "Joint Statement by Secretaries Clinton and Sebelius on a 1946-1948 Study" (http:/ / www. 1 October 2010. hhs. from October 1. rather than the surface hemagglutinin and neuraminidase proteins targeted by traditional flu vaccines.youtube. 2010 [11] "US medical tests in Guatemala 'crime against humanity'" (http:/ / www. "U. 80 External links • "Normal Exposure" and Inoculation Syphilis: A PHS "Tuskegee" Doctor in Guatemala. Retrieved 2 October 2010. U. since its formulation would not change. The National Institute of Allergy and Infectious Diseases (NIAID) awarded H5N1 vaccine contracts to Aventis Pasteur (now Sanofi Pasteur) of Swiftwater.com/ watch?v=ZwTwefKjh1s) H5N1 clinical trials H5N1 clinical trials are clinical trials concerning H5N1 vaccines.edu/WomenSt/Reverby Normal Exposure. WHO made an H5N1 prototype seed strain available to manufacturers. bbc.S. Apologizes for Syphilis Tests in Guatemala" (http:/ / www. prisoners and mental patients with syphilis and other sexually transmitted diseases. plus the vaccine could be produced constantly.S. U. Washington Post. The universal vaccine is made through bacterial fermentation technology. Retrieved 1 October 2010. "A universal influenza vaccine could provide protection against all types of influenza and would eliminate the need to develop individual vaccines to specific H and N virus types. Retrieved 2 October 2010.Guatemala syphilis experiment [6] Donald G. National Public Radio. Such a vaccine would not need to be reengineered each year and could protect against an emergent pandemic strain. Department of Health & Human Services. . Retrieved 1 October 2010. html). McNeil. Developing a universal vaccine requires that researchers identify conserved regions of the influenza virus that do not exhibit antigenic variability by strain or over time. Each manufacturer is using established techniques in which the virus is grown in eggs and then inactivated and further purified before being formulated into vaccines. washingtonpost.pdf) • NBC Nightly News segment on the experiments. 1 October 2010. . [7] "Findings from a CDC Report on the 1946-1948 U. California. Jr. which would greatly speed up the rate of production over that possible with culture in chicken eggs. A universal vaccine is being developed by the British company Acambis [2] and is being researched by others as well. hhs. com/ 2010/ 10/ 02/ health/ research/ 02infect. In August 2006. org/ blogs/ health/ 2010/ 10/ 01/ 130266301/ u-s-apologizes-for-medical-research-that-infected-guatemalans-with-syphilis). Pennsylvania. 2010 [8] "U. wellesley. Public Health Service Sexually Transmitted Disease (STD) Inoculation Study" (http:/ / www.

.. scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion. attenuated vaccine technology.8-microgram (mcg) doses found that three fourths of their subjects were protected not only against the clade 1 Vietnam virus on which the vaccine was based. and commercial—but they also have generated more excitement than any other type of vaccine thus far. the National Institutes of Health (NIH) began enrolling participants in a Phase 1 H5N1 study of an intranasal influenza vaccine candidate based on MedImmune's live. researchers would have to ascertain the right dose and dose interval. And in September."[4] (See also Universal flu vaccines) In June 2006. phase I clinical trials on humans are underway in which a vaccine that focuses on the M2 viral protein "is being administered to a small group of healthy people in order to verify the safety of the product and to provide an initial insight into the vaccine’s effect on the human immune system. regulatory. and the safety data that would need to be gathered once the vaccines went into use". Current flu vaccine manufacturing plants can not produce enough pandemic flu vaccine at this high dose level. Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company's own proprietary formula induced EU-accepted levels of protection after two doses of 1. They come with obstacles—immunologic.[10] . 2007 the US FDA approved "Influenza Virus Vaccine. and use. H5N1" by manufacturer Sanofi Pasteur Inc for manufacture at its Swiftwater. [In August 2007].[5] Oct 2010 Inovio starts a phase I clinical trial of its H5N1 vaccine (VGX-3400X). determine how long priming lasts. even the lowest dose of 3. but against a drifted clade 2 virus from Indonesia as well [. Trials in 2006 and 2007 using two 30-mcg doses produced unacceptable results while a 2006 trial using two doses of 90 mcg each achieved acceptable levels of protection."[9] The "GlaxoSmithKline-backed team that described an acceptable immune response after two adjuvanted 3. PA facility.[8] "Adjuvanted vaccines appear to hold the greatest promise for solving the grave supply-demand imbalance in pandemic influenza vaccine development.[7] Results of trials Early results from H5N1 clinical trials showed poor immunogenicity compared to the 15-mcg dose that induces immunity in a seasonal flu vaccine.] To achieve prepandemic vaccines. after the second injection."[3] As of July 2007.H5N1 clinical trials from full testing.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007).[6] 81 Approved human H5N1 vaccines On April 17. regulatory authorities would have to determine the trial design that could deliver those answers. the public discussion that would be necessary for prepandemic vaccines to be accepted. Further. approval.9 mcg. and solve the puzzle of measuring primed immunity.

H5 booster after two doses . dose-ranging. To determine the dose-related effectiveness of flu vaccine in healthy adults approximately 1 month following receipt of 2 doses of [12] vaccine. Subjects who participate in this study will have participated in a previous vaccine study (involving the A/Hong/Kong/97 virus) during the fall of 1998 at the University of Rochester. Subjects who participate in this study.75. Study completion: June 2006 The purpose of this study is to determine whether a third dose of vaccines containing A/Vietnam/1203/04 provides more immunity than two doses. H5 in the elderly . controlled.5.August 2006 Study start: October 2005.January 2006 Study completion: January 2006 The purpose of this study is to determine whether having received an H5 vaccine in the past primes the immune system to respond rapidly to another dose of H5 vaccine. is designed to investigate the safety. In this study. 7. To provide information for the selection of the best dose levels for further studies. and dose-related immunogenicity of an investigational inactivated influenza A/H5N1 virus vaccine when given alone or combined with aluminum hydroxide. Study completion: August 2006 This study is intended to examine the safety and dose-related immunogenicity of three dosage levels of the Influenza A/H5N1 vaccine. each subject will be asked to receive a third dose of the H5 [13] vaccine at the same level administered in protocol 04-063. A secondary goal is to guide selection of vaccine dosage levels for expanded Phase II trials based on reactogenicity and immunogenicity profiles. as compared to saline placebo.November 2006 Study start: March 2006. Subjects who meet the entry criteria for the study will be enrolled at one of up to 5 study sites and will be randomized into 8 groups to receive two doses of influenza A/H5N1 vaccine containing 3.H5N1 clinical trials 82 Individual studies Revaccination . reactogenicity. or 45 mcg of HA with or without aluminum hydroxide adjuvant by IM injection (N= 60 or 120/vaccine dose group).February 2006 Study start: April 2005.June 2006 Study start: October 2005. given intramuscularly to healthy elderly adults approximately 4 weeks apart. will have participated in DMID protocol 04-063 involving the A/Vietnam/1203/04.[15] .[11] A/H5N1 in adult . 18 to 49 years old. Study completion: February 2006 The purpose of this study is to determine the dose-related safety of flu vaccine in healthy adults.[14] H5 in healthy adults . Expected completion: November 2006 This randomized. Phase I-II study in 600 healthy adults. 15. double-blinded. This dose optimization will be applied to both younger and older subject populations in subsequent studies.

February 2007 Study start: January 2006.Part 4: The promise and problems of adjuvants (http:/ / www. com/ [3] CIDRAP (http:/ / www. cidrap. html) [10] THE PANDEMIC VACCINE PUZZLE .[16] Pandemic flu . umn.gov (http:/ / clinicaltrials. gov/ cber/ approvltr/ h5n1san041707L.Last updated September 26.gov (http:/ / clinicaltrials. 2006 [4] eurekalert (http:/ / www. staged. com/ news/ home/ 20100930005454/ en/ Inovio%E2%80%99s-SynCon%E2%84%A2-Universal-Influenza-DNA-Vaccine-Technology [7] FDA (http:/ / www. edu/ cidrap/ content/ influenza/ panflu/ biofacts/ panflu. while maintaining an [18] adequate safety profile. umn. placebo-controlled. and the immunogenicity (capability of inducing an immune response) of A/H5N1 virus vaccine in healthy adults. Each subject will participate for 7 months and will be randomly placed in one of several different study groups receiving a different dose of vaccine. double-blinded. Children . gov/ show/ NCT00296634) H5 Vaccine Alone or With Adjuvant in Healthy Adults [16] clinicaltrials. medicalnewstoday. in their muscle tissue. A small amount of blood will also be drawn before the first injection. cidrap.H5N1 clinical trials 83 Bird flu . tolerability. htm) approval letter [8] THE PANDEMIC VACCINE PUZZLE . A secondary goal is to identify an optimal dosage level of the vaccine that generates an acceptable immunogenic response. Up to 280 healthy adults. Study completion: January 2007 This Australian study will test the safety and immunogenicity of an H5N1 pandemic influenza vaccine in healthy [17] adults. edu/ cidrap/ content/ influenza/ panflu/ news/ oct3107panvax5. php) [6] http:/ / www. gov/ show/ NCT00280033) H5 Adult . about 28 days apart. gov/ show/ NCT00115986) A/H5N1 Adult . gov/ show/ NCT00136331) Study of a Pandemic Influenza Vaccine (Australian CSL) .Part 5: What role for prepandemic vaccination? (http:/ / www. vaccine plus adjuvant. businesswire. gov/ show/ NCT00230750) H5 Aventis in the Elderly [15] clinicaltrials.Aventis [13] clinicaltrials. html) [9] THE PANDEMIC VACCINE PUZZLE . 2007 [5] MedImmune And National Institutes Of Health Begin Clinical Testing Of A Live. umn. tolerability. 7 days after each injection. fda. php) article Universal flu vaccine being tested on humans published July 17.January 2007 Study start: October 2005. Study completion: November 2006 This study is designed to gather critical information on the safety. com/ articles/ 45286.November 2006 Study start: March 2006. reactogenicity. umn. Subjects will keep a journal of their temperature and any adverse effects between study visits. acambis. aged 18 to 64. cidrap.gov (http:/ / clinicaltrials.gov (http:/ / clinicaltrials. dose-ranging. or placebo. cidrap.Part 3: H5N1 poses major immunologic challenges (http:/ / www. Study completion: February 2007 This is a randomized. All subjects will receive two injections of their assigned study product.gov (http:/ / clinicaltrials. Phase I/II study to evaluate the safety. edu/ cidrap/ content/ influenza/ panflu/ news/ oct3007panvax4. gov/ show/ NCT00240968) H5 Booster After a Two Dose Schedule [14] clinicaltrials. Sources [1] IFPMA glossary (http:/ / clinicaltrials-dev. Attenuated Intranasal Vaccine Against An H5N1 Avian Influenza Virus (http:/ / www. org/ ) [2] http:/ / www.Chiron Study of Bird Flu Vaccine [17] clinicaltrials.gov (http:/ / clinicaltrials. gov/ show/ NCT00240903) Revaccination With Subunit Influenza A/Vietnam/1203/2004 (H5N1) Vaccine [12] clinicaltrials. ifpma. edu/ cidrap/ content/ influenza/ panflu/ news/ oct2907panvax3. html) [11] clinicaltrials. aged 2 through 9 years.gov (http:/ / clinicaltrials. eurekalert. This study is designed to investigate the safety. and dose-related immunogenicity of an investigational inactivated influenza A/H5N1 vaccine. and 6 months after the second injection. and immunogenicity of 2 doses of an IM inactivated influenza A/H5N1 vaccine in healthy children. will participate in the study. html) article Pandemic Influenza . org/ pub_releases/ 2007-07/ vfii-nuf071707.

By comparison.html) article Glaxo says its H5N1 vaccine works at low dose published July 26. an experimental H5N1 avian influenza vaccine with an adjuvant showed modestly better performance at a lower dose compared with a similar H5N1 vaccine that was tested earlier in the United States. A typical dose of seasonal flu vaccine is 15 mcg. Garnier called the GSK vaccine a breakthrough because. one of the NIH Institutes. Garnier said in the news release. according to findings reported in May. MD.cidrap. with the effectiveness of the low dose.10 84 Further reading • CIDRAP (http://www." GSK Chief Executive Officer J. published in this week’s The Lancet.html) article Sanofi reports results for H5N1 vaccine with adjuvant published May 12. The vaccine is manufactured by Sanofi Pasteur. 2006 "In a human trial in China.umn.P. gov/ show/ NCT00133536) H5 Aventis Children 2 . . however.html) article Chinese report results for whole-virus H5N1 vaccine published September 7.edu/cidrap/content/influenza/panflu/news/may1206vaccine.H5N1 clinical trials [18] clinicaltrials. a GSK spokeswoman in Philadelphia. to produce hundreds of millions of doses of an effective pandemic vaccine. 80% of volunteers who received two vaccine doses containing 3.cidrap. 2006 "An H5N1 avian influenza vaccine made by GlaxoSmithKline (GSK) triggered a good immune response in human volunteers at a much lower dose than other H5N1 vaccines reported so far. showed an immune response in 67% of patients receiving two doses of 30 micrograms (mcg) of the vaccine plus an adjuvant. the British-based company said in a news release.gov (http:/ / clinicaltrials. a subsidiary of France-based Sanofi Aventis. starting later this year.umn. The vaccine is made by Sinovac Biotech in Beijing. so this is a big breakthrough.cidrap. suggesting that it could be used to immunize more people than may be possible with some other vaccines under development.8 mcg of antigen with an adjuvant (a chemical that stimulates the immune system) had a strong immune response. The GSK vaccine was made from an inactivated H5N1 virus collected in Vietnam in 2004. pointed out several obstacles that need to be addressed before an effective vaccine can be mass-produced. 2007 "The first human trial of a DNA vaccine designed to prevent H5N1 avian influenza infection began on December 21. as reported today by Agence France-Presse (AFP). published online today in The Lancet. when the vaccine was administered to the first volunteer at the National Institutes of Health (NIH) Clinical Center in Bethesda. the company announced today." Garnier said on BBC Radio.nih. split-virion strain of H5N1 known as Vietnam/1194/2004. which means that hundreds of millions of doses could be produced by next year. 2006 "In a human trial in France. The new study. Scientists from the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID). 2006.gov/news/pr/jan2007/ niaid-02. from an inactivated strain of H5N1 known as Vietnam/1194/2004. China. In a clinical trial. designed the vaccine. according to Jennifer Armstrong. "The meaning of this is that we are going to be in a position." • CIDRAP (http://www.edu/cidrap/content/influenza/panflu/news/jul2606glaxo.htm) news article NIAID DNA Vaccine for H5N1 Avian Influenza Enters Human Trial published January 2. an H5N1 vaccine developed by Sanofi Pasteur induced a good immune response in 67% of volunteers who received two 30-mcg doses with an adjuvant.umn. a whole-virus H5N1 avian influenza vaccine generated an immune response with a relatively low dose of antigen." • CIDRAP (http://www. An accompanying commentary. It is an inactivated. a given amount of antigen will go much further than it would otherwise." • National Institute of Allergy and Infectious Diseases (NIAID) (http://www. showed an adequate immune response in 78% of volunteers after two 10-microgram (mcg) doses of the vaccine plus an aluminum hydroxide (alum) adjuvant. The US government is stockpiling the Sanofi vaccine. "This is the first time such a low dose of H5N1 vaccine has been able to stimulate this level of strong immune response.edu/cidrap/content/influenza/avianflu/news/sep0706vaccine. That exceeds the European Union's requirement of an acceptable response (a hemagglutinin-inhibition titer of 40 or more) in 70% of volunteers. The study.

VRC Director Gary Nabel. the PROSPER study found more cancer deaths and significantly more cancer incidence). [. There was no mortality benefit in women. The number needed to treat in the study was 57 patients to postpone one death and 19 to prevent one cardiovascular "event" (in those taking the drug simvastatin for 5 years). which are developed by growing the influenza virus in hens' eggs and then administered as a weakened or killed form of the virus. was manufactured at the VRC Vaccine Pilot Plant. Unlike conventional flu vaccines. Ph. DNA-based vaccines contain only portions of the influenza virus' genetic material. It studied the use of statin (simvastatin 40 mg) medication and vitamin supplementation (vitamin E. Nabel and his colleagues previously have shown the DNA vaccine approach to be effective against influenza viruses in animal models. the DNA instructs human cells to make proteins that act as a vaccine against the virus. . these were rare in this study..H5N1 clinical trials The vaccine does not contain any infectious material from the influenza virus.] The candidate vaccine.. M.D. a disease for which effective vaccines have long been made.. which indicated that vitamins made little difference in modifying cardiovascular risk. The candidate vaccine went from the research bench into clinical trials in less than 6 months. Volunteers will not be exposed to influenza virus. This is the first VRC candidate vaccine manufactured at the VRC Vaccine Pilot Plant. and simvastatin did not decrease osteoporosis. but that simvastatin could significantly reduce the risk of cardiovascular events.] The study will enroll 45 volunteers between the ages of 18 and 60.[1] Initial results[2] were published in 2002. While there have been concerns about side-effects (myopathy and rhabdomyolysis). including highly pathogenic viruses such as the H5N1 strain and the H1N1 virus that caused the deadly 1918 pandemic.. SARS and West Nile. Ebola.[5] Interpretation The HPS is to date the largest study to investigate the use of statins in the prevention of cardiovascular disease. but for which the reliability of supply and manufacturing capacity has been problematic. Further results.[4] A 2005 paper analyses the cost-effectiveness of a prescribing strategy similar to the one employed in the study.com/search/trials/H5N1) Heart Protection Study The Heart Protection Study was a large randomized controlled trial run by the Clinical Trial Service Unit. such as HIV. synthesized using a modified version of the hemagglutinin (H) gene from the H5N1 influenza virus.D. vitamin C and beta carotene) in patients who are at risk of cardiovascular disease. The DNA vaccine used in this study is similar to other investigational vaccines evaluated by the VRC that hold promise for controlling other viruses. [. Results An outline of the study protocol was published in 1999. focused on the role of simvastatin in diabetics[3] and preventing stroke. and funded by the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the United Kingdom.. an initial concern with statin drugs.." 85 External links • Currently recruiting H5N1 clinical trials in the US (http://localclinicaltrials. from 2003 and 2004. No worsening of lung disease was found. Once inside the body. Dr. Fifteen will receive placebo injections and 30 will receive three injections of the investigational vaccine over 2 months and will be followed for 1 year. Cancer risk was suggestively lower in the treatment group (this has been the subject of other studies. for example. together with a team of scientists from the VRC recognized the potential for employing new vaccine technology against influenza.

issued in January 2005 and updated November 2008. PMID 15910950. Glossary and Easy Explanation of Medical Expressions. Es. [6] http:/ / blogs. the European Federation of Pharmaceutical Industries and Associations(EFPIA.536 high-risk individuals: a randomised placebo-controlled trial. to define specific search queries. wsj.361:2005-16. Pharmaceutical Industry Clinical Trials database. Patients and physicians can search quickly and easily on-going clinical trials (registry) or results of completed trials (database) conducted by the international research-based pharmaceutical industry. PDF (http:/ / eurheartj. and then request an e-mail alert. the Pharmaceutical Research and Manufacturers of America (PhRMA) and Canada’s Research-Based Pharmaceutical Companies (R&d). Current Controlled Trials. Peto R. through my Portal.Heart Protection Study The CTSU branch of Oxford has been criticized for not releasing all group study data about deaths and for inappropriately combining dissimilar endpoints and groups to suggest benefit for all. [3] Collins R.org. IFPMA Clinical Trial Portal provides links to the following sources: ClinicalStudyResults. Heart Protection Study Collaborative Group. com/ health/ 2008/ 09/ 18/ statistics-smackdown-experts-duel-over-vytorin-cancer-data/ IFPMA Clinical Trials Portal The IFPMA Clinical Trial Portal [1] is a major pharmaceutical industry initiative designed to increase the transparency of clinical trials by providing a convenient "one-stop-shop" for published clinical trial information. Lancet 2005. Fr.[6] 86 References [1] MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. It also allows the user. Having received over £m105 ($m200) from cholesterol-lowering drug manufacturers in addition to the funding from the sources listed above. doi:10. to provide a coherent industry blueprint for improving clinical trial transparency. Parish S.363:757-67. PMID 10329064.1016/S0140-6736(02)09327-3 PMID 12114036. . It helps to fulfill the commitment made by the research-based pharmaceutical industry in its Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases . Eur Heart J 1999. De. oxfordjournals. org/ cgi/ reprint/ 20/ 10/ 725). Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. PMID 15016485. Parish S. The IFPMA Clinical Trial Portal is a single entry point allowing healthcare professionals to search for comprehensive information on clinical trials. Parish S. [2] Heart Protection Study Collaborative Group. PMID 12814710 [4] Collins R.365:1779-85. Lancet 2003.20:725-41. Sleight P. their objectivity has been questioned. the Japan Pharmaceutical Manufacturers Association (JPMA). Japan Pharmaceutical Information Center. Gray A. Briggs A. Language interfaces (En. say trials for a particular disease in a particular country. [5] Mihaylova B. Armitage J. Jp). Sleigh P.536 individuals. which will be sent every time a relevant new clinical trial is posted.360:7-22. It provides the following basic search features: Search by Medical Condition and Drug Name. This joint statement was developed by the IFPMA. Collins R. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20. Lancet 2004. Armitage J. Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20. Heart Protection Study Collaborative Group.gov. Lancet 2002. Peto R. Geographical Search. Armitage J. ClinicalTrials.

physical exam. or procedure to be approved for regular use in the U. Spiculation increases the probability of the lesion being cancer. External links • IFPMA [3] References [1] http:/ / clinicaltrials. search by trial location and e-mail alert. it must be rigorously tested in clinical trials. org [2] http:/ / www. the creator of the X-ray.S.se [2].IFPMA Clinical Trials Portal 87 Improving the portal Since the Portal was launched in September 2005. History Imaging biomarkers are as old as the X-ray itself. can also be a very difficult endpoint to measure clinically. as it is often very subjective. imaging biomarkers have grown as well. End-points. synonyms.[1] In the medical context. the IFPMA has worked to expand its functionality and ease-of-use. are used as measures to compare groups within a clinical trial. An imaging biomarker is a biologic feature detectable by imaging modalities. ifpma. plus features such as spelling suggestion. and demonstrate sufficient efficacy.[2] As the field of medical imaging developed and expanded to include numerous imaging modalities. fass. The most basic endpoint used in clinical trials. and pathology to reach a proposed diagnosis. it applies to any and all detection modalities. a simple lesion in the lung detected by X-ray. Unfortunately clinical trials are also extremely expensive and time consuming. spiculation. This was pioneered in the Swedish language medicine information site www. The lesion itself serves as a biomarker. calcification. Improvements subsequently added to the Portal include four additional language interfaces. in both quantity and complexity as finally in chemical imaging.fass. device. and can collectively be used to assess the risk of neoplasm. Each piece of information from the image represents a probability. For example. laboratory tests. a number of biomarkers are frequently used to determine risk of lung cancer. and rate of metabolism. org Imaging biomarker The word biomarker can be defined as any detectable biologic feature that provides information about its source. se [3] http:/ / www. cavitation. The Use of Imaging Biomarkers in Clinical Trials Clinical trials are known to be one of the most valuable sources of data in evidence-based medicine. location within the lung. mortality. although potentially faster to measure than mortality. an imaging biomarker is a feature of an image that represents a particular aspect of the patient being imaged. A feature of a radiograph that represent some kind of pathology was first coined "Roentgen signs" after Wilhelm Röntgen. such as morbidity and mortality. but the minute details of the lesion serve as biomarkers as well. These variables can be added to the patient’s history. The IFPMA has also created a technology package that allows access to the Portal to be integrated into others websites. As a general term. rate of growth. requires years and sometimes decades of follow-up to sufficiently assess. For a pharmaceutical. Some of the imaging biomarkers used in lung nodule assessment include size. ifpma.. CT. or MRI can lead to the suspicion of a neoplasm. A slow rate of growth indicates benignity. Morbidity. in other languages. These are some of the reasons why biomarkers have been increasingly used in clinical trials to detect subtle changes in physiology and pathology before they can are . First.

They also evaluate the qualification study strategy methods and results and ultimately make a decision to accept or reject. a biomarker must demonstrate that the treatment versus control differences are similar to the treatment versus control differences for clinical outcome. The FDA Modernization Act of 1997 was instituted to improve the regulatory process for medical products. The Biomarker Qualification Review Team.[3] The wording is much more general than the provision for pharmaceuticals. . probable validation and known validation. to assist in selecting appropriate candidates for particular treatment.Imaging biomarker detected clinically. but can only be used in phase III trials for early futility analyses. There are two steps to validation. For a biomarker to become qualified it must go through a somewhat formal qualification process.[4] For full validation. A request must be submitted to IPRG to qualify an imaging biomarker for a specific use. Predictive classifiers are frequently used in molecular imaging in order to ensure enzymatic response to treatment. There are two steps of certification for a surrogate endpoint to be fully established: Qualification and Validation. it allows participants to act as their own control. assesses the context and available data regarding the biomarker. The biomarkers act as surrogate endpoints. imaging biomarkers can be used as predictive classifiers." Qualification and Validation Developing an understanding of clinical significance for specific biomarkers can be a difficult process. They may be used in phase I and II clinical trials. 88 FDA approval of surrogate end-points The United States Congress and the Food and Drug Administration have acknowledged the value of imaging biomarkers as evidenced by recent actions that encourage their use. The use of surrogate endpoints has been shown to significantly decrease the time and resources used in clinical trials. a biomarker may have limited use as a surrogate endpoint. Because surrogate end-points allow researchers to assess a marker rather than the patient. Section 112 of the Act gives explicit authority to give expedited approval for drugs that treat serious conditions as long as it has shown to have an effect on a surrogate end-point that reasonably indicates a clinical benefit. "Known validation" requires a scientific framework or body of evidence that appears to elucidate the marker’s efficacy. It is not sufficient to simply demonstrate that the biomarker responders survive longer than the biomarker non-responders. In addition to surrogate endpoints. section 205 requires that the "least burdensome means necessary" be used in their approval. recruited from nonclinical and clinical review divisions. but is generally accepted that surrogate endpoints will often qualify as being the "least burdensome means. After qualification. Other provisions enables monitoring of the products following market approval to ensure the efficacy of the surrogate end-points and requires the FDA to establish a program that promotes the development and use of surrogate end-points for serious diseases. and in many cases allows for easier blinding. "Probable validation" requires widespread agreement in the medical or scientific community as to its efficacy. Although the act does not specifically mention the use of surrogate end-points for medical devices.

2. The catalogue includes the pathology specific to the biomarkers. The presence of the imaging biomarker is closely coupled or linked to the presence of the target disease or condition. the FDA has encouraged the creation of consortia between public and private organization in order to facilitate the sharing of data for the qualification and validation of biomarkers. Imaging Response Assessment Teams was created by the National Cancer Institute and AACI to advance the role of imaging in assessment of response to therapy and to increase the application of quantitative. and the modalities used in the detection of the biomarker. founded the MGH Center for Biomarkers in Imaging. and industry representatives (now available on their website). the Radiology department at Massachusetts General Hospital. and secures its own funding. . Oncology Biomarker Qualification Initiative was created by the Food and Drug Administration and the National Cancer Institute to qualify new cancer biomarkers. anatomic. The measured changes over time in the imaging biomarker are closely coupled or linked to the success or failure of the therapeutic effect and the true end-point sought for the medical therapy being evaluated. Their initial project was to catalogue the known biomarkers in order to make them readily available to scientists. the investigator(s) involved in creating and using the biomarker. was created by the C-Path Institute and the Food and Drug Administration to develop a framework needed for data sharing between its members in order to make biomarker qualification easier.[5] 1. and molecular imaging endpoints in clinical therapeutic trials. They are also working with regulatory agencies to replace the currently unstructured qualification process. a center dedicated to encourage the development and use of imaging biomarkers. The Biomarkers Consortium was created by the Foundation for the National Institutes of Health.Imaging biomarker 89 Quality of imaging biomarkers The following are 3 measures of quality to determine the strength of biomarker for use in clinical trials. Food and Drug Administration. Each international team chooses a cancer site(s) for study. regulators. International Cancer Biomarker Consortium was created to assist in discovery of biomarkers by facilitating coordinated research and by leveraging resources. functional. It is a public-private biomedical research partnership aimed to provide grants for the generation of data for clinical biomarker qualification. The detection and/or quantitative measurement of the imaging biomarker is accurate. In 2001. Uniform Protocols for Imaging in Clinical Trials (UPICT) was created by the American College of Radiology. Their first project involves PET imaging in non-Hodgkin lymphoma. is a nobel prize winner for physiology/medicine in 2001. 3. The president of the organization. and feasible over time. National Institute of Health. and Pharmaceutical Research and Manufacturers of America. The Predictive Safety Testing Consortium. Leland Hartwell. functions independently. Aims to strengthen clinical collaboration between imaging scientists and oncologic investigators. reproducible. Organizations Because the project of compiling a library of validated biomarkers requires an enormous amount of resources.

participants must have two or more antibodies (against insulin. 1956 [3] Smith JJ. Roentgen Signs in Clinical Diagnosis. GAD65. the INIT I trial was designed to test safety. but significant destruction of the pancreatic beta cells has not yet occurred. insulin was administered onto the nasal mucosa of mice with a genetic predisposition to type 1 diabetes. In pre-clinical tests. 38 individuals were treated with either intranasal insulin spray or placebo. daily for 10 days. Background Pre-clinical Evidence There is evidence from a mouse model of type 1 diabetes that the administration of intranasal insulin can reduce the immune attack on the insulin-producing beta cells of the pancreas. the probability that a family member of someone with type 1 diabetes will meet the criteria to . 55:435-447 [4] Goodsaid. Nat Rev Cancer 2002. AAPS Journal. and then 2 days a week for 6 months. The promise and peril of surrogate endpoints in cancer research. and Thrall. and tyrosine phosphatase-like insulinoma antigen 2). thus acting as a vaccine against the condition. The trial showed that intranasal insulin does not accelerate the onset of diabetes. This caused the induction of regulatory T-cells. Frueh. INIT II is a randomized. 9(1):105-108 [5] Schatzkin A. This indicates that they are in the process of developing type 1 diabetes. aged between 4 and 30. 2:19-27 INIT II The Intranasal Insulin Trial (INIT II) began in late 2006. Although type 1 diabetes can be hereditary.B. Biomarker Qualification Pilot Process at the US FDA. Defining “least burdensome means” under the Food and Drug Administration Modernization Act of 1997. but a normal response in a glucose tolerance test. An immune effect was also observed in children and young adults at risk of type 1 diabetes.[1] INIT I The predecessor of INIT II. 2007. Sorensen. Shyjan AM. Those who are positive undergo a glucose tolerance test to make sure they do not already have diabetes. Food Drug Law J 2000. Intranasal insulin produced effects that suggested a change in the immune attack on the insulin-producing beta cells. To enter the treatment arm of the trial. placebo-controlled multi-centre clinical trial.Biomarkers in Imaging: Realizing Radiology’s Future. and is being run by an Australian non-profit organization. double-blind. which will determine whether intranasal insulin can delay or prevent the onset of type 1 diabetes in children and young adults at risk. relatives of people with type 1 diabetes are screened for antibodies. Philadelphia. the INIT II trial will test whether intranasal insulin can delay or prevent type 1 diabetes in a larger population. The trial requires 300 participants. To find enough eligible people. Radiol 2003.Imaging biomarker 90 References [1] Smith. which were protective against the destruction of beta cells in the mice. the Diabetes Vaccine Development Centre (DVDC). Eligibility A significant feature of the INIT II trial is the recruitment of people at risk for type 1 diabetes. The aim of the trial is to test a new preventative treatment for type 1 diabetes in young people who are at risk of developing this condition.[2] Trial design Based on the success of INIT I. Saunders Company. 227:633-638 [2] Meschan. W. Farrer-Meschan. Gail M.

jem. Perth Royal Melbourne Hospital. participants are monitored every four months. diabetesjournals. (2004) Diabetes Care 27. During this time. 91 Treatment arm After screening. and then once a week for 12 months. (1996) J Exp Med 184. This is expected to be lower in participants who were exposed to insulin. Brisbane Women’s and Children’s Hospital.au) • Australian INIT II website (http://www.stopdiabetes. Melbourne North Shore Hospital. New Zealand Other hospitals based in Sydney and Melbourne are expected to become active trial sites in 2008. It is therefore expected that over 20. org/ cgi/ content/ full/ 184/ 6/ 2167) [2] Harrison et al. and the other two receive a solution that contains one of two doses of insulin: either 40IU or 440IU.INIT II enter the trial is only around 2-3%. Adelaide Princess Margaret Hospital. 2348-2355. Endpoint The primary clinical endpoint of INIT II is the development of type 1 diabetes.org. • • • • • • • • Mater Children’s Hospital.com. Canberra Liggins Institute. org/ cgi/ content/ full/ 27/ 10/ 2348) External links • The Diabetes Vaccine Development Centre (http://www. Auckland.nz) . The treatment is self-administered using a nasal spray every morning for 7 consecutive days. including. The trial will take place at a number of centers across Australia and New Zealand. then every six months for a further four years. One group receives placebo solution. References [1] Harrison et al. New Zealand INIT II website (http://www. New Zealand Christchurch Hospital. stopdiabetes. participants are staged into a treatment arm.dvdc. (http:/ / care. Sydney Canberra Hospital.au).co. 2167-2174 (http:/ / www.000 people will need to be screened.

ac.edu • What is meant by intention to treat analysis? Survey of published randomised controlled trials (http://bmj.au/public/ issues/179_08_201003/her10586_fm.Intention to treat analysis 92 Intention to treat analysis In epidemiology. this effect is greater the larger the trial.edu/mlava/ITT Workshop. not on the treatment eventually administered. even a completely ineffective treatment may appear to be providing benefits if one merely compares the condition before and after the treatment for only those who finish the treatment (ignoring those who were enrolled originally. Controlled Clinical Trials 21 (3): 167–189. everyone who begins the treatment is considered to be part of the trial.medicine.mja.jerrydallal. PMID 10822117. Campbell.bu. Sally.uk/bandolier/booth/glossary/ITT. This is different from per-protocol analysis. efficacy subset analysis selects the subset of the patients who received the treatment of interest—regardless of initial randomization—and who have not dropped out for any reason.html) – eMJA (http://www. [2] Hollis.1016/S0197-2456(00)00046-5.edu • Intention-to-Treat Analysis (http://people. "Statistical Considerations in the Intent-to-Treat Principle".[2] References [1] Lachin JM (June 2000).ox.com. Fiona (September 1999). "What is meant by intention to treat analysis? Survey of published randomised controlled trials". Intention to treat analysis provides information about the potential effects of treatment policy rather than on the potential effects of specific treatment. doi:10. PMC 28218. an intention to treat (ITT) analysis (sometimes also called intent to treat) is an analysis based on the initial treatment intent.com. it is often incorrectly described and its application may be flawed. This approach can: • introduce biases to the statistical analysis [1] • inflate the chance of a false positive.html) Bandolier's definition • Intention to Treat (http://www.htm) – Tufts.pdf) – Bu. Full application of intention to treat can only be performed where there is complete outcome data for all randomized subjects. which may break the randomization to the treatment groups in a study. Although intention to treat is widely cited in published trials.com/LHSP/itt. Rationale Intention to treat analyses are done to avoid the effects of crossover and drop-out. For example. In contrast. if people who have a more refractory or serious problem tend to drop out at a higher rate.ca/cgi/content/full/165/10/1339) – CMAJ • Inclusion of patients in clinical trial analysis: the intention-to-treat principle (http://www. bmjjournals. For the purposes of ITT analysis.com/cgi/content/full/319/7211/670) – BMJ • Intention-to-treat principle (http://www.mja.cmaj. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research. BMJ 319 (7211): 670–674. PMID 10480822 External links • Intention to Treat (http://www.au/) . but have since been excluded or dropped out). whether he or she finishes it or not.

Zareba W. References • Armitage. such a design feature can reduce study participants' exposure to the inferior treatment. some adjustment of the usual hypothesis testing procedure must be made to maintain an overall significance level (Armitage. Klein H.K.1056/NEJMoa013474.. In addition to saving time and resources. McPherson. 1971). B.[1] Notes [1] Moss AJ. MADIT II is the latest in a series of trials involving the use of ICDs to improve management and clinical treatment of arrhythmia patients. 235–244. Statistical methods of interim analysis The design of many clinical trials includes some strategy for early stopping if an interim analysis reveals large differences between treatment groups. but this assumption can be relaxed to allow for unplanned or unequally spaced analyses. . Wilber DJ. C. After inclusion of 1. 132. among others. Daubert JP. PMID 11907286. The Antiarrhythmics versus Implantable Defibrillators (AVID) Trial compared ICDs with antiarrhythmic-drug therapy (amiodarone or sotalol. Sometimes interim analyses are equally spaced in terms of calendar time or the information available from the data. New England Journal of Medicine 346 (12): 877–83. doi:10. Cannom DS. The methods described by Pocock (1977) and O'Brien & Fleming (1979). predominantly the former) in patients who had survived life-threatening ventricular arrhythmias. the investigators are ethically obliged to assess that difference using the data at hand and to make a deliberate consideration of terminating the study earlier than planned. (1969) Repeated significance tests on accumulating data. Andrews ML (2002). the MADIT II study was terminated when interim analysis showed significant (31%) reduction in all-cause death in patients assigned to ICD therapy. It is a tool used for statistical purpose. Brown MW.. Example for Interim analysis and early termination . McPherson & Rowe. This means that if a treatment is particularly beneficial or harmful compared to the concurrent placebo group while the study is on-going.232 patients. Higgins SL.Interim analysis 93 Interim analysis Clinical trials are unique in that enrollment of patients is a continual process staggered in time. McPherson & Armitage. MADIT II trial The second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) was conducted to help better identify patients with coronary heart disease who would benefit from an ICD. 1969. However.C. are popular implementations of group sequential testing for clinical trials. J R Stat Soc A. Hall WJ. when repeated significance testing on accumulating data is done. Rowe. P. "Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction".

"ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction". It recruited 58. Skerrett. Charles H..1540-8183. The Lancet 332 (8607): 349–360. doi:10. More than 134. Both.x [2] Hennekens.1002/0470011815. doi:10. All patients were also given aspirin. or Neither Among 17 187 Cases of Suspected Acute Myocardial Infarction: ISIS-2". The Lancet 328 (8607): 57–66. It recruited 17.J.1016/S0140-6736(95)90865-X .187 patients and was completed in 1988.b2a01031 [3] ISIS-1 (Second International Study of lnfarct Survival) Collaborative Group (1986). and also compared the anticoagulant heparin to no heparin. The Lancet 345 (8951): 669–682.International Studies of Infarct Survival 94 International Studies of Infarct Survival The International Studies of Infarct Survival (ISIS) were four randomized controlled trials of several drugs for treating suspected acute myocardial infarction ("heart attack"). "Randomised trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction: ISIS-1". Charles H.1016/S0140-6736(88)92833-4 [5] ISIS-3 (Third International Study of lnfarct Survival) Collaborative Group (1992). It recruited 16. It recruited 41. Journal of Interventional Cardiology 11: 1. The Lancet 339 (8796): 753–770. coordinated from Oxford. "International Studies of Infarct Survival (ISIS)".000 patients from over 20 countries took part in four large simple trials between 1981 and 1993.050 patients and was completed in 1993. doi:10.[6] References [1] Hennekens. oral mononitrate.[5] ISIS-4 The Fourth International Study of Infarct Survival (ISIS-4) was a 2×2×2 factorial placebo-controlled trial of the angiotensin-converting enzyme inhibitor (ACE inhibitor) captopril. England.1111/j.1998.tb00089.027 patients and was completed in 1985.299 patients and was completed in 1991. isosorbide mononitrate and magnesium sulphate.1016/0140-6736(92)91893-D [6] ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group (1995).[3] ISIS-2 The Second International Study of Infarct Survival (ISIS-2) was a 2×2 factorial placebo-controlled trial of aspirin and the thrombolytic drug streptokinase. P.1016/S0140-6736(88)92833-4 [4] ISIS-2 (Second International Study of lnfarct Survival) Collaborative Group (1988). doi:10. Oral Aspirin. "Randomised Trial of Intravenous Streptokinase. doi:10. doi:10.[4] ISIS-3 The Third International Study of Infarct Survival (ISIS-3) was a 3×2 factorial trial that compared the three thrombolytic drugs streptokinase. (2005). "Trials of Thrombolytic Therapy: the International Studies of Infarct Survival Experience".[1] [2] ISIS-1 The First International Study of Infarct Survival (ISIS-1) was a placebo-controlled trial of the beta-blocker atenolol. and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction". tissue plasminogen activator (tPA) and anistreplase to each other. Encyclopedia of Biostatistics. (1998). "ISIS-4: A randomised factorial trial assessing early oral captopril.

et al. chemical.898. Br Med J 334 (7599): 0. An IB is intended to provide the investigator with insights necessary for management of study conduct and study subjects throughout a clinical trial. [2] Godlee F (2007). and clinical information on the investigational product(s). and blood pressure. An IB may introduce key aspects and safety measures of a clinical trial protocol. pharmaceutical.55. This understanding should be based on the available physical. doi:10.47. and of the specific tests. The IB is a document of critical importance throughout the drug development process and is updated with new information as it becomes available. The results were disputed by the Salt Institute (the salt producers' trade organisation). PMID 8634612. doi:10. and precautions that may be needed for a clinical trial. measured by urinary excretion. PMC 1857760. "Intersalt: an international study of electrolyte excretion and blood pressure. PMID 3416162. Investigator's brochure The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product ("IP" or "study drug").1126/science. Science 281 (5379): 989–907.297.604896. [4] Cook NR.[4] In 1997 the science writer Gary Taubes. Results for 24 hour urinary sodium and potassium excretion". G. Stamler J. Nichols R. (2007). toxicological. who demanded that the results be handed over for re-analysis.5379.6644. [5] Taubes. "Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations.Intersalt study 95 Intersalt study The Intersalt study was an observational study that showed an association between dietary salt.1136/bmj. [3] Elliott P. Br Med J 297 (6644): 319–28.39196. "The (Political) Science of Salt. Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on [1] previous human experience and on the pharmacology of the investigational product". References [1] Intersalt Cooperative Research Group (1988). doi:10. pharmacological. .[3] The results have since been confirmed by the TOHP I and TOHP II studies. observations. The purpose of the IB is to compile data relevant to studies of the IP in human subjects gathered during preclinical and other clinical trials. "Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP)".[2] A re-analysis was published in 1996 and the results were the same.[1] The study was based on a sample of 10 079 men and women age 20-59 sampled from 52 populations spread across the world. The overall aim of this section is to "provide the investigator with a clear understanding of the possible risks and adverse reactions. PMID 17449506. (1996). such as when a drug has received marketing approval and can be prescribed for use commercially. PMC 2351086. published an article in Science Magazine. PMC 1834069. Intersalt Cooperative Research Group". Obarzanek E. Br Med J 334 (7599): 885–8.1136/bmj. "Editor's choice: Time to talk salt". which was heavily critical of the statistical analysis published by Intersalt. (1998). [5] He criticized the failure to account for population heterogeneity in establishing the weak association between salt intake and blood pressure and the assumptions made when deploying regression dilution bias. Br Med J 312 (7041): 1249–53.39147.1136/bmj.281.319. such as: • • • • Dose (of the study drug) Frequency of dosing interval Methods of administration Safety monitoring procedures The sponsor is responsible for keeping the information in the IB up-to-date. Cutler JA. He also cited the TOHP II study as showing only "negligible benefit of salt reduction". et al. The IB should be reviewed annually and must be updated when any new and important information becomes available.". doi:10. PMID 9722464.679537.

the sponsor is responsible for updating the IB at least annually. an exact outline.. the IB describes the pharmacological. pharmacokinetic. the U. thus. and as part of their guidance on Good Clinical Practice (GCP). ICH has published guidances for the studies needed to acquire this data. the organization of the document should be driven by logic and clear communication of content. early in drug development. Food and Drug Administration (FDA) has written regulatory codes and guidances for authoring the IB. Acquired immune deficiency syndrome (AIDS). An abbreviation is a shortened form of a word or phrase that is used in place of an entire word or phrase.. an acronym is a word formed from the initial letter or letters of each of the successive parts or major parts of a compound term. In addition. On the other hand. e. but does not dictate. and the International Conference on Harmonisation (ICH) has prepared a detailed guidance for the authoring of the IB in the European Union (EU). e. an IB should contain information on the nonclinical and toxicology studies. The ICH suggests. the information that the FDA and ICH guidances strongly suggest incorporating into the IB include the following. At the sponsor's discretion. and the United States (US). when known. and pharmacokinetic. which can be summarized later on in the program when information from later clinical study phases (such as Phase I and Phase II clinical studies) are included.Investigator's brochure Owing to the importance of the IB in maintaining the safety of human subjects in clinical trials.g. and.[2] 96 Content details In detail. and toxicological data on the drug obtained in nonclinical animal studies. Japan. including the following aspects: • Nature and frequency of pharmacologic or toxic effects • Severity or intensity of pharmacologic or toxic effects • Time to onset of effects • Reversibility of effects • Duration of effects • Dose response • It is also important to include a list of abbreviations to define abbreviations and acronyms used in the IB.[3] the FDA and other regulatory agencies may require additional studies. Specifically. or more often when new information becomes known and providing the updated IB to the investigator who is then responsible for submitting it to the appropriate review board. metabolistic. • Description of the formulation of the drug product (to permit appropriate safety measures) • Instructions for the storage and handling of the dosage form(s) • Nonclinical studies summary: • Species tested • Number and sex of animals in each group • Unit dose • Dose interval • Route of administration • Duration of dosing • Information on systemic distribution • Duration of post-exposure follow-up • Results. efficacy. A word must be spelled the first time it used in the body copy of the IB and must be followed by the abbreviation in parenthesis. safety data obtained in human clinical trials. . information from earlier in the drug development program may be summarized as a development program advances.g.S. Investigator's brochure (IB). The sponsor is responsible for compiling the information and data contained in the IB and must provide a copy of the IB to each local site investigator before the start of a trial.

pharmacodynamics. absorption. distribution. dose response. Pharmacokinetics (PK) and product metabolism in animals Authors should provide a summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied. irritancy and sensitization) Reproductive toxicity Genotoxicity (mutagenicity) Effects on humans Authors are expected to provide the following information regarding administration of the study drug to humans: • A thorough discussion of the known effects of the investigational product in humans. • Information regarding results of any use of the investigational product other than from clinical trials. results of population studies performed within clinical trials) . The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites. Toxicology Authors should provide a summary of the toxicologic effects found in relevant studies conducted in different animal species. Pharmacokinetics and product metabolism in humans Authors should provide a summary of information on the pharmacokinetics of the investigational product. including the following. and impaired organ function) • Interactions (eg. a summary of each completed clinical trial should be provided. where appropriate. or relative) using a reference dosage form • Population subgroups (eg. age. where possible. where possible. Summaries should incorporate studies that assess potential therapeutic activity as well as those that access safety. efficacy. product-product interactions and effects of food) • Other pharmacokinetic data (eg. and their relationship to the pharmacologic and toxicologic findings in animal species. and elimination) • Bioavailability of the investigational product (absolute. brief overview of completed and ongoing trials. gender. its significant metabolites studied in animals. and other pharmacologic activities. A brief description of the investigational plan. when appropriate. plasma protein binding. These effects should be described where appropriate under the following headings: • • • • • • Single dose Repeated dose Carcinogenicity Special studies (eg. such as from experience during marketing. if available: • Pharmacokinetics (including metabolism. metabolism. including information on pharmacokinetics. and. safety.Investigator's brochure 97 Nonclinical pharmacology Authors of the IB are asked to provide a summary of the pharmacologic aspects of the investigational product and.

Any important differences in adverse drug reactions across indications or subgroups should be addressed. These data should be obtained from preceding trials that were carried out in healthy volunteers. If special precautions or special monitoring is necessary during the use of the investigational product(s).g. • A discussion of the important differences in adverse drug reaction patterns/incidences across indications or subgroups. Efficacy refers to the potential maximum therapeutic response that a drug can produce. was the rate . • A description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. Data shown in the tables in text is not repeated. Data on adverse drug reactions for all studied indications from all clinical trials can be presented together in tabular form. the basis for including adverse reactions in the table (e. Reprints of published articles on such studies may be appended when useful. and the way in which adverse reaction rates were derived (e. Efficacy results in clinical studies Drug efficacy or effectiveness is evaluated based on therapeutic response in its proposed indication. comparator studies. • Use summaries of efficacy across multiple studies (summary tables and graphs) where a number of clinical studies have been completed to provide a clear presentation of efficacy data. • Presentation of Common Adverse Reactions (the Adverse Reactions Table): • Describe the data sources reflected in the table. children. special groups of subjects (the elderly. and other studies that may help the reader.Investigator's brochure 98 Safety and efficacy The IB should include a summary of the safety. or both. • Describe individual studies when clinical experience is limited. This section of the IB provides a summary of the currently available information relating to the effectiveness of the drug/candidate in humans obtained from prior clinical studies. This section should also include a discussion on possible risks and adverse drug reactions based on previous data from the investigational and related product(s). patients. • Consider providing both the primary and secondary efficacy parameters from tables/figures used in the final clinical study report when only one Phase 2 study is completed. They must also include rationales for the use of specific endpoints if they are not obvious. the safety and efficacy data can be presented by indication in subgroups across multiple trials. pharmacodynamics. • Group information under headings such as dose-ranging studies.g. efficacy. efficacy studies. • Describe the populations used and the variables that contributed to the efficacy evaluation. • Include conclusion statement(s) of the results shown in a table/graph in the text. Safety results in clinical studies Authors of the IB should provide the following: • Tabular summaries of adverse drug reactions for all the clinical trials (including those for all the studied indications). for a given adverse reaction. and dose response of the investigational product(s). Authors of the IB should: • Summarize the details of the clinical studies that were designed to demonstrate evidence of efficacy. • For the efficacy studies presented. by sex... The results of these previous studies should be discussed in relation to safety and efficacy. If several clinical trials were carried out. all reactions occurring at >n% in the treated group and for which the rate for drug exceeds the rate for placebo). by race). briefly describe materials and methods and provide a table (or figure) of the primary and secondary efficacy parameters. a description should be provided. • Summarize the efficacy data by indication if more than one indication has been studied.

This understanding should be based on the available physical. Summary of data and guidance for the investigator The overall aim of the summary of data and guidance is to provide the investigator with a clear understanding of the possible risks and adverse reactions and of the specific tests. and precautions that may be needed for a clinical trial. pharmaceutical. If rates of specific adverse reactions were gathered for only a subgroup of patients or studies (e.. it is usually preferable to present rates of abnormal values and to specify the cutoff value for inclusion (e. observations. in a footnote to the table. abnormal laboratory values.g. for example.. adverse reactions should be listed in decreasing order of severity. ECGs). ICH guidance regarding the content of this section of the IB is relatively nonspecific.. Classify adverse reactions using meaningful and specific terms that best communicate the nature and significance of the reaction. in the title to the table. and that denominator should be identified in a footnote. chemical. adverse reactions should be listed in decreasing order of frequency. The intent is to summarize all the product information into a format that is familiar and readily understood by the intended audience. The rates for reactions that are specific to a subgroup (e. or by a combination of these. vital signs.. The frequency cutoff for the listing of common adverse reactions identified from clinical trials must be appropriate to the safety database.Investigator's brochure derived from all reported adverse events of that type not present at baseline or from a subset of reported events deemed by investigators to be drug related). and in the US.g. 99 • • • • • • • Marketing experience Authors of the IB should: • Identify countries where the investigational product has been marketed or approved. There should ordinarily be a common classification scheme across all studies in the safety database.[4] . 5 times the upper limit of normal) than to refer to a grading system. Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions. or some combination of these. pharmacological. and adverse product reactions). This information can be provided in text preceding the table. it should be structured similarly to the package insert. Indicate the types of studies from which the information in the table was derived and whether the study data were pooled. Within a category. If frequency information cannot be reliably determined. For quantitative data (e. • Summarize any significant information arising from the marketed use (e. Provide the denominator (N = number of patients) for each column in a table or listing. • Identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration. Adverse reactions should be categorized by body system.. dosages. or in order of decreasing frequency.g. gender-specific reactions such as menstrual irregularity) should be determined using the appropriate denominator. toxicological. routes of administration.g. as appropriate. It is often though of as the "first draft" of the product's label. formulations. by severity of the reaction. or in a footnote. The frequency cutoff should be noted in the listing or table header. in the text accompanying the listing or table. that fact should be disclosed in a footnote.g. an adverse effect on a laboratory test). This information should be based on previous human experience and on the pharmacological properties of the investigational product. and clinical information for the investigational product.

cure. or for the relief of symptoms associated with a recognized disease or condition.. Detailed information pertaining to drug preparation may include a brief description of acceptable storage conditions (e. teratogenic and nonteratogenic effects. reconstitution fluids and procedures. Other content to be provided by authors according to the Guidances include: Preparation instructions Text should designate any standard preparation instructions to ensure consistent administration of the investigational product. Dosage forms and strengths Warnings and precautions Possible risks and side effects anticipated based upon prior experience with the investigational product (or related drugs) should be clearly described. mitigation. recommendations may be provided for appropriate monitoring frequencies and tests to be conducted in patients with normal liver function as well as (if appropriate) those with mild. Hepatic impairment The IB should contain any safety data available on subpopulations of patients with hepatic impairment (e. Any special monitoring to be completed as part of the investigational use of the product should also be described. Based on this evidence. temperature and duration). retrieval. overdosage. or diagnosis of a recognized disease or condition.g. of a manifestation of a recognized disease or condition.g.g.g. A brief summary of conclusions from nonclinical studies and/or ongoing trials should also be included to describe any possible precautions. formulation and specific dosages to be evaluated. Adverse reactions Here. AST as a multiple of the upper limit of normal). including safety and efficacy data available from nonclinical studies and/or clinical trials to support human exposure (as proposed in any given study protocol). The sponsor should align the proposed indication with sufficient information on the investigational product. and/or potential drug-drug interactions.) Pediatric use Here. moderate or severe hepatic impairment. pharmacokinetic data). safety and efficacy in children. Precautionary statements may address.. prevention. grouped the severity of the dysfunction (e. dispensing. and return of unused investigational product to the sponsor. and the trial population to be studied. Text may refer to instructions for handling. safety during pregnancy. for example. driving or operating machinery. Detailed information on the investigational product may include the route of administration. pregnancy. . and devices for product infusion. etc.. the author describes any plans for assessing pediatric safety and effectiveness.Investigator's brochure 100 Indications and usage Authors should state whether the drug is indicated for the treatment.. preparation. Use in specific populations (E. authors are asked to describe the overall adverse reaction profile of the drug based on the entire safety database. nursing mothers. labor and delivery. The text should include reference to safety and efficacy parameters that have not yet been established.

How supplied/storage and handling This section should designate how the investigational product will be supplied to the trial site.Investigator's brochure 101 Drug abuse and dependence • If the drug is a psychotropic substance or otherwise has abuse potential. Description Nonclinical toxicology A summary of nonclinical toxicological effects of the investigational product in laboratory animals and in vitro should be described. Other agency requirements When a new drug enters a Phase I clinical trial. Depending on the nature of the drug and phase of clinical development.. As drug development continues through Phase II and Phase III trials. the drug's effect on reproduction and the developing fetus. to assess stability. appearance. The drug formulation.. a basic package insert or a product information brochure may be an appropriate alternative. if applicable. as well as precautions and special monitoring to be conducted. e. information relating to safety and effectiveness efficacy and pharmacokinetics and product metabolism in humans obtained from previous clinical trials must be included in subsequent IB updates. subacute.. and solubility). Data pertaining to drug stability should be described. and chronic toxicity testing. the IB must include possible anticipated risks and side effects.[5] If specific changes are made in the investigational product over the course of clinical development. dosage should be included. A list of individual components. and any in vitro studies that aimed to evaluate the drug's toxicity. as well as identifying those countries where the drug did not receive approval for marketing or was withdrawn from marketing. Text should specify that responsibility and accountability for the investigational product lies exclusively with the investigator/trial site. If the pharmacology of an approved drug is widely understood by medical professionals. special toxicity related to the route of administration. the authors are asked to describe any relevant clinical studies and experience and studies in test animals. All nonclinical toxicology data should conclude that it is reasonably safe to conduct the proposed clinical investigation(s). adverse drug reactions) obtained from the marketed use and should identify the countries where the drug has been approved to be marketed. tables that summarize findings across the various studies can be very useful to demonstrate outcomes in. data from any additional studies (e. Clinical trials may be conducted for new indications of drugs already marketed. including stability over time in specific packaging (e.g. If many clinical trials have been completed. Specific instructions for security and storage should be included. A complete tabulated summary for each toxicology study intended to support the clinical investigation should be included.g. different patient populations or different indications.g. chemical name.. Information may include a description and characterization of the drug substance (e.. In addition. the IB must contain nonclinical information about the pharmacological and toxicological effects and the pharmacokinetics and biological disposition in animals and the relevance of these findings to possible effects in humans. high density polyethylene bottles or blister packs).g. the summary may include data on the following: acute. molecular weight. the IB should discuss significant information (e. should be described. including their respective function in the drug formulation. or dissolution rate) should be included to properly characterize the new formulation in updated versions of the IB. .g. on the basis of the sponsor's or others' prior experience with the investigational drug or with related drugs. bioavailability. In this case.

Switzerland. emea. eds. fda. ich. depending on the stage of development and the volume of new relevant information generated. gov/ downloads/ Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ ucm073122.Investigator's brochure Even after the investigational drug has been approved for medical use. An example of an IB that incorporates Phase IV data is found at the following link [6]. europa. it is common practice to have the site sign and return a document indicating the updated IB has been received and reviewed.gcphelpdesk. As part of the site management process for regulated studies. then he or she should provide the necessary information to the trial personnel. New information may be so important that it should be communicated to the investigators.pdf) gcp investigator brochure (http://www. fda. If a formal IB is impractical. If the investigational product is provided by the sponsor-investigator.com) . pdf) [6] http:/ / www. p. pdf • International Conference on Harmonisation (ICH) Topic E6-Guideline for Good Clinical Practice (http://www. and possibly to the IRBs/IEBs before it is included in a revised IB. fda. Foote M. The Principal Investigator conducting the study at each site is responsible for ensuring the current IB has been provided to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) while the study is ongoing at their site. The IEC or IRB reviews the IB as part of its responsibilities in reviewing and approving the clinical trial protocol and the investigators conducting the study. html [4] Wood LF. org/ cache/ compo/ 276-254-1. Documentation of IEC/IRB approval is also required to be maintained in the study files both at the study site and by the study sponsor. pdf ICH GCP guidelines [2] http:/ / www. to have a document control system in place to manage the editing and publishing process. Basel. the sponsor-investigator should provide an expanded background information section in the trial protocol as a substitute. but is sponsored by the investigator. This section must contain the minimum current information described in the ICH guideline. therefore. eu/ pdfs/ human/ ich/ 013595en. It is important. Birkhouser-Verlag. [5] International Conference on Harmonisation (ICH) Topic E6-Guideline for Good Clinical Practice (http:/ / www. the IB may continue to be updated well into Phase IV Clinical trials. 102 IB updates An IB is usually revised and updated to include new information at least annually. When providing an updated IB to the IEC/IRB. References [1] http:/ / www. 2009. It is often helpful to the study sites to provide the change history to help ensure the study staff are aware of the changes. The competent authority in the country where the research is being conducted should also be informed of updates to the IB. gov/ ohrms/ dockets/ AC/ 05/ briefing/ 2005-4191B1_07_Genzyme-Campath. if not more frequently. fda. If the clinical trial is not sponsored by the pharmaceutical company. pdf [3] http:/ / www. Targeted regulatory writing techniques. the sponsor-investigator is responsible for obtaining any updates to the brochure from the commercial manufacturer and distributing the updates to the clinical sites. it is common practice to provide a listing of the changes made between the previous and current version. 105-120. gov/ downloads/ Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ ucm073122.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.

accessdata. a surgical procedure. is a procedure to independently assess the methodological quality of a clinical trial.gov/scripts/ cdrh/cfdocs/cfCFR/CFRSearch. Part 312.fda. a medical device. Investigational New Drug Application (https://www. and the United States (US). (http://www.pdf) • CDER Guidance for Industry. or an established treatment for comparison. • Code of Federal Regulations. at the University of Oxford.[1] [2] and as of 2008. Part 201. Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products — Content and Format. describing it in a 2007 book as "one of the simplest. sometimes known as Jadad scoring or the Oxford quality scoring system. Nuffield Department of Anaesthetics.fda.57) (https://www. its seminal paper has been cited in over 3000 scientific works.[6] but typically in a controlled trial researchers gather a group of volunteers and subject some to the test treatment.fda.accessdata. the patients in the test group are assessed for health improvements in comparison with the control group.23) • Code of Federal Regulations.pdf) If many clinical trials have been completed. (http://www.[5] The treatment might be. (http://www.cfm?fr=312.cfm?fr=201.[4] Background Clinical trials are conducted for the purpose of collecting data on the efficacy of medical treatments.pdf) Jadad scale The Jadad scale. most powerful and revolutionary forms of research".fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch. The Jadad scale is named after Alejandro Jadad-Bechara. different patient populations or different indications.fda. for example.pdf) • CDER Guidance for Industry.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.56 (and Part 201.g. Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format.[3] Jadad felt that the randomised controlled trial was of great importance for the advancement of medical science.Investigator's brochure 103 Guidance documents As part of its guidance on Good Clinical Practice (GCP). After a defined time period. Jadad and his team outlined their views of the effectiveness of blinding on published studies in a 1996 paper in the Journal of Controlled Clinical Trials. the International Conference on Harmonisation (ICH) has prepared a detailed guidance for the contents of the IB in the European Union (EU).cfm?fr=312.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM075057.56) • CDER Guidance for Industry. fda. Part 312. Investigational New Drug Application (https://www. Title 21. accessdata. tables that summarize findings across the various studies can be very useful to demonstrate outcomes in. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.23) • Code of Federal Regulations. Japan. a Colombian physician who worked as a Research Fellow at the Oxford Pain Relief Unit.fda. a new drug. gov/ downloads/ Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ ucm073122.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM075057. An appendix to the paper described a scale allocating trials a score of between zero (very poor) and five (rigorous). (http:/ / www. Title 21. or a preventative regime. .[5] Clinical trial protocols vary considerably depending on the nature of the treatment under investigation. It is the most widely used such assessment in the world. e. while giving the others either no treatment (known as a placebo).. Title 21.

trials can vary greatly in quality.[7] 104 Randomisation Randomisation is a process to remove potential distortion of statistical results arising from the manner in which the trial is conducted. abandoned the course of treatment. the subject patient or any other involved parties. both conscious and subconscious. and that method was appropriate. the attrition rate can skew results of a study. The Jadad scale is sometimes described as a five-point scale.[3] Each question was to be answered with either a yes or a no. Jadad et al. that nonrandomised trials are more likely to show a positive result for a new treatment than for an established conventional one.[8] Blinding frequently takes the form of a placebo. in particular in the selection of subjects.[9] Blinding should be appropriate to the study. each no zero points. In smoking cessation studies. Was the study described as double blind? 3. and is ideally double blind. Was there a description of withdrawals and dropouts? To receive the corresponding point.[10] Jadad questionnaire In an appendix to their 1996 paper.[7] Blinding The importance of scientific controls to limit factors under test is well established. Experimental blinding is a process to prevent bias. The Jadad team stated that they expected it should take no longer than ten minutes to score any individual paper. The reasons for doing so might be varied: the individuals may have moved away. However. published a three-point questionnaire that formed the basis for a Jadad score. an article should describe the number of withdrawals and dropouts. or fail to report back on its outcome to the researchers. particularly if any such effects are small. A paper reporting a clinical trial could therefore receive a Jadad score of between zero and five.Jadad scale However. Blinding can however be difficult to achieve in some trials. Studies have indicated. • The method of blinding was described. but was inappropriate. Each yes would score a single point. wherein neither the patient nor doctor is aware of whether they are in the control or test group. Whatever the reason. but was inappropriate. for example. and it was appropriate. an inactive dummy that is indistinguishable from the real treatment. surgery or physical therapy. in each of the study groups. .[8] The placebo effect is known to be a confounding factor in trials. it is routine to consider all dropouts as failures. Was the study described as randomized? 2. particularly for those subjects who ceased treatment due to perceived inefficacy. should allow their own prior expectations to affect reporting of results. Poor blinding can exaggerate the perceived effects of treatment. affecting the ability of both patients and doctors to report accurately on the clinical outcome. skewing results. it is also important that none of those involved in a clinical trial. though there are only three questions.[8] for example. The questions were as follows:[3] 1. Additional points were given if:[3] • The method of randomisation was described in the paper. • The method of blinding was described. Methodological errors such as poor blinding or poor randomisation allow factors such as the placebo effect or selection bias to adversely affect the results of a trial. eliminating any such psychological effects from the study. whether the researcher. for example. Points would however be deducted if:[3] • The method of randomisation was described. or died. Withdrawals and dropouts Withdrawals and dropouts are those patients who fail to complete a course of treatment. and the underlying reasons. there were to be no fractional points.

. php/ cca/ article/ view/ 5053). [11] [12] [13] Criticism The Jadad scale is not without its critics.. 2.J. bmj. [16] "Systematic Review of Quality Assessment Instruments for Randomized Control Trials" (http:/ / www.. Alejandro R. [10] Lancaster T. as much as he questions the assessment of quality of online medical information. Rheumatology 33 (8): 1710–1712. com/ ?id=DMiH5y6SDuQC& printsec=PPA5). (2007).. com/ cgi/ content/ full/ 321/ 7259/ 504). Carroll D.. pp. (1999 Oct. . Murray (2007). 8 (4): pp. Retrieved 2008-11-12. PMID 17825697. Afshar. Answers and Musings (2nd ed. Moore R. For critical analysis of an individual paper. de/ OJS/ cca/ index. pp. ISBN 978-1405132664. ISSN 0315-162X. PMID 10948038. doi:10. McQuay H. Jen-pei (2004). (2006). DG. [3] Jadad.Jadad scale 105 Uses Jadad scores may be used in a number of ways: 1. SA. Stephen D. com/ p/ articles/ mi_hb237/ is_2_88/ ai_n29412210/ pg_1).. British Medical Journal 2000 (321): p. Miller J. Imperial College Press. com/ ?id=e2KkvlQI7sYC& pg=PA109& lpg=PA109). T Lang.023.2007. pp. . MacNeily. gov/ MeetingAbstracts/ ma?f=102184966. Shein-Chung. "The revised CONSORT statement for reporting randomized trials: explanation and elaboration".J. Annals of Internal Medicine 134 (8): 663–694. Liu. 7th Best Evidence Health Care Cochrane Colloquium. Design and Analysis of Clinical Trials (http:/ / books. Gadotti IC.H. [9] Altman. Enkin.441–454. . Clinical therapeutics 29 (7): 1456–1467. [11] White. To evaluate the general quality of medical research in a particular field. W.M. nlm. Simon J. PC Gøtzsche. et al. PMID 11304107. com/ ?id=HXMUEjZ4vyAC& pg=PA2). [13] Welk.[18] References [1] Haynes. "Assessing the quality of randomized trials: reliability of the Jadad scale"..L. Adrian.A. Everitt.. et al. A.N. google. pp. "Assessing the quality of reports of randomized clinical trials: Is blinding necessary?". KF Schulz. Guyatt G. Universita San Tommaso d'Aquino.. . . A. 109. Ernst. [17] Clark.. (2006)..D. . PMID 10503804. Gavaghan D. D Moher. . doi:10. PMID 16753430.B. Gang. 5. Wiley. pp. "Scales to Assess the Quality of Randomized Controlled Trials : A Systematic Review" (http:/ / findarticles. who have charged that it is flawed. google.clinthera. PMID 2727468. [2] Olivo. Lippincott Williams & Wilkins. Physical therapy 88 (2). ISBN 9780781745246. CONSORT GROUP (Consolidated Standards of Reporting Trials) (2001-04-17).[15] [16] and can show low consistency between different raters. Jenkinson C. ISBN 9780198567615. Stat Med. uni-freiburg. Blackwell.1016/0197-2456(95)00134-4. "How study design affects outcomes in comparisons of therapy". D Elbourne.[14] 3.. J. html). Pickles. Control Clinical Trials 20 (5): 448–52. doi:10. [6] Brian.. being over-simplistic. Statistical Aspects of the Design and Analysis of Clinical Trials (http:/ / books. google. placing too much emphasis on blinding. Reynolds D. Macedo LG.E. R.504. Stanton T. 43. . doi:10. and even questions the value of quality assessments of clinical trials. Altman. ISBN 9780750641630. 2.R. com/ subscribers/ 06/ 08/ 1710-c. [8] Day. . [12] Wang. K.. Statistical Evidence in Medical Trials: What Do the Data Really Tell Us? (http:/ / books. [4] Jadad. imbi.1016/S0022-5347(06)00560-X. "Randomized controlled trials in pediatric urology: room for improvement". (1989). "Blinding in clinical trials and other studies" (http:/ / www. google. Magee DJ (2008). ISSN 0031-9023. [14] Simon. html).07. H. Randomized Controlled Trials: Questions.A. J Urol 176 (1): pp 306–310.). 122.. ISBN 9781860944413. Douglas G (2000). com/ ?id=zaq99M2p_sEC& pg=PA121). Sackett D. google. Controlled Clinical Trials 17 (1): 1–12. Andrew (2004). G. [7] Colditz.1016/j. F Davidoff. Tugwell P. com/ ?id=cuvY6TItIwgC& pg=PA31). . "The quality of reporting of randomized controlled trials of traditional Chinese medicine".[17] Jadad has accepted these criticisms. Fuentes J. nih. PMID 8721797. B. (2005).1002/sim. jrheum. [5] Chow. Acupuncture: A Scientific Appraisal (http:/ / books. 31. "Is the Jadad Score the Proper Evaluation of Trials?" (http:/ / www. The Cochrane Collaboration. A researcher conducting a systematic review for example might elect to exclude all papers on the topic with a Jadad score of 3 or less. To set a minimum standard for the paper's results to be included in a meta analysis. Elsevier. M Egger. Oxford University Press..4780080408. pp.). (1996). V. Edzard (1999). Stead L (1999). ISBN 9780471249856. Clinical Epidemiology (http:/ / books. [15] Berger.J. Mosteller F. "Dealing with drop-outs in clinical trials and meta-analyses" (http:/ / gateway.

stroke. Paul Ridker. and profits from its use. and a reduction of 0.7337.[4] [5] [6] The study's authors estimated that the number needed to treat with rosuvastatin to prevent one cardiovascular event was 95 over 2 years. has been cited by those urging caution before expanding indications for statin treatment.[1] The trial. . along with concerns over the safety of very low LDL levels.569. patients given rosuvastatin had reductions in LDL and CRP levels. doi:10. and the validity of biomarkers used in the diagnosis of cardiovascular disease. an effect that has also been seen in studies with other statins.[8] Adverse events The researchers noted small but significant increases in the rate of physician-reported diabetes and glycated hemoglobin values in the rosuvastatin group. is directed by Paul Ridker of Brigham and Women’s Hospital. "Examination of instruments used to rate quality of health information on the internet" (http:/ / www. (2002).[3] Elevated hs-CRP levels are thought to be a biomarker of inflammation..[4] This finding.S. and whether statin therapy could prevent cardiovascular events among them. results presented at the American Heart Association meeting and published in the New England Journal of Medicine found that patients with low-to-normal LDL cholesterol receiving rosuvastatin had a lower rate of major cardiovascular events. rosuvastatin's higher cost compared to generic statins. British Medical Journal 2002 (324): 569–573. bmj. peripheral arterial disease. JUPITER was designed to determine whether hs-CRP testing could identify these patients. Gagliardi. Compared to patients taking a placebo. The trial was stopped early by the study's independent data and safety monitoring board because the interim results met the study's predefined stopping criteria.Jadad scale [18] Jadad.[2] Because half of all vascular events occur in patients with normal or low levels of LDL cholesterol.6% in their absolute risk of heart attack. A. JUPITER was the first clinical trial to indicate that statin therapy may provide benefit to patients with low-to-normal LDL levels and no known cardiovascular disease. and have been associated with an increased risk of myocardial infarction.1136/bmj.2% to 0.[3] Study details The trial analyzed 17. the marketer of Crestor (rosuvastatin). PMID 11884320. or 25 over 5 years. is the inventor of the CRP assay utilized in the study.[1] The trial is sponsored by AstraZeneca. statin drug market following the November 2008 New England Journal of Medicine publication. A. and death at 1 year. Study rationale JUPITER was a randomized double-blind placebo-controlled study investigating the use of rosuvastatin in the primary prevention of cardiovascular disease. In 2008.R.802 patients without evidence of heart disease but with high CRP levels. 106 JUPITER trial The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) is a study aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.[9] [10] [11] [12] .324. and sudden cardiac death.[2] The company saw an increase in its share of the U.[7] The NEJM study's lead author. com/ cgi/ content/ full/ 324/ 7337/ 569). The trial focused on patients with normal low-density lipoprotein (LDL) cholesterol levels but increased levels of high-sensitivity C-reactive protein (hs-CRP). which began in 2003. stroke.

but what does it mean?" (http:/ / www. 2009. suggested that CRP does not play a causal role in cardiovascular disease. . reuters. Poll Shows" (http:/ / www.1161/01. published in the Journal of the American Medical Association. com/ 2009/ 07/ 01/ health/ 01heart. N. . .[8] References [1] "JUPITER: Using hsCRP to identify primary prevention patients who may benefit from statin therapy" (http:/ / endocrinetoday. doi:10. Brigham and Women’s Hospital [3] Ridker PM. doi:10. Endocrine Today. nejm. endocrinetoday. marketwatch. "Expanding the orbit of primary prevention--moving beyond JUPITER" (http:/ / content. 1 December 2008 [7] "Astra's Crestor gets sales boost after positive data" (http:/ / www. com/ view. "The Clinical Utility of High-Sensitivity C-Reactive Protein in Cardiovascular Disease and the Potential Implication of JUPITER on Current Practice Guidelines" (http:/ / www. Engl. [13] Elliott P et al. Engl. Group (November 2003).1056/NEJMoa0807646. PMID 19095730. Los Angeles Times.109728. External links • Clinicaltrials. [9] Hlatky MA (November 2008).0000100688. latimes. org/ cgi/ pmidlookup?view=short& pmid=18997196& promo=ONFLNS19). (2009). org/ cgi/ content/ full/ 302/ 1/ 37). 24 November 2008 [8] Kolata. com/ features/ health/ la-hew-plaquebox8-2008dec08. pdf). Circulation 108 (19): 2292–7. 25 November 2008 [2] JUPITER trial information page (http:/ / www. doi:10. "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein" (http:/ / content. 55 (2): 219–28.gov entry (http://clinicaltrials. N. New York Times. [10] "Dramatic JUPITER Findings Fail to Sway Prescribing Behavior.0. Blumenthal RS (February 2009). particularly on the role of C-reactive protein. J. PMC 2803020. PMID 18997195. "Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial" (http:/ / www.1001/jama. doi:10. Retrieved July 1. Chem. com/ comments. doi:10. Hazen SL (January 2009). story). . Jupiter Study. org/ cgi/ pmidlookup?view=short& pmid=18997195& promo=ONFLNS19). doi:10. (November 2008). clinchem.3949/ccjm. ccjm. Clin.E6. nejm. org/ preventivemedicine/ research/ jupiter. Fonseca FA. "Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease" (http:/ / jama. Cleve Clin J Med 76 (1): 37–44. aspx?rid=32617). MarketWatch. Med. 359 (21): 2280–2.2607843. 8 December 2008 [6] "Treating elevated C-reactive protein with a statin" (http:/ / www. org/ preventivemedicine/ Research/ Circv108p2292. Gina (June 30. [12] Mora S. com/ news/ story/ Dramatic-JUPITER-Findings-Fail-Sway/ story. aspx?guid={BEADADD0-E088-48E9-9B31-91A1D5A5401D}).CIR.17280. aspx?rid=33130).1373/clinchem.954.2009. [4] Ridker PM. nytimes. PMID 19122109. PMID 18997196. Endocrine Today. Danielson E. org/ cgi/ pmidlookup?view=long& pmid=19095730). ama-assn. J. press release. PMC 2836530. A 2009 study employing Mendelian randomization. "JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP. . "Study Dismisses Protein’s Role in Heart Disease" (http:/ / www. Musunuru K.gov/show/NCT00239681) . et al. brighamandwomens. org/ cgi/ pmidlookup?view=long& pmid=19122109). 359 (21): 2195–207. aspx).[13] The discordant results of this subsequent study provoked debate over the role and value of CRP as a biomarker and possible therapeutic target in heart disease. brighamandwomens. 2009). [5] "To combat plaques. .JUPITER trial 107 Contrasting results from other studies Some subsequent studies have contrasted with the JUPITER trial results. JAMA 302 (1): 37–48. PMID 19567438. research targets inflammation-fighting statins" (http:/ / www. html).1056/NEJMe0808320. Reuters.2008. com/ article/ rbssHealthcareNews/ idUSLO23065120081124). Med. PMID 14609996. .08105.75a. 25 November 2008 [11] Shishehbor MH.

however. Pfizer. albeit at a lower dose than was standard. Inc. Representative Tom Lantos of California. Plaintiffs alleged that “they suffered grave injuries from an experimental antibiotic administered by defendant Pfizer Inc. For a time. the Declaration of Helsinki. the senior Democrat on the House International Relations Committee. described the report’s findings as “absolutely [3] appalling” and called for Pfizer to open its records. it seemed that the end result would be that the Nigerian plaintiffs would be barred from bringing suit in the United States. (“Pfizer”) without their informed consent. Dutse falsified the letter for [2] research ethics approval. All of the children treated with the drug were already severely ill with meningitis.”[4] On 29 August 2001. P 96. Pfizer developed Trovafloxacin Mesylate. the plaintiffs' putative claims had been dismissed three times. with many others suffering life-altering injuries. The District Court summarized the Nigerian plaintiffs’ allegations as follows: In the mid-1990s. In May 2006.S. Overall. Nigeria's position on the African continent The survivors of the trovafloxacin test attempted to bring a number of legal actions against Pfizer in the United States.[1] five of whom died.000 people.[5] to recover damages for Pfizer’s alleged violations of the Nuremberg Code. Pfizer also treated 100 children with the standard anti-meningitis drug ceftriaxone (a cephalosporin antibiotic). a group of Nigerian minors and their guardians sued Pfizer in the United States District Court for the Southern District of New York. plaintiffs brought this action under the Alien Tort Claims Act.” Pfizer projected that its total annual sales could exceed $ 1 billion a year. at least one member of the United States Congress. These attempts to bring suit against Pfizer resulted in four judicial opinions. The lead investigator was Dr. Six of those 100 children died. 28 U. Chemical structure of trovafloxacin Abdullahi v. However in late January 2009 the United States Court of Appeals for the Second Circuit ruled that the Nigerian victims and their families are entitled to bring suit against Pfizer in the United States under the Alien Tort Statute. Dr. with no decision on the merits. I In 2002. the 1996 meningitis epidemic in northern Nigeria killed about 12. during the worst known meningitis outbreak in Sub-Saharan Africa.C.) . After four attempts to sue Pfizer in America.Kano trovafloxacin trial litigation 108 Kano trovafloxacin trial litigation The Kano trovafloxacin trial litigation relates to a 1996 incident when the pharmaceutical company Pfizer conducted tests of trovafloxacin (a quinolone antibiotic) in Nigeria on 100 children. the International Covenant on Civil and Political Rights and customary international law (otherwise known as the “law of nations”). (Compl. Abdulhamid Isa Dutse. § 1350. an antibiotic that is also known by its brand name as “Trovan.

PP 2-3. P 3. however.) Plaintiffs allege. (Compl. (Compl. (Compl. a drug recommended by the World Health Organization to treat bacterial meningitis in epidemic situations. traveled to Kano’s IDH to treat the sick. Pfizer informed the FDA of its intent to conduct the Kano study. plaintiffs allege that no IDH ethics committee existed as of 28 March 1996 and that the 28 March letter was back-dated in response to a 1997 FDA audit. Pfizer dispatched a medical team to establish a treatment center at Kano's Infectious Disease Hospital (“IDH”). Nigerian officials allocated to Pfizer two of IDH’s wards to conduct the testing. MSF established their headquarters in tents beside the IDH due to space constraints. Pfizer administered only one-third of ceftriaxone's recommended dosage. PP 132-33. (Compl. prior animal testing indicated that Trovan might cause significant side effects in children such as joint disease. Food and Drug Administration’s (“FDA”) authorization to export Trovan. P 105-06. (Compl. P 108.) In 1996. from lines of those awaiting treatment. 124-25. (Compl. PP 11.) However. that Pfizer neglected to analyze the patients’ blood samples and therefore could not determine if a patient had a negative reaction until the manifestation of a visible and permanent injury. untested and unproven” antibiotic “Trovan. measles and cholera besieged the impoverished Nigerian city of Kano.) To travel to Kano. (Compl.) There. (Compl. (Compl.) Thereafter. 101-07. P 108. and then only after all other antibiotics failed. Pfizer switched his or her treatment to ceftriaxone.) The medical teams operated under squalid conditions in a hospital consisting of several single story cinder block buildings.) The beds were filled to capacity and patients seeking care overflowed on to the hospital's grounds. P 7. Pfizer embarked on a medical experiment involving the “new.) Pfizer divided them into two groups and treated half with Trovan.S. abnormal cartilage growth (osteochondrosis. 95.) Although Pfizer’s protocol called for its team to obtain consent from the parents of the children treated who were too young to sign. epidemics of bacterial meningitis. P 125.) In addition to Pfizer team. P 126. 8.) If a child was not responding well to Trovan. (Compl. (Compl. (Compl. (Compl. On 15 March 1996. or that other organizations offered more conventional treatments at the same site free of charge. that they could refuse it.) Pfizer’s protocol also called for the children selected to have their blood tested on arrival and five days later.) Prior to Kano. Pfizer needed the U. some of which lacked electricity and running water. (Compl. joint stiffness. 6. (Compl.) The other half was “purposefully ‘low-dosed’” with ceftriaxone. an FDA-approved drug shown to be effective in treating meningitis. No child had ever received it orally.) Plaintiffs further allege that low-dosing ceftriaxone resulted in injuries and deaths among the control group. P 127. (Compl. P 3. (Compl. (Compl. (Compl. PP 98-99. Pfizer obtained a 20 March letter from the Nigerian government and a 28 March letter from IDH’s ethics committee permitting Pfizer to export Trovan to Kano. 101.) Although both letters predate Pfizer’s departure for Kano. (Compl. P 97. 109.) MSF treated pediatric meningitis patients with chloramphenicol.) Pfizer selected. only one child had ever been treated with Trovan. 8. few parents could speak or read English. (Compl. PP 2. P 126. (Compl. 101-02. a disease resulting in bone deformation) and liver damage. humanitarian organizations such as Medecins Sans Frontieres ("MSF"). children ranging in age from one to thirteen years who exhibited symptoms of neck stiffness. P 126. 115. PP 2. 111.) Pfizer.) In order to enhance the comparative results of Trovan. P 110. P 112.) Meanwhile. P 3. (Compl. MSF admitted their sickest patients to hospital beds in the IDH and confined the less ill to floor mats in their tents. (Compl. P 5.) Plaintiffs allege that while MSF and other organizations offered safe and effective treatments for bacterial meningitis.) According to plaintiffs. also known as Doctors Without Borders. P 110. six weeks after it first learned of the epidemics. 5. P 3.) Plaintiffs claim that Pfizer failed to explain to the children’s parents that the proposed treatment was experimental. (Compl.Kano trovafloxacin trial litigation Beginning in 1996. P 111.) In April 1996. Pfizer conducted the largest drug testing program ever undertaken by enrolling thousands of participants in clinical tests. PP 109 . (Compl.” (Compl.[6] Plaintiffs further contend that Pfizer’s sole purpose for traveling to Kano was to expedite the FDA's approval of Trovan to treat pediatric victims. P 113. and high fevers with headaches.

(Compl. (Compl. Pfizer launched Trovan after it received FDA authorization for treatment of a number of adult illnesses. P 224. P 218. the FDA recommended that Trovan be prescribed only for patients in nursing homes or hospitals suffering from life-threatening conditions.” Next. the court denied the motion to dismiss on these grounds.Kano trovafloxacin trial litigation 3. (Compl. (Compl. P 120. Pfizer withdrew its application.” However. P 224-25.) Further. the European Union's Committee for Proprietary Medicinal Products suspended all sales of Trovan in part due to results from the Kano tests. thereby Pfizer acted as a “de facto state actor. Pfizer applied with the FDA for approval to market Trovan in the United States for various uses including the treatment of pediatric infectious diseases. deafness and blindness. because their actions did not fit the narrow exceptions when a private party will be held liable for the “law of nations. P 216. 110 . 157. Pfizer and the FDA received reports regarding Trovan patients suffering liver damage. regulators informed Pfizer that they planned to deny its application to use the drug against epidemic meningitis and expressed several concerns including Pfizer's failure to conduct follow-up examinations. Despite the plaintiff’s claims that the Nigerian court system is corrupt and could not provide an adequate alternative forum. and. P 223.) In June 1997.) In January 1999. PP 16-50. 128-30. (Compl.) On 30 December 1996. Pfizer agreed to return to the United States if Nigeria declined to accept jurisdiction.[8] alleging that the Plaintiffs’ fail to plead a violation of the law of nations. FDA inspectors discovered inconsistencies in the data resulting from Pfizer’s Kano treatments.) After two weeks. 154-55. Pfizer filed a motion to dismiss. Accordingly. (Compl. the Pfizer team left Kano and never returned for follow-up evaluations. provided Pfizer consented to suit and acceptance of process in Nigeria. PP 221-22.) In addition.) On 18 February 1998. P 219. the court ultimately found that Nigeria did provide an adequate alternative forum and the “Gilbert factors” weighed in favor of transferring the case to Nigeria. (Compl.) Plaintiffs allege that five children who received Trovan and six children whom Pfizer “low-dosed” died.) Others suffered paralysis. (Compl. (Compl. (Compl. In response.)[7] In response to Plaintiffs’ allegations. Pfizer made available documents and employees. P 217. Pfizer agreed to limit distribution of Trovan to hospitals and long term nursing facilities.) Shortly thereafter. the court granted the defendant’s motion to dismiss this action on grounds of forum non conveniens. pursuant to Rule 12(b)(6) of the Federal Rules of Civil Procedure. 117-20. P 224. (Compl. Pfizer waived possible statute of limitation problems. (Compl. because the complaint sufficiently alleged that Pfizer had worked in concert with the Nigeria government.) Thereafter.) That following June. Pfizer sought dismissal on grounds of forum non conveniens. P 217.) The FDA announced that it received reports of more than 100 cases where Trovan patients exhibited clinically symptomatic liver toxicity and advised physicians to use Trovan only for patients who met certain criteria. (Compl. the FDA issued a public health advisory on liver toxicity associated with oral and intravenous Trovan following post-marketing reports of acute liver failure strongly associated with the drug. P 122.

"[10] The Court of Appeals noted that plaintiffs had submitted a number of affidavits from State Department and United Nations officials to buttress their claims about corruption in the Nigerian judiciary. The court’s somewhat searching review of the Zango litigation came in direct response to the Court of Appeals holding. While under normal circumstances Nigeria appeared to be an adequate forum. Finding instead. United States Court of Appeals. The District Court discussed the "Zango litigation"’s procedural history. instead opting to vacate the district court’s dismissal on grounds of forum non conveniens and remanding the case to the district court to consider the implications of the "Zango litigation" on its forum non conveniens analysis. “having declined jurisdiction in this matter for personal reasons. “If the plaintiff shows that conditions in the foreign forum plainly demonstrate that plaintiffs are highly unlikely to obtain basic justice. concluding that the Plaintiffs’ filed a Notice of Discontinuance.[11] Adequate Alternative Forum Analysis After setting forth the factual and procedural background the District Court turned its attention to the Zango litigation. the Court of Appeals acknowledged that on appeal both parties had requested judicial notice of facts contained within the record of a parallel proceeding. For these reasons. the District Court granted Pfizer’s dismissal under Rule 12(b)(6) and found that the Zango litigation did not preclude dismissal for forum non conveniens. Pfizer (“Zango litigation”). II The Nigerian Plaintiffs appealed from the District Court’s order of final judgment to the United States Court of Appeals for the Second Circuit. involving different plaintiffs. which questioned whether Nigeria was in fact an adequate alternative forum. that dismissal was a result of the Plaintiff’s waiting “endlessly for a new judge to replace Judge Hobon. The Court of Appeals. because the "Zango litigation" had ended in dismissal.Kano trovafloxacin trial litigation 111 Abdullahi v. The Court of Appeals reviewed the forum non conveniens dismissal under the “clear abuse of discretion” standard. The Zango litigation had recently been dismissed in Nigeria.” who had recused himself for personal reasons. the Court of Appeals vacated and remanded to the District Court. the court ultimately held that Plaintiffs were unable to establish corruption and bias in the "Zango litigation". revisited the Court’s analysis of the adequate alternative forum. Although Plaintiff’s provided allegations of corruption and anecdotal evidence. both dismissal pursuant to Rule 12(b)(6) of the Federal Rules of Civil Procedure and dismissal pursuant to the doctrine of forum non conveniens. . Next. III After the Court of Appeals vacated and remanded. Inc.[9] Pfizer cross-appealed denial of its motion to dismiss pursuant to Rule 12(b)(6) of the Federal Rules of Civil Procedure. Pfizer. Abdullahi v. in a Nigerian Court. the District Court readdressed the dual grounds for dismissal. For these reasons. The court declined to take judicial notice of the "Zango litigation". in rare cases this may not be enough. again found that Nigeria provided an adequate alternative forum. On remand. Pfizer. Inc. a defendant’s forum non conveniens motion must be denied.”[12] Next. The Court of Appeals referred to the Nigerian litigation as Zango v. the court addressed the Plaintiff’s allegations of corruption within the Nigerian judiciary. based upon the Federal High Court. however. the District Court.

which the court mistakenly refers to as Federal Rule of Civil Procedure 12(b)(6). for failure to state a claim under the Alien Tort Claims Act and. the action would be dismissed on forum non conveniens grounds (under the same conditions set forth in Abdullahi I).”[15] Having set forth the relevant standard.” None of the sources of international law cited by the Plaintiffs were a proper predicate for jurisdiction under the Alien Tort Claims Act. the court relied heavily upon Sosa. Instead. the Alien Tort Claims Act creates no new causes of action but confers on federal courts the power to hear a narrow set of alien tort claims for violations of international law. Inc The District Court recites the facts set forth in Abdullahi I. the District Court concluded that Nigerian — not Connecticut — substantive law governs. even if subject matter jurisdiction were found. First. with the same additional conditions required by Abdullahi I and Abdullahi III. The court began by analyzing Connecticut’s choice of law principles. and accordingly.” [Id. to recognized new actionable rules based on evolving principles of international law.[16] In addition to lack of subject matter jurisdiction. the District Court found that the Universal Declaration of Human Rights does not impose obligations as a matter of international law. Second. the District Court found that the Declaration of Helsinki and the CIOMS guidelines does not contain a private cause of action.[14] However. before turning to the claims under the Connecticut Unfair Trade Practices Act and the Connecticut Products Liability Statute. the court evaluated whether Pfizer did in fact violate customary international law. it is “merely aspirational. under both the Alien Tort Claims Act and the Connecticut statutory causes of action. exercising a vigorous gatekeeping function. Finally.Kano trovafloxacin trial litigation 112 Applying Sosa In finding that dismissal was also appropriate under for lack of subject matter jurisdiction.S. the District Court found that the ICCPR was not “self executing” and that a private right of action should not be implied. the Supreme Court did leave the door open for courts. Supreme Court building courts should require any claim based on the present-day law of nations to rest on a norm of international character accepted by the civilized world and defined with a specificity comparable to the features of the 18th-century paradigms. Under Connecticut’s qualified lex loci delicti doctrine. the court also granted the motion to dismiss on grounds of forum non conveniens. . at 34. does not contain a private cause of action. the court granted Pfizer’s motion to dismiss.] Third. “federal U. finding these guidelines are merely a “general statement of policy that is unlikely to give rise to obligations in any strict sense. For the reasons discussed. which governs scientific research on human subjects. However. and the analysis of the Alien Tort Claims Act set forth in Abdullahi III. the District Court found that the Nuremberg Code. Ajudu Ismaila Adamu v.[13] Under Sosa. Instead. Pfizer. both Connecticut law claims were dismissed.

2005 U. 2005) (“Abdullahi III”). "Pfizer accused of testing new drug without ethical approval". 503 (N.. A01.. at *1 n. N.[18] In October 2009. co. PMID 11159610. 48.D. 2002 U. the District Court ultimately dismissed for lack of subject matter jurisdiction. 2006).95 bln" (http:/ / www.Y. Sarah (9 December 2010). 2005). LEXIS 20704 (2d Cir. Pfizer. Reuters.N. seeks $6. Inc. the Abdullahi Court refers to the act consistently as the "Alien Tort Statute" “because the statute is purely jurisdictional in nature.S. 2d 495. Supp. 2005 U. Inc.S. the case was adjourned until 26 June of that year. 399 F. Dist.S. Lack of subject matter jurisdiction is governed by Federal Rule of Civil Procedure 12(b)(1). (2001). Inc. [16] Ajudu Ismaila Adamu v. irinnews. PMC 1119465. 692. com/ article/ health-SP/ idUSL). The Washington Post: p. 1. LEXIS 16126." [19] The talks were brokered by the former Nigerian military leader Yakubu Gowon and the former U. LEXIS 17436 at *4-7. at 52.Y.Y. org/ PrintReport. washingtonpost.D. com/ wp-dyn/ content/ article/ 2006/ 05/ 06/ AR. Pfizer. LEXIS 16126 (S. [8] Despite the Court’s consistent citation of Federal Rule of Civil Procedure 12(b)(6). Ed. [5] Although titled the Alien Tort Claims Act.N.. Joe (May 7. "WikiLeaks cables: Pfizer 'used dirty tricks to avoid clinical trial payout'" (http:/ / www. com/ stories/ 200910050887.. September 17.D. [4] Abdullahi v. [15] Abdullahi v. 124 S. seeking US$6. Pfizer issued a public statement that the letter was “incorrect.” . the government of Nigeria filed against Pfizer in the Nigerian Federal High Court. AFP. [11] Abdullahi v.Y. Appx... Pfizer's country manager admitted that "Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases. Pfizer.S. Dist. conducted their own investigation. 2005 U. [9] Abdullahi v.Y.link leads to UN IRIN news report) [2] Wise. at 22-23. and does not provide a private cause of action.. the Nigerian government Pfizer as part of the $75million settlement of the protracted dispute. nor did the defendant seek or receive approval to conduct any clinical trial at any time before their illegal conduct". LEXIS 17436 at *1 (S.S.D. it was announced that the medical records of the victims of the 1996 Pfizer Trovan clinical trial could not be found at the Kano State Ministry of Health nor at the Infectious Diseases Hospital (IDH) where the trials were conducted according to the state's Attorney General and Commissioner for Justice Barrister Aliyu Umar. .S. The Guardian (London).) 322 (7280): 194. Pfizer. html). The announcement was made shortly after Umar confirmed that the state government had received $10million from [20] Additionally.S. An out-of-court settlement was reached and will be put in writing at a meeting scheduled to take place in Rome. 2d 718. 2002 U. [20] http:/ / allafrica. html [6] When confronted with evidence that the 28 March letter was in fact back-dated. Dist. 4 June 2007 [18] "Pfizer settles multi-billion dollar Nigerian case: source" (http:/ / www. 2003 U..[17] 2009 settlement In February 2009. Nigeria claimed that Pfizer "never obtained approval of the relevant regulatory agencies. Pfizer. 2002) (“Abdullahi I”). .95 billion in damages. Ct. Italy in March 2009. [10] Id. Ct. guardian. Inc. 2003) (“Abdullahi II”). Pfizer decided to settle its legal case with the 200 plaintiffs. BMJ (Clinical research ed. com/ hostednews/ afp/ article/ ALeqM5gn2FKY2RU91rq4vfD36UmsCOkwLA). References [1] (Source of number: http:/ / www. App.[18] The settlement followed months of negotiations between Pfizer and the Kano state government which represented the plaintiffs. August 9.. 159 L. 2739. [14] Id. October 8. [19] Boseley. LEXIS 16126. Inc. [7] Abdullahi I. Pfizer. at *23 (S. [17] "Nigeria files suit against Pfizer. This report was kept secret for five years with the only three printed copies being lost and disappearing. President Jimmy Carter. aspx?ReportId=72601 -. [12] Id. . Dist. J. [13] 542 U. reuters.N. Dist. Inc. google. at )." Abdullahi v. After preliminary arguments. 77 Fed.Kano trovafloxacin trial litigation 113 Nigerian government lawsuit On 5 June 2007. uk/ business/ 2010/ dec/ 09/ wikileaks-cables-pfizer-nigeria).S. 124 S. "Panel Faults Pfizer in '96 Clinical Trial In Nigeria" (http:/ / www. August 9. 2003) (“Abdullahi III”) (citing Sosa.[18] According to Wikileaked US embassy cables . [3] Stephens.S.

faster-growing tumors are also often associated with a poorer prognosis. Length time bias can occur when the lengths of intervals are analysed by selecting intervals that occupy randomly chosen points in time or space. This process favors longer intervals. This can mean screening tests are erroneously associated with improved survival. For example.com/files/news/trovan_statement_defense_summary.pfizer. and so are less likely to be detected. thus skewing the data. . fpnotebook. length time bias can affect data on screening tests for cancer.Kano trovafloxacin trial litigation 114 External links • Statement of Defense (http://media. However. htm) Length time bias in cancer screening. com/ Prevent/ Epi/ LngthBs.pdf) on Trovan. a statistical distortion of results which can lead to incorrect conclusions about the data. Slower-growing tumors are hence likely to be over-represented in screening tests. Screening appears to lead to better survival. even if they have no actual effect on prognosis. Kano State Civil Case Length time bias Length time bias is a form of selection bias. Faster-growing tumors generally have a shorter asymptomatic phase than slower-growing tumours. even when no effective treatment is given.[1] References [1] Length Bias (http:/ / www.

But given the history of Western medicine trials in Africa that are consciously done. Studies showed that the infections may have been due to needles not washed properly prior to the Bulgarian nurses arrival to Libya [8] . including Nature. Chad and Burkina Faso because many people avoid vaccinations[8] . suggested that in one case against Bulgaria where Libyan children were infected through the re-use of incompletely cleaned medical instruments.Medical experimentation in Africa 115 Medical experimentation in Africa African countries have been sites for clinical trials by large pharmaceutical companies[1] . African nations minimize regulation on the conduct of medical research so that many legal battles do not arise[6] . They believe that the vaccines are contaminated with H. For example. International and National Codes of Ethics African Charter on Human and Peoples The provision of article 4(2)(h) of the Protocol to the African Charter on Human and Peoples' Rights on the Rights of Women in Africa seeks to prohibit all medical and scientific experiments on women without their prior informed consent[3] .[7] . In most cases this is because nations cannot afford such research without subsidies from multinational pharmaceutical corporations[5] . Poverty and experimentation People living in the rural areas and slum area are more vulnerable to experimentation since they are largely illiterate and may not understand the effects of the experimentation[2] . polio has been on the rise in Nigeria. There have been reports of unethical experimentation and unethical clinical trials in Africa and improper informed consent methods. or sterilization agents[8] . The African Charter on Human and Peoples' Rights on the Rights of Women in Africa seeks to prohibit all experiments on women without their informed consent during clinical trials[3] . there were accusations of iatrogenic. or healer-transmitted infections. Human rights activists are asking for more accountability in reference to informed patient consent in Medical experimentation in Africa. Iatrophobia in Africa Medical experimentation has been occurring in Africa for a long time in some cases it has led to iatrophobia particularly on new drug clinical trials [8] . Due to medical experimentation in the past. Nuremberg Code and Helsinki Declaration The Nuremberg Code and Helsinki Declaration both offer protection to subjects in clinical trials and medical experimentation[4] .V. Programs for researchers doing research in Africa are being encourage to understand the clinical trial histories to improve informed consent process. there is a fear and mistrust in some countries and areas in Africa of medical experimentation[8] .[8] .I. They are also forced with making Hobson's choice: "experimental medicine or no medicine at all". Several science journals. This means that the acts may have been accidental.[2] . To court these pharmaceutical corporations. there was heightened mistrust that it was not intentional [8] . National codes of Ethics Many African nations lack any legislative protections for subjects of medical research.

Many of these experiments were conducted at the Military Hospital at Voortrekkerhoogte. This has led to mistrust of medical vaccines in Nigeria. Aubrey Levin is now Clinical Professor in the Department of Psychiatry (Forensic Division) at the University of Calgary’s Medical School and a member at the College of Physicians and Surgeons of Alberta[9] . Pfizer countered that it met all the necessary regulations[17] .S.[16] He joined the Nazi party thereafter where he did similar experiments in the Jewish concentration camps. He was charged with killing hundreds of blacks in South Africa and Namibia via injected poisons. The United States began testing AZT treatments in Africa in 1994. His experimentation was largely done on mixed-race offspring in order to provide justification to ban mixed-race marriages. electric shock. Late stage studies were later continued by Doctor Hams Harmsen. Meningitis testing in Kano. 16 to 24-year-old white males drafted into the apartheid army although a few women did have to undergo experimentation[9] [10] . It included testing of over 17. Eugen Fischer." in detail and with consistency" about the medical crimes they conducted against blacks[8] . Dr. founder of the German branch of International Planned Parenthood Federation (IPPF) whose name is also associated with the compulsory sterilisation in Nazi Germany. Sterilisation experiments in Namibia In the case for sterlisation experiments were initially conducted on Herero women in German-occupied South West Africa (Namibia) by Dr.Population control interests motivated many of the family planning programs. Nigeria The Pfizer drug. 200 children were disabled and 11 were dead. Once approved. Many had to undergo to chemical castration. where they refuse to participate in many trials now[17] . Nigeria[17] [18] . even though his lieutenants testified.[14] [15] . Trovan was used in a clinical trial in Nigeria. . He was never convicted in South African courts. Many of the victims were young. a former head of South Africa’s chemical and biological weapons unit under apartheid in South Africa[8] . By the time the trial ended. This led to its eventual ban in Zimbabwe [13] . particularly in Kano. Aubrey Levin South Africa’s apartheid army forced white lesbian and gay soldiers to undergo ’sex-change’ operations. physicians and the University of Zimbabwe were not performed with proper informed consent. Depo-Provera in Zimbabwe Depo-Provera for example. This was supported by psychological treatment by army psychologists. HIV/AIDS Short-Course AZT Testing in Zimbabwe (1994-1998) AZT trials conducted on HIV-positive African subjects by U.It was part of a secret program to purge homosexuality in the army[9] . This led to a lawsuit from the Nigerian government over informed consent in Kano.Medical experimentation in Africa 116 Controversial medical experimentation In Africa The Aversion Project in South Africa (1970s-1980's) In a project headed by Dr. An estimated 900 forced ’sexual reassignment’ operations may have been performed between 1971 and 1989 at military hospitals[9] . There was coercion of women to accept Depovera on white-run commercial farms [12] . Project Coast in South Africa (1979-1987) South Africa's Project Coast was conducted by Wouter Basson. [19] . the drug was then used as a population control measures in the 1970's.000 women for a medication that prevents mother to child transmission of HIV/AIDS. and other unethical medical experiments if they could not be 'cured' with drugs. through projects funded by Centers for Disease Control (CDC) and the National Institutes of Health (NIH). was clinically tested on Zimbawean women[11] .

The New York Times. Amy. com/ 2007/ 07/ 31/ opinion/ 31washington. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [6] Meier. .Harriet A. New York Times best seller Harriet A Washington's book Medical Apartheid. "Why Africa Fears Western Medicine" (http:/ / www. Medical Apartheid.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [5] Meier. html [4] Meier. wikipedia. htm [16] http:/ / en. com/ content/ 3/ 3/ 306. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [23] Meier. 2006-06-01. West Africa — Clinical Trials" (http:/ / ctj. mindpowernews. Medical apartheid. Nigeria[18] . [3] http:/ / allafrica. 1998. Half of these women received a placebo that has no effect which means transmission was likely and a result an estimated 1000 babies contracted HIV/AIDS when a proven life-saving regimen already existed[22] .Harriet A. com/ stories/ 200805290720. 1981. Nigeria. or the nature of a placebo in testing situations[20] . ac. Harriet A.Harriet A. Retrieved 2010-11-12. anchor books p390 [15] http:/ / www.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. Journal of Southern African Studies 24(2):p 347 [13] Kaler.Medical experimentation in Africa The subjects did not fully understand the testing methods. za/ healthsystems/ aversion. org/ wiki/ Eugen_Fischer [17] Washington. htm [10] http:/ / www. Amy. uk/ 2/ hi/ africa/ 6719141. the possible dangers. co. com/ UnethicalExperiments. Legal suits Nigeria sued Pfizer over the meningitis experiments conducted in Kano. . the effectiveness. Medical apartheid. abstract). Anchor Books 2006 p392-393 [18] "Africa | Nigeria sues drugs giant Pfizer" (http:/ / news. mrc.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. The CDC ended the short course testing in 1998 after they announced they had enough information from Thailand trials[23] . Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [20] Meier. (2007-07-31). . Journal of Southern African Studies 24(2):p 347 [14] Washington. A Threat to the Nation and a Threat to the Men: the Banning of Depo-Provera in Zimbabwe. html). Ctj. Harriet A. References [1] Washington.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [22] Meier.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. Medical Apathied. ezakwantu.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent. bbc. Anchor Books 2006 p394 [8] Washington.sagepub. stm). Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [21] Meier. [19] Meier. sagepub. Medical Apathied. 2007-06-05. This was based on a real-life case in Kano. [9] http:/ / www.com. They were also told about the trials under duress[21] . A Threat to the Nation and a Threat to the Men: the Banning of Depo-Provera in Zimbabwe. 117 Pop culture references The movie 'The Constant Gardener' highlighted the dynamics of conduct in clinical trials in Africa in the slum areas. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 [7] Washington. pdf [11] Washington. 1981. Anchor books p390 [12] Kaler. BBC News. 1998. Harriet A. but also includes the links to African experimentation[17] . nytimes. Berkeley journal of international law [1085-5718] Meier yr:2002 vol:20 iss:3 pg:513 -554 . Anchor Books 2006 p390 [2] "Problems in comprehension of informed consent in rural and peri-urban Mali. Retrieved 2010-11-12. provides a historical account of experimentation on African Americans. com/ Gallery%20Herero%20and%20Namaqua%20Genocide.Benjamin Mason: International Protection of Persons Undergoing Medical Experimentation: Protecting the Right of Informed Consent.

List of variation in N of 1 trial . Another variation is non-concurrent experimental design where different points in time are compared with one another. along with the Danish CapOpus trial. ac. The single case experimental design has been very effective in psychology and other field of behavior science. This can be achieved in many ways. midastrial. If the problem vanished during the treatment it can be established that the treatment was effective. A trial in which random allocation can be used to determine the order in which an experimental and a control intervention are given to a patient is an N of 1 randomized controlled trial. External links • MIDAS Trial website [1] References [1] http:/ / www. The trial is. The order of experimental and control interventions can also be fixed by the researcher. uk/ N of 1 trial An N of 1 trial is a clinical trial in which a single patient is the entire trial. this means that causality cannot be definitively demonstrated. But the N=1 study can also be executed in a AB quasi experimental way. a single case study. It is led by Professor Christine Barrowclough and operates in both Manchester and London. This type of study has enabled practitioners to achieve experimental progress without the overwhelming work of designing a group comparison study. It can be very effective in confirming causality. where the patient problem is measured before a treatment is introduced (baseline) and then measured again during the treatment and finally when the treatment has terminated. One of the most common procedures is the ABA withdrawal experimental design. among the only trials aimed at this particular group of comorbid substance abusers with schizophrenia. This experimental design also has a problem with causality. A variation of experimental design in single case studies is great. But the replication of studies has a great value and can be as effective as a group study.MIDAS Trial 118 MIDAS Trial The MIDAS Trial is a randomized controlled trial in Manchester. England using Motivational Interventions for Drugs & Alcohol misuse in Schizophrenia.

doi:10.02. Mitchell GK. PMID 16740846. Our three-year experience". doi:10. • Avins AL. "N-Of-1 Randomized Controlled Trials: An Opportunity for Complementary and Alternative Medicine Evaluation". Bent S. PMID 15911473. J Altern Complement Med 10 (6): 979–84.004.1016/j. Clavarino A. Neuhaus JM (June 2005). • Nikles CJ. • Johnston BC. Contemporary Clinical Trials 26 (3): 397–401. Newhouse MT (February 1990). Adachi JD. . 112 (4): 293–9.979. Pediatrics 117 (6): 2040–6.2005. PMID 15673992. "Use of an embedded N-of-1 trial to improve adherence and increase information from a clinical study". Experiment means that it can be demonstrated.N of 1 trial 119 Design A-B A-A -A A-B-A A-B-A-B A-B-A-B-A-B A-B -B -B -B -A 1 2 3 n 1 Causality Use Quasi experiment Often the only possible method Experiment Experiment Experiment Experiment Experiment Placebo design where A is no drug and A is a placebo Withdrawal design where effects of B face can be established Withdrawal design where effects of B face can be established Withdrawal design where effects of B face can be established Establishing the effect of different versions of B face 1 Quasi experiment means that causality cannot be definitively demonstrated.2005-1328.1542/peds. Intern.1089/acm. Keller JL. Ann. doi:10. "The n-of-1 randomized controlled trial: clinical usefulness. Med. Jaeschke R. Rosenbloom D. PMID 2297206.cct. Del Mar CB. McNairn N (June 2006).10. "An n-of-1 trial service in clinical practice: testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder".2004. Sources • Guyatt GH. Mills E (December 2004).

46. p.[1] Third arm The natural history group is often referred to as the third arm of a controlled drug trial. from the simple notion that a trial has three arms. which is the course and outcome of that illness in the absence of treatment. Austin Flint (1812–1886) in his report of the first-ever trial that directly compared the efficacy of a placebo treatment with that of an active treatment. The observed outcomes within this group are then compared with the outcomes manifested by a group that has been given the active drug. and with that manifested by a second group who have been given a dummy. left to run its "natural" course. A. First usage In 1863. the natural history group is the trial's "third arm"). Consisting of a Report of Thirteen Cases Treated Solely with Palliative Measures". Vol. "A Contribution Toward the Natural History of Articular Rheumatism. The term stems from the natural history of an illness. pp. .18. References • Flint. placebo drug (thus. spoke of "the natural history of [an untreated] disease". (July 1863). American Journal of Medical Science.Natural history group 120 Natural history group The term natural history group refers to subjects in a drug trial that receive no treatment of any kind and whose illness is. as a consequence. 17–36.. Notes [1] Flint (1863).

media.9 billion per year. monitor side effects. However. benefits. Institutional Review Boards.S.[1] Patient enrollment is the most time-consuming aspect of the clinical trial process. Origin The discipline of patient recruitment was formed nearly three decades ago in the U.000) to confirm its effectiveness. Patient recruitment service providers educate the public about the value of clinical trial participation and the [3] measures in place to protect study participants.000-3. Pharmaceutical companies submit trial data to the U. They are conducted in a series of phases. • Phase III: The study drug or treatment is given to large groups of people (1.S. and public relations. after learning about these protective measures. The leading cause of missed clinical trial deadlines is patient recruitment. The patient recruitment sector has experienced rapid growth in recent years.S. • Phase II: The study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. to meet the challenge of successful on-time enrollment. but also for tasks such as tracking data and measuring site performance. site selection. Food and Drug Administration (FDA) as part of a New Drug Application. As the number of patients needed for clinical trails rises – as safety and regulatory issues drive trends toward larger and longer trials – the demand for patient recruitment services grows. Technology has impacted the evolution of patient recruitment. and optimal use. each designed to address a separate purpose: • Phase I: Researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety. and collect information that will allow the drug or treatment to be used safely. training and support. • Phase IV: Post marketing studies delineate additional information including the drug's risks. compare it to commonly used treatments.Patient recruitment 121 Patient recruitment Patient recruitment includes a variety of services—typically performed by a Patient Recruitment Service Provider—to increase enrollment into clinical trials.000 people in the U. nearly 40 percent of respondents reported they would be more likely to participate in a clinical trials.[2] Improving patient recruitment rates offers pharmaceutical and medical device companies one of the biggest opportunities to accelerate the pace of clinical trials – making it possible to reduce time to market. the patient recruitment industry is claimed to total $5. marketing communications. showed that 81 percent of the population was not aware of safeguards such as the Declaration of Helsinki.S. and the informed consent process. country selection. The Belmont Report. Presently. . and providers increasingly rely on the Internet not only for advertising and early screening. It has evolved into a field that includes feasibility modeling and analysis. taking up to 30 percent of the clinical timeline. Clinical trials are conducted to collect data regarding the safety and efficacy of new drug and device development. metrics and evaluation. and identify side effects. The 2001 “Will & Why Survey” of more than 5. particularly in response to increasing number of global clinical trials. determine a safe dosage range. Many companies have developed proprietary software to help make processes more efficient. the application for FDA approval to market a drug in the U.

the study website usually describes the study. • Site selection: Choosing the optimal recruiting sites for study participation. Some patient recruitment providers possess in-house capabilities of developing. management. Services are contracted for by pharmaceutical companies. and may involve caregivers and physicians. Twitter messages and YouTube videos).. technical.. posters. specialists.g. a patient who recently moved and needs a closer site location). It may also include direct mail programs where collateral is sent to physicians with the aim of increasing referral volume. and protocol clarifications). • Monitoring and reporting: To assess the effects of the patient recruitment activities on enrollment.. while others rely on third-party vendors. banner ads and word links).g. Assessing study metrics allows the sponsor to adjust recruitment efforts as needed to ensure maximum return on investment. • Population research: Discovering the motivational drivers of target patient populations is commonly gathered through focus groups.g. • Translations: Providing cultural and regulatory-compliant translation of recruitment materials into various languages in accordance with country-specific requirements. . and social media • Media management: To exact the greatest value from media advertising.g. churches and barbershops).g. and flyers. • Site assessment: Investigating the operational. referral processing. stops). letters. outreach measures can include forums where doctors. subject status updates. outreach efforts may include participation at local health fairs or networking among community service groups. web (e. medical device companies.. and other neighborhood organizations and institutions (e. • Recruitment materials: Patient-directed communications designed to attract study referrals and raise enrollment. explaining study procedures to patients. improving forecasting and return on investment. • Community outreach: To expand study awareness. media buying services ensure placement in patient-rich geographic areas along with current market buying discounts and opportunities.Patient recruitment 122 Services Patient recruitment The goal of patient recruitment is to raise awareness of clinical trial opportunities and to encourage enrollment. patient support groups. Services include: • Study feasibility: Evaluating whether the study may be performed in a given country and how effective it will be in enrolling patients. radio. • Media support: Whether directed to patients and/or caregivers. and healthcare providers gather to view a presentation on the study and how their patient pool may be eligible for participation. bus [4] [5] (e. • Physician outreach: When study recruitment depends in large part on physician referrals. • Patient referral follow-up: When a site may be short of staff or overwhelmed by a spike in patient referrals. contract research organizations (CROs). or a medical research site. May include brochures. Some popular media for patient recruitment advertising are: television. a PRO may offer administrative support by scheduling site appointments and following up with patients who may present enrollment challenges (e. and clinical experience capabilities of participating sites helps decide what support they will need to successfully recruit patients for the study. and editing all content. • Site training materials: Specially-designed instructional tools that assist site staff in introducing the study to patients. ongoing monitoring is performed. biotechnology companies. provides disease-related resources.g. site supports ensures study challenges are immediately addressed. newspaper.. and performing informed consent procedures with patients.. producing. • Study Web site: Serving as an online hub for study information and sometimes pre-screening. and allows patients to indicate their interest in study participation. • Site support: From resolving pre-trial operational issues to tailored support (e. outdoor (e. advertising can raise study awareness and drive patient referral volume.

patient recognition items reflect appreciation for study participation and encourage retention (e.. Bachenheimer.Patient recruitment 123 Patient retention If a trial is lengthy or if it requires invasive procedures. Reminders may take the form of post cards. the need for patient retention services is significant. Brescia. Recognizing the needs of the caregiver (e. 2001 [4] Pharma's Facebook (http:/ / www. visit alerts ensure compliance as they contribute to keeping the study top-of-mind. • Caregiver support: In some studies. the caregiver plays an integral role in ongoing patient participation. a pillow or blanket may be given to a patient to prevent discomfort). e-mails.g. References [1] IBM Institute for Business Value analysis (https:/ / www-935. as in many Alzheimer's disease research trials. Newsweek. com/ id/ 187882). A variety of support services that are considered retention specific include: • Visit reminders: To stem the possibility of missed appointments. a Harris Interactive/BBK Healthcare Poll.g. March 2009 . March 10. com/ services/ sg/ index. and home nurse visits) contributes to patient retention.. coping skill resources. newsweek. wss/ ibvstudy/ igs/ x1014229?cntxt=x1013529). 2003 report [2] Reinventing Patient Recruitment: Revolutionary Ideas for Clinical Trial Success. com/ whispering-tweets-into-a-patient s-ear-top-ten-suggestions-for-clinical-trial-recruiters/ ). study guides. twitip. text messages. 2007 [3] The Will & Why Survey. ibm. 2009 [5] Whispering Tweets into a Patient's ear: Top Ten Suggestions for Clinical Trial Recruiters (http:/ / www. or phone calls. the greater the need for retention support to help keep patients involved for the entire trial timeline. For those engaged in global clinical studies. particularly lengthy trials with extension studies. where lengthy infusions are repeatedly required in a study. Bonnie A. • Patient support items: With particularly lengthy studies or where many invasive or extensive study procedures are involved. modest food cards to compensate for lunchtime visits. Joan F. Gower Publishing.

Point values represent the relative importance of the criteria or attributes to decision-makers.Per-protocol analysis 124 Per-protocol analysis In epidemiology.[1] [2] The PAPRIKA method – usually implemented via software – is used to calculate point values (or ‘weights’) on the criteria or attributes for decision problems involving ranking. nih. including those who did not complete the study. Intention to treat analysis uses data from all patients. com/ glossary/ clinicalpractice/ [3] http:/ / gateway. nlm. prioritising or choosing between alternatives. interest rates and exchange rates[12] • Discovering agronomists’ preferred grass breeding traits for pasture plant species in Australia[13] • Characterising the ‘ideal’ sheep to breed in terms of traits preferred by sheep farmers in Ireland[14] • Incorporating climate change and mitigation information into environmental resources management for the ocean[15] . gov/ MeetingAbstracts/ 102214217. the point values are used to rank alternatives – enabling decision-makers to prioritise or choose between them (perhaps subject to a budget constraint). do?uid=ncp_488 [2] http:/ / www. nature.Glossary [2] of the Nature Clinical Practice • Intent-to-treat versus on treatment analysis: how to interpret the results of a clinical trial? [3] References [1] http:/ / www. com/ glossary/ clinicalpractice/ defDetails. geriatrics and gastroenterology services in Canada[5] [6] [7] Classifying individuals by their risks of suffering from rheumatoid arthritis[8] Health technology prioritisation[9] Measuring patient responses in clinical trials for chronic gout[10] [3] [4] Applications in other areas include: • Corporate strategic management[11] • Revealing central bankers’ monetary-policy preferences with respect to tradeoffs between inflation and volatility in GDP. Applications Applications of the PAPRIKA method in the area of health care decision-making include: • • • • • Prioritising patients for access to elective (non-urgent) surgery in New Zealand Referring patients for rheumatology. Examples of applications of the PAPRIKA method appear in the next section. html Potentially all pairwise rankings of all possible alternatives Potentially all pairwise rankings of all possible alternatives (PAPRIKA) is a method for multi-criteria decision making (MCDM) or conjoint analysis based on decision-makers’ pairwise rankings of alternatives. per-protocol (PP) analysis is a strategy of analysis in which only patients who complete the entire clinical trial are counted towards the final results. As well as representing decision-makers’ preferences. nephrology. nature. External links • Per-protocol analysis [1] .

can usually be represented in terms of two or more categories – which must be listed from lowest ranked to highest ranked within the criterion. but his references. • Harry’s education is good. ‘point-count’ or ‘linear’ systems or models. criteria can be quantitative or qualitative in nature. • Dick’s education is poor. the alternatives under consideration are prioritised or ranked (or otherwise classified) relative to each other. This is illustrated in the following simple example. a value model (or ‘points system’) is simply a schedule of point values for a collection of criteria deemed relevant for the decision problem at hand. he has > 5 years of experience. additive multi-attribute value models with performance categories – hereinafter referred to simply as ‘value models’ – consist of multiple criteria (or ‘attributes’) that are combined additively.Potentially all pairwise rankings of all possible alternatives 125 Additive multi-attribute value models (or ‘points systems’) As for other methods for MCDM or conjoint analysis. As the name implies. ‘scoring’. and his references.) In other words. he has 2 . Table 1: Example of a value model (points system) for ranking job candidates Criterion Education Category poor good very good excellent Experience < 2 years Points 0 8 20 40 0 2 – 5 years 3 > 5 years References poor good Social skills poor 10 0 27 0 . An example Imagine that ‘Tom’. See Table 1 in the sub-section below for an example for ranking candidates for a job. This simple representation of point values is equivalent to an alternative approach where normalised criterion weights and ‘single-criterion value functions’ for each criterion are used to represent the relative importance of the criteria and to combine values overall. social skills and enthusiasm are all good. Each criterion has two or more categories (or ‘levels’) that are each worth a certain number of points that is intended to reflect both the relative importance (‘weight’) of the criterion and its degree of achievement corresponding to the particular category. Applying a value model involves ‘scoring’ each alternative according to its performance on the criteria and then summing the corresponding point values across the criteria to get the alternative’s ‘total score’ (thus these are additive value models). social skills and enthusiasm are all good. and his references. he has < 2 years of experience. social skills and enthusiasm are all poor. the PAPRIKA method specifically applies to additive multi-attribute value models with performance categories[16] – also commonly known as ‘points’. ‘Dick’ and ‘Harry’ are three candidates for a job and they are to be ranked using the value model in Table 1 below. Suppose that after being assessed they are scored on the five criteria (see Table 1) like this: • Tom’s education is excellent.5 years of experience. Based on their total scores. Also. such as a continuum of possible outcomes. (Incidentally. criteria that are not naturally categorical.

Pairwise rankings of alternatives The PAPRIKA method is based on the fundamental principle that an overall ranking of all possible alternatives representable by a value model is defined when all pairwise rankings of the alternatives vis-à-vis each other are known (provided the rankings are consistent). this still leaves 2. In the analogy above.047.Potentially all pairwise rankings of all possible alternatives good Enthusiasm poor good 10 0 13 126 Summing the point values in Table 1 corresponding to the descriptions for Tom. Of course.536 possible alternatives – there are 2.880 pairwise rankings. Nonetheless. many pairwise rankings are automatically resolved due to one alternative in the pair having a higher category for at least one criterion and none lower for the other criteria than for the other alternative (known as ‘dominated pairs’. Deriving valid and reliable point values is arguably the most difficult task when creating a value model. he is the best of the three candidates. Harry is not as good as the best hypothetically-possible candidate – who would score a ‘perfect’ 40 + 10 + 27 + 10 + 13 = 100 points. thereby defining an overall ranking of all possible alternatives representable by the value model – is kept to a minimum (typically in the tens or low hundreds) – so that the method is practicable. In general. The PAPRIKA method does this based on decision-makers’ pairwise rankings of alternatives.500. As demonstrated in the next major section. performing anywhere near this many pairwise rankings is impossible without a special method. though.880 pairwise rankings. depending on the number of possible alternatives. for each possible pair of individuals. In the previous example involving 2. having specified the criteria and categories for a given value model.416 pairwise rankings to be performed (requiring judgements). Therefore. Clearly. Harry has the highest total score. there are still likely to be millions or even billions of pairwise rankings to worry about. .497. The PAPRIKA method ensures that the number of pairwise rankings that decision-makers need to perform – such that potentially all pairwise rankings of all possible alternatives are identified. with 5000 people to be ranked (i. In another example. even after excluding all such inherent pairwise rankings.450.516. If you knew how each person was pairwise ranked relative to everyone else – i. relative to other candidates who could potentially have applied for the job. As an analogy.e. you identified who is the taller of the two individuals or that they’re the same height – then you could produce an overall ranking of the 5000 people.934. as discussed later below). Dick and Harry gives their total scores: • Tom’s total score = 40 + 10 + 0 + 0 + 0 = 50 points • Dick’s total score = 0 + 3 + 27 + 10 + 13 = 53 points • Harry’s total score = 8 + 0 + 27 + 10 + 13 = 58 points Clearly.147.) In general terms. (Of course.e.464 pairwise rankings that are automatically resolved (and so no judgements are required). suppose you wanted to rank 5000 people from the tallest to the smallest. according to the value model and how the candidates were assessed. the challenge is to derive point values (or weights) that accurately reflect the relative importance of the criteria and categories to the decision-maker. n = 5000 alternatives) the number of pairwise rankings is n(n−1)/2 = 12. PAPRIKA does this by exploiting the special properties of additive multi-attribute value models (specifically. the number of pairwise rankings is potentially in the millions or even billions.450. for a value model with eight criteria and four categories within each criterion – and 48 = 65.147. after eliminating the 99. transitivity).

This cycle is repeated for undominated pairs defined on successively more criteria (four. etc. . the procedure advances to undominated pairs defined on three criteria at-a-time (again where. In contrast to undominated pairs. all those that are implicitly ranked as corollaries of the explicitly ranked pairs defined on two criteria are identified and discarded. This cycle is repeated until all undominated pairs defined on two criteria have been either explicitly or implicitly ranked. in effect. both highly educated and experienced whereas the other person is both uneducated and inexperienced (and so no judgement is required to pairwise rank this pair). until potentially all undominated pairs for the value model have been either explicitly or implicitly ranked. After he or she ranks it. all other undominated pairs defined on just two criteria at-a-time that are implicitly ranked as corollaries of this ranked pair – via the transitivity property of additive multi-attribute value models – are then identified and discarded. ‘dominated pairs’ comprise two alternatives that are inherently pairwise ranked due to one having a higher category for at least one criterion and none lower for the other criteria. Next. Central to this procedure (and continued below) are computationally efficient processes for identifying undominated pairs and implicitly ranked pairs respectively. all other criteria’s categories are pairwise identical). in effect. all other criteria’s categories are pairwise identical). Central to the PAPRIKA method is the result that the decision-maker needs to explicitly pairwise rank only a small fraction of the potentially millions or billions of undominated pairs in order for potentially all pairwise rankings of all possible alternatives representable by the value model to be identified – as either dominated pairs (given) or undominated pairs explicitly ranked by the decision-maker or implicitly ranked as corollaries. all other pairs defined on two criteria that are implicitly ranked as corollaries of both it and the first explicitly ranked pair are identified and discarded. An ‘undominated pair’ is a pair of alternatives where one is characterised by a higher ranked category for at least one criterion and a lower ranked category for at least one other criterion than the other alternative.[1] Beginning with undominated pairs defined on just two criteria at-a-time (where. With reference to the example of ranking job candidates in the previous section. Continuing with the job candidates example. from the inequalities (strict preference) and equalities (indifference) corresponding to the explicitly ranked pairs. If she or he continues. point values are obtained via linear programming. a randomly-selected pair is presented to the decision-maker for him or her to pairwise rank. and hence a judgement is required in order for the alternatives to be pairwise ranked. Because these pairwise rankings are consistent. the resulting point values all reproduce the same overall ranking of alternatives. six. an example of a dominated pair would be where one person in the pair is. say. another undominated pair defined on two criteria is presented to the decision-maker to rank and. except that as the undominated pairs defined on three criteria are being identified. a complete overall ranking of all possible alternatives is defined. Overview of PAPRIKA’s procedures The PARRIKA method proceeds as follows (and see the next major section for a simple demonstration). five. – up to the number of criteria included in the value model). say. highly educated but inexperienced whereas the other person is uneducated but highly experienced (and so a judgement is required to pairwise rank this pair). an example of an undominated pair (of candidates) would be where one person in the pair is.Potentially all pairwise rankings of all possible alternatives 127 ‘Undominated pairs’ Implicit in the discussion above and central to the remainder of the article is the concept of an ‘undominated pair’. The decision-maker may cease pairwise ranking undominated pairs at any time (that’s why the method has “potentially all pairwise rankings” in its title). Although multiple solutions to the linear program of inequalities and equalities are possible. Finally. and the cycle is repeated. again.

b2 > b1 and c2 > c1 (i. e. approximately 95 pairwise rankings are required. Clearly. 211. poor and good. when the value model is used to rank actual candidates. Arguably.) Notation and basic set-up For economy of expression. and (c) references. ‘b’ and ‘c’.e. by ‘1’ and ‘2’ (where 2 is the higher ranked category). the total .Potentially all pairwise rankings of all possible alternatives 128 How many pairwise rankings does the decision-maker need to perform? Simulations of PAPRIKA’s use reveal that if the decision-maker explicitly pairwise ranks just undominated pairs defined on two criteria at-a-time (i. (If it helps. 221. etc. let’s represent the three criteria. 222 = ‘Lisa’. 112 = ‘Alison’.[1] Therefore for most practical purposes decision-makers are unlikely to need to rank pairs defined on more than two criteria. (b) experience. though. 122 = ‘Kirsten’. 122. They can be represented as ordered triples of the categories (‘1’ or ‘2’) on the criteria (abc): 222. in effect. though. all other criteria’s categories are pairwise identical). and references. these eight possible alternatives can be thought of as being ‘types’ (or profiles) of candidates who might ever apply. and this is sufficient for most applications. and 111 = ‘Ray’. and good on references. poor on experience. For the earlier example of a value model with eight criteria and four categories within each criterion. 212 = ‘Colin’.e. you can think of each of these eight profiles as being an imaginary person.) The total scores for the alternatives – by which they will be ultimately ranked – are derived by simply adding up the variables corresponding to the point values (which are as yet unknown. (This is a simplified version of the illustrative value model in Table 1 earlier in the article. different types of judgments are involved. each of which has two ‘performance’ categories: (1) poor or (2) good. c1 and c2 – where a2 > a1. PAPRIKA entails a greater number of judgments than most ‘traditional’ methods for determining point values (or weights). 211 = ‘Paul’. the judgements entail pairwise comparisons of undominated pairs. that at this stage they are only hypothetically-possible – or potential – candidates for the job. 212. education. such as the Analytic Hierarchy Process (AHP). b1. ‘221’ is a candidate who is good on education and experience but poor on references. good is better than poor on each of the criteria). For example. 212 a third who is good on education. by the letters ‘a’. In the context of ranking candidates for a job. 112 and 111. Real-world applications suggest that decision-makers are able to rank comfortably more than 50 and up to at least 100 pairs. 221 = ‘Lavina’.[1] An example that most people can probably relate to is a value model for ranking candidates for a job – in this deliberately simple example. Notwithstanding the apparent ability of decision-makers to rank this many pairs. In practice. experience. and in a short period of time. for example. as noted earlier. ‘222’ denotes a candidate who is good on all three criteria. consisting of these three criteria: (a) education. to be determined by the method being demonstrated here).g. A simple demonstration of the PAPRIKA method The PAPRIKA method can be easily demonstrated via the simple example of deriving the point values for a value model with just three criteria and two categories within each criterion. 121 = ‘Norman’. and the two categories. a2. not all of these profiles may be represented by the candidates who apply. Note. the resulting overall ranking of all possible alternatives is very highly correlated with the decision-maker’s ‘true’ overall ranking obtained if all undominated pairs (involving more than two criteria at-a-time) were ranked. Thus. 121. b2. the judgments for PAPRIKA are simpler and more natural and might reasonably be expected to reflect decision-makers’ preferences more accurately. the total score for alternative 121 is represented by equation a1 + b2 + c1. whereas most traditional methods involve interval scale or ratio scale measurements of the decision-maker’s preferences with respect to the relative importance of criteria and categories respectively. This value model’s six point values (two for each criterion) can be represented by the variables a1. ‘Scoring’ the value model involves determining the ‘point values’ of these six variables so that the decision-maker’s preferred ranking of the 23 = 8 possible alternatives representable by the model is realised. where. For PAPRIKA.

Each alternative on the left-hand side is pairwise compared with each alternative along the top with respect to which of the two alternatives is higher ranked (i. In the example above. their total-score equations. which candidate is more desirable for the job). The cells with hats (^) denote dominated pairs (where no judgement is required) and the empty cells are either the central diagonal (each alternative pairwise ranked against itself) or the inverse of the non-empty cells containing the undominated pairs (where a judgement is required). Table 3: Undominated pairs for a value model with three criteria and two categories within each criterion – identified here by pairwise comparing the eight possible alternatives shown . For the present example with just eight alternatives this is easily done by pairwise comparing all of the alternatives vis-à-vis each other and discarding the dominated pairs. where the eight possible alternatives (in bold) are listed down the left-hand side and also along the top. 121 vs 112 is an undominated pair because alternative 121 has good experience and poor references whereas 112 has the opposite characteristics (and they both have poor education). the pairwise ranking will always be the same). Table 2: The eight possible alternatives.Potentially all pairwise rankings of all possible alternatives score for alternative 112 is a1 + b1 + c2. Thus. Identifying undominated pairs The first step when applying the PAPRIKA method is to identify the undominated pairs for the value model. an ‘undominated pair’ is a pair of alternatives where one is characterised by a higher ranked category for at least one criterion and a lower ranked category for at least one other criterion than the other alternative (and hence a judgement is required for the alternatives to be pairwise ranked). and the imaginary job candidates corresponding to each of the eight possible profiles. the alternatives in a ‘dominated pair’ (e. This simple approach can be represented by the matrix in Table 3. in terms of the equations for the total scores. etc. 121 vs 111 – corresponding to a1 + b2 + c1 vs a1 + b1 + c1) are inherently pairwise ranked due to one having a higher category for at least one criterion and none lower for the other criteria (and no matter what the point values are. Recall. and eight imaginary job candidates Alternative 222 221 212 122 211 121 112 111 Total-score equation a2 + b2 + c2 a2 + b2 + c1 a2 + b1 + c2 a1 + b2 + c2 a2 + b1 + c1 a1 + b2 + c1 a1 + b1 + c2 a1 + b1 + c1 Imaginary candidate ‘Lisa’ ‘Lavina’ ‘Colin’ ‘Kirsten’ ‘Paul’ ‘Norman’ ‘Alison’ ‘Ray’ 129 Undominated pairs can be represented as ‘121 vs (versus) 112’ or. as explained earlier. who is the better candidate ultimately depends on the decision-maker’s preferences with respect to the relative importance of experience vis-à-vis references.g. b2 > b1 and c2 > c1. their total-score equations. Conversely. Table 2 lists the eight possible alternatives. as ‘a1 + b2 + c1 vs a1 + b1 + c2’. etc. in the present example.e. given a2 > a1.

Unique undominated pairs are identified with Roman numerals. and listed later below). remains.(iii). Thus. like b2 + c1 vs b1 + c2. three are duplicates after any variables common to a pair are ‘cancelled’: the pairs with asterisks before their Roman numerals are duplicates of pairs (i) . these subtractions reflect the ‘joint-factor’ independence property of additive value models:[17] the ranking of undominated pairs (in uncancelled form) is independent of their tied rankings on one or more criteria. Likewise. there are nine undominated pairs in total. Clearly. etc. The three other pairs with asterisks before their Roman numerals are duplicates of pairs (i) . . are also representable as _21 vs _12 – i. undominated pairs in their cancelled forms. leaving b2 + c1 vs b1 + c2.(iii).Potentially all pairwise rankings of all possible alternatives 130 vs 222 221 222 221 212 ^ ^ (i) b2 + c1 vs b1 + c2 122 ^ c2 (iii) a2 + b1 vs a1 + b2 112 ^ b1 + c2 ^ ^ 121 ^ ^ (v) a2 + b1 + c2 vs a1 + b2 + c1 ^ (*i) b1 + c2 vs b2 + c1 211 ^ ^ ^ (vi) a1 + b2 + c2 vs a2 + b1 + c1 (*ii) a1 + c2 vs a2 + c1 (*iii) a1 + b2 vs a2 + b1 111 ^ ^ ^ ^ ^ ^ ^ (ii) a2 + c1 vs a1 + (iv) a2 + b2 + c1 vs a1 + 212 122 112 121 211 111 Table notes: ^ denotes dominated pairs. there are six unique undominated pairs (identified with Roman numerals in Table 2.e. for both undominated pairs the same ‘cancelled’ form. with the objective that the decision-maker is required to perform the fewest pairwise rankings possible (thereby minimising the elicitation burden). a2 can be subtracted from both sides of a2 + b2 + c1 vs a2 + b1 + c2. also leaving b2 + c1 vs b1 + c2. For example. As summarised in Table 3. Notationally. In summary. Formally. b2 + c1 vs b1 + c2. This practice of ‘cancelling’ variables common to an undominated pair can be illustrated as follows. a1 can be subtracted from both sides of a1 + b2 + c1 vs a1 + b1 + c2. where ‘_’ signifies identical categories for the identified criterion. when comparing alternatives 221 and 212. However. pair *i is a duplicate of pair i. here are the six undominated pairs for the value model: (i) b2 + c1 vs b1 + c2 (ii) a2 + c1 vs a1 + c2 (iii) a2 + b1 vs a1 + b2 (iv) a2 + b2 + c1 vs a1 + b1 + c2 (v) a2 + b1 + c2 vs a1 + b2 + c1 (vi) a1 + b2 + c2 vs a2 + b1 + c1 The task is to pairwise rank these six undominated pairs. When comparing alternatives 121 and 112. for example.

all else the same. to b2 + c1 > b1 + c2 [where ‘≻’ and ‘~’ (used later) denote strict preference and indifference respectively.e. this ranking of pair (ii) as a1 + c2 > a2 + c1 implies pair (vi) is ranked as a1 + b2 + c2 > a2 + b1 + c1.e. Central to the PAPRIKA method is the identification of all undominated pairs implicitly ranked as corollaries of the explicitly ranked pairs. b1 = 0. for this simple value model are now known – a complete overall ranking of all eight possible alternatives is defined.e. Simultaneously solving the three inequalities – subject to a2 > a1. poor education and good references is preferred to good education and poor references). pair i _21≻_12. Thus. the ‘points system’). the ranking of pair (i) as b2 + c1 > b1 + c2 (as above) implies pair (iv) is ranked as a2 + b2 + c1 > a1 + b1 + c2. given a2 > a1 (i. Suppose the decision-maker answers: “I prefer _21 to _12” (i. the most important criterion is revealed to be (good) experience (b. as above) then this implies (iv) 221≻112 – equivalently. or are you indifferent between them?” This choice. a2 = 2. Next. Specifically. 122≻221 and 221≻212 implies 122≻212. Again. c1 = 0 and c2 = 3 (or normalised so the ‘best’ alternative.Potentially all pairwise rankings of all possible alternatives 131 Ranking undominated pairs and identifying implicitly ranked pairs Undominated pairs with just two criteria are intrinsically the least cognitively difficult for the decision-maker to pairwise rank relative to pairs with three criteria. as a result of two explicit pairwise comparisons – i. 3 points) and. corresponding to the usual relations ‘>’ and ‘=’ for the total score equations].e. where n = 8. This can easily be seen by adding the corresponding sides of the inequalities for pairs (i) and (ii) and cancelling common variables. 212≻112 and 221≻212 implies 221≻112. b2 = 44. or are you indifferent between them?” This choice. b1 = 0. this preference can be represented by ‘_21 ≻ _12’. This reflects the transitivity property of additive value models. 4 points) followed by references (c. 222. least important. _21 or _12 (given they’re identical on criterion a). Thus all six undominated pairs have been ranked as a result of the decision-maker explicitly ranking just three: (i) b2 + c1 > b1 + c2 (ii) a1 + c2 > a2 + c1 (v) a2 + b1 + c2 > a1 + b2 + c1 Because these three pairwise rankings are consistent – and as a result all n(n−1)/2 = 28 pairwise rankings. 1_2 or 2_1 (given they’re identical on criterion b). good experience and poor references is preferred to poor experience and good references). this reflects the transitivity property: (i) 121≻112 and (ii) 112≻211 implies (iii) 121≻211 – equivalently. the two explicitly ranked pairs (i) b2 + c1 > b1 + c2 and (ii) a1 + c2 > a2 + c1 together imply that undominated pair (iii) is ranked as a1 + b2 > a2 + b1. Notationally.2. one solution is: a1 = 0.3). but let’s suppose she continues and ranks the remaining pair (v) as 212≻121 (i. c1 = 0 and c2 = 33. is between a candidate with poor education and good references and another with good education and poor references. in the context of the example of a value model for ranking candidates for a job. b2 > b1 and c2 > c1 – gives the point values (i. all else the same.e. education (a. The decision-maker may cease ranking whenever she likes (before all undominated pairs are ranked). b2 = 4. good education ≻ poor education). the decision-maker is asked: “Which alternative do you prefer. a2 = 22. Suppose the decision-maker answers: “I prefer 1_2 to 2_1” (i. explicitly performed by the decision-maker – five of the six undominated pairs have been ranked.4. is between a candidate with good experience and poor references and another with poor experience and good references. scores 100 points: a1 = 0. Thus. in other words. Given b2 > b1 (good experience ≻ poor experience).e. in terms of total score equations. Thus. which corresponds. Thus. . This corresponds to a1 + c2 > a2 + c1. Furthermore. For example.e. given 221≻121 (by dominance) and 121≻112 (i. suppose the decision-maker is asked: “Which alternative do you prefer. in other words. arbitrarily beginning here with pair (i) b2 + c1 vs b1 + c2. corresponding to undominated pair (ii) a2 + c1 vs a1 + c2. in response to an analogous question to the two spelled out above).

indifference) instead of _21≻_12 (as above).e.516. which means they have many more undominated pairs.e. which are unknown beforehand. which most decision-makers are likely to be comfortable with. Although multiple solutions to the three inequalities are possible.2 + 44. then she would have needed to rank only one more pair rather than two (i. However.4 points normalised) 132 6th 112: 0 + 0 + 3 = 3 points (or 0 + 0 + 33.416 undominated pairs in total (analogous to the nine identified in Table 1).4 + 33.4 + 0 = 66. the decision-maker may decline to explicitly rank any given undominated pair (thereby excluding it) on the grounds that at least one of the alternatives considered corresponds to an impossible combination of the categories on the criteria. therefore. identifying all pairs implicitly ranked as corollaries of the explicitly ranked pairs becomes increasingly intractable as the numbers of criteria and categories increase. she may skip it – and the pair may eventually be implicitly ranked as a corollary of other explicitly ranked pairs (via transitivity). the resulting point values all reproduce the same overall ranking of alternatives: 1st 222: 2 + 4 + 3 = 9 points (or 22.3 points normalised) 7th 211: 2 + 0 + 0 = 2 points (or 22. if the decision-maker cannot decide how to explicitly rank a given pair. relies on computationally efficient processes for identifying unique undominated pairs and implicitly ranked pairs respectively. Also.e. On the whole. four explicitly ranked pairs in total).100.3 = 33.7 points normalised) 4th 212: 2 + 0 + 3 = 5 points (or 22. For example.6 points normalised) th 5 121: 0 + 4 + 0 = 4 points (or 0 + 44.047. Applying PAPRIKA to ‘larger’ value models Of course.560 are unique (analogous to the six in the example above). the order in which the decision-maker ranks the undominated pairs affects the number of rankings required.e. just two explicitly ranked pairs in total).Potentially all pairwise rankings of all possible alternatives 2 points).[1] . the decision-maker will usually be required to perform fewer pairwise ranking if some indicate indifference rather than strict preference. The PAPRIKA method. the value model referred to earlier with eight criteria and four categories within each criterion (and 48 = 65.2 + 44.) For such real-world value models.3 = 100 points normalised) – i. as well as pair (v) (i. but are available elsewhere.8 points normalised) 3rd 221: 2 + 4 + 0 = 6 points (or 22. 2nd 122: 0 + 4 + 3 = 7 points (or 0 + 44. Finally. total score from adding the point values above.4 + 0 = 44.3 = 55.4 + 33. Likewise.2 + 0 + 0 = 22.[1] (As mentioned earlier. excluding replicas. indifferently ranked pairs generate more corollaries with respect to implicitly ranked pairs than pairs that are strictly ranked.536 possible alternatives) has 2.2 points normalised) 8th 111: 0 + 0 + 0 = 0 points (or 0 + 0 + 0 = 0 points normalised) Other things worthwhile noting First. the decision-maker is required to perform approximately 95 pairwise rankings for a model of this size. if the decision-maker had ranked pair (i) above as _21~_12 (i. Second. For example. the simple pairwise-comparisons approach to identifying undominated pairs used in the previous sub-section (represented in Table 1) is highly impractical.3 = 77. For example.2 + 0 + 33. determining the optimal order is problematical as it depends on the rankings themselves. 402. most real-world value models have more criteria and categories than the simple example above. The details of these processes are beyond the scope of this article. if the decision-maker had ranked pair (iii) before pairs (i) and (ii) instead of afterwards (as above) then it is easy to show that all three would have had to be explicitly ranked. in order for all undominated pairs to be ranked. of which.

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T.10. OI and Moshkovich. Science. O (2010). “Strategic mobilization: What strategic management can learn from social movement research” (http:/ / scindeks. rs/ article. Disability & Rehabilitation. 62: 355-65. [8] Neogi. DH (1972). cfm?nid=43& ver=3& pip=CP10320). R (2009). De Coster. [5] Fitzgerald. Academy of Medicine. Crop & Pasture Science. “Commentary: A climate change atlas for the ocean” (http:/ / www. 15: 87-107. Annals.[21] As explained in the present article. Ombler. McMillan. European Journal of Operational Research 82: 503-21. nz/ research/ discusspapers/ dp09_01. AB and Wind. [19] Green. O. GA and Noseworthy. blackwellpublishing. “Priority-setting tools for improving access to medical specialists” (http:/ / www. G (2010). 38: S78. [7] Noseworthy. Hansen. JA. V and Stewart. Silman AJ et al. T. asp?MeetingID=761& id=79687). [9] Golan. pdf). P. 11: 23-31. abstract) The Journal of Rheumatology 38: 1467-70. S (2011). 2010. tos. (2011). org/ 10. healthpol. 2009. the PAPRIKA method overcomes this efficiency problem. poster presentation. “The 2010 American College of Rheumatology / European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report” (http:/ / onlinelibrary. The Asian Wall Street Journal. business. Oceanography. com/ journal/ 122577495/ abstract). [20] References [1] Hansen. TJ. K and Fennessy. A. “Measurement structures and psychological laws”. Multiple Criteria Decision Analysis: An Integrated Approach. C and Doney. aspx?artid=0354-86350644023R). [15] Boyd. J (2006). [2] Wagstaff. Singapore. pairwise trade-off analysis is based on the idea that undominated pairs that are explicitly ranked by the decision-maker can be used to implicitly rank other undominated pairs.

JA. • Hanley.9957 ≈ 3. if testing parachutes from the same batch.05) = ln(20) = 2. In either case. They are designed to test the efficacy of a drug. References [1] http:/ / www. PMID 6827763. the factor of three arises from –ln(0. For example. you test 300 and they all open successfully. The rule can then be derived either from the Poisson approximation to the binomial distribution. i. This rule is useful in the interpretation of drug trials. or from the formula (1-p)n for the probability of zero events in the binomial distribution by taking logarithms and keeping only the first term of a series expansion of the natural logarithm.05. The rule of three says we should have 95% confidence that the rate of adverse events is no more frequent than 1 in 500. "Probability of adverse events that have not yet occurred: a statistical reminder" [1]. European Journal of Operational Research 137: 635. AI and Olson. PMC 2550668. BMJ 311 (7005): 619–620. It need not refer to medical or clinical settings. there can be 95% confidence that the chance of major adverse events is less than one in n / 3 (or equivalently. is everything alright?". References • Eypasch. in a trial of a drug for pain relief in 1500 people. Rolf Lefering. which frequently do not have the statistical power or duration to find the relationship between the intervention and adverse events. given that it has not been observed to occur in n Bernoulli trials. but is a very good approximation when n > 30. PMID 7663258.e. the rule of three states that if no major adverse events occurred in a group of n people. Retrieved 2008-04-15. less than 3 in n). Ernst. JAMA 249 (13): 1743–5. Denoting the number of events by X. Hans Troidl (1995-09-02). 134 Rule of three (medicine) In the statistical analysis of clinical trials. For example. com/ cgi/ content/ full/ 311/ 7005/ 619 . Lippman-Hand A (1983). Mechitov. the chance of another parachute from the same batch failing to open is likely to be less than 3/300. less than 1 in 100. none have a major adverse event.Potentially all pairwise rankings of all possible alternatives [21] Moshkovich. This is an approximate result. It should also be noted that this rule applies equally well to any trial done n times. and often the discovery of adverse events is not in the interests of the sponsors. HM. “Ordinal judgments in multiattribute decision analysis”. bmj. we therefore wish to find the values of the parameter p of a binomial distribution that give Pr(X = 0) ≥ 0. C K Kum. "If nothing goes wrong. particularly in phase 2 and phase 3. Outline of derivation We seek a 95% confidence interval for the probability p of an event occurring. DL (2002).

Am J Cardiol 1993.Scandinavian Simvastatin Survival Study 135 Scandinavian Simvastatin Survival Study The Scandinavian Simvastatin Survival Study (also known under the abbreviation 4S) is a multicenter clinical trial that was performed in 1990s in Scandinavia. Additionally there was no excess morbidity of non-cardiac deaths from causes like cancer or suicide. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction.Faergeman. making the number needed to treat around 30 (thirty patients would need to be treated to prevent one death).0%. O. There was a 30% relative reduction in the risk of death with simvastatin treatment. et al.5% to 5. The 4S study turned out to be a milestone in cardiology and evidence-based medicine . Lancet 1994. between 5.: Follow-up study of patients randomized in the Scandinavian Simvastatin Survival Study (4S) of cholesterol lowering.R. A host of other large multicenter clinical trials followed that paved way to widespread use of this class of pharmaceuticals.4 years.344:1383-1389 PMID 7968073 • The Scandinavian Simvastatin Survival Study Group. aged between 35 and 70 years.0 mmol/l.5 and 8.71:393-400 PMID 8430625 • Pedersen. The objective of the study was to assess effect of a cholesterol-lowering drug called simvastatin on mortality and morbidity in a group of 4444 patients with coronary heart disease. The treatment of 100 patients for six years would prevent four deaths of the disease and seven non-fatal myocardial infarcts. Am J Cardiol 2000. 2223 patients were assigned placebo and 2221 were assigned simvastatin treatment for a mean period of 5.86:257-262 PMID 10922429 . a concern that has occasionally arisen in respect to the statins. References • The Scandinavian Simvastatin Survival Study Group.Wilhelmsen..it was clearly proven that treatment with statins saved lives of patients with coronary heart disease. T. The trial showed that treatment of patients suffering from coronary heart disease with simvastatin had a lowering effect on mortality and morbidity. The patients exhibited moderate hypercholesterolemia. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). L. The absolute coronary heart disease-mortality was reduced from 8.

The set of Qualifier variables can be further categorized into five sub-classes: • Grouping Qualifiers are used to group together a collection of observations within the same domain. A Role determines the type of information conveyed by the variable about each distinct observation and how it can be used. Examples include --ORRESU. and --DOSU and --DOSFRM. --STRESC. It is the answer to the question raised by the topic variable. . which specify the focus of the observation (such as the name of a lab test) • Timing variables. The Identifier variable is the subject identifier. • Record Qualifiers define additional attributes of the observation record as a whole (rather than describing a particular variable within a record). and the sequence number of the record • Topic variables. or numeric values that describe the results or additional traits of the observation (such as units or descriptive adjectives). Clinical Data Managers will need to become proficient in the SDTM to prepare submissions and apply the SDTM structures. --NAM. --ORNRHI. 'NAUSEA'. For example. Eventually. Examples include --MODIFY and --DECOD. subject of the observation. --SPEC. --POS and --LOC. all of which are variable qualifiers of --DOSE. and --ORNRLO. which captures the information. the value for which is 'MILD'. the domain. Many of the values in the DM domain are also classified as Result Qualifiers. where appropriate. On July 21. and all other SAE (serious adverse event) flag variables in the AE domain. can express an algorithm or executable method to define start. end. which identify the study. AESLIFE. • Synonym Qualifiers specify an alternative name for a particular variable in an observation. 2004. which describe the timing of the observation (such as start date and end date) • Qualifier variables. Background SDTM is built around the concept of observations collected about subjects who participated in a clinical study. '101'. 'starting on Study Day 6'. and --BLFL. for operational data management. all data submissions will be expected to conform to this format. Each observation can be described by a series of variables. Examples include --CAT and --SCAT. which are equivalent terms for a --TRT or --TERM topic variable. which include additional illustrative text. all of which are variable qualifiers of --ORRES. --LOT. --TEST and --LOINC which are equivalent terms for a --TESTCD. Examples include --REASND. Rule.' the Topic variable value is the term for the adverse event. Examples include --ORRES. Variables can be classified into four major roles: • Identifier variables. 'Subject 101 had mild nausea starting on Study Day 6. while an example of a Record Qualifier is the severity. • Result Qualifiers describe the specific results associated with the topic variable for a finding. As a result. and --STRESN. The Submission Data Standards team of Clinical Data Interchange Standards Consortium (CDISC) defines SDTM. Each variable can be classified according to its Role. The Timing variable is the study day of the start of the event. in the observation. SDTM was selected as the standard specification for submitting tabulation data to the FDA. • Variable Qualifiers are used to further modify or describe a specific variable within an observation and is only meaningful in the context of the variable they qualify.SDTM 136 SDTM SDTM (Study Data Tabulation Model) defines a standard structure for human clinical trial (study) data tabulations that are to be submitted as part of a product application to a regulatory authority such as the United States Food and Drug Administration (FDA). corresponding to a row in a dataset or table. or looping conditions in the Trial Design model. A fifth type of variable role.

The metadata are described in a data definition document named 'Define' that is submitted along with the data to regulatory authorities. each domain is represented by a dataset. Timing. Topic.. 137 Datasets and domains Observations are normally collected for all subjects in a series of domains. Comments are included as necessary according to the needs of individual studies. and type are listed with a set of CDISC guidelines that provide a general description for each variable used by a general observation class. label. Submission Metadata Model uses seven distinct metadata attributes to be defined for each dataset variable in the metadata definition document: • • • • The Variable Name (limited to 8-characters for compatibility with the SAS System Transport format) A descriptive Variable Label.g. and more than one role may be assigned per variable to meet different needs. The dataset structure for observations is a flat file representing a table with one or more rows and columns. Actual submission metadata may use additional role designations. using up to 40 characters. which should be unique for each variable in the dataset The data Type (e. Data stored in dataset variables include both raw (as originally collected) and derived values (e. and as a prefix for most variable names in the dataset. or to its role in the trial.. whether the variable value is a character or numeric) The set of controlled terminology for the value or the presentation format of the variable(Controlled Terms or Format) • The Origin or source of each variable • The Role of the variable. This set of values may be sponsor-defined in cases where standard vocabularies have not yet been defined (represented by a single *) or from an external published source such as MedDRA (represented by **). Since these roles are predefined for all domains that follow the general classes. one dataset is submitted for each domain. the value of the DOMAIN variable within that dataset. In SDTM only the name. two-character DOMAIN code that should be used consistently throughout the submission. A domain is defined as a collection of logically-related observations with a topic-specific commonality about the subjects in the trial. or the five types of Qualifiers. The presence of an asterisk (*) in the 'Controlled Terms or Format' column indicates that a discrete set of values (controlled terminology) is expected to be made available for this variable. This DOMAIN code is used in the dataset name. such as an average). • Comments or other relevant information about the variable or its data. or computed on the basis of multiple values. converted into standard units. The logic of the relationship may relate to the scientific subject matter of the data. Each row of the dataset represents a single observation and each column represents one of the variables. they do not need to be specified by sponsors in their Define data definition document. Typically. which determines how the variable is used in the dataset. Roles are used to represent the categories of variables as Identifier.g.SDTM Additional Timing and Qualifier variables could be included to provide the necessary detail to adequately describe an observation. Normally. but it is possible to have information relevant to the same topicality spread among multiple datasets. Each dataset is distinguished by a unique. Each dataset or table is accompanied by metadata definitions that provide information about the variables used in the dataset. .

g. and sets of individual questions listed on questionnaires.DM Comments . or comments related to records or groups of records in other domains. Additional fixed structure.SV Interventions: • Concomitant Medications . or caffeine) • The Events class captures occurrences or incidents independent of planned study evaluations occurring during the trial (e. 'medical history'). “concomitant medications”).g. • Any valid Timing variable is permissible for use in any submission dataset (such as to describe studies with more precise time points such as a Pharmacokinetics trial). Often the Findings general class is the best choice for general observational data collected as measurements or responses to questions. laboratory tests. In most cases. therapeutic treatments. the choice of class may be based more on the scientific intent of the protocol or analysis plan or the data structure. The general domain classes Most observations collected during the study (other than those represented in special purpose domains) should be divided among three general observation classes: Interventions.CO Subject Elements . • The Findings class captures the observations resulting from planned evaluations to address specific questions such as observations made during a physical examination.SE Subject Visits .. coincident with the study assessment period (e. • Any additional Qualifier variables from the same general class may be added to a domain model.. Three general rules apply when determining which variables to include in a domain: • The same set of Identifier variables applies to all domains based on the general observation classes... the identification of the general class appropriate to a specific collection of data by topicality is straightforward.CM • Exposure . or Findings: • The Interventions class captures investigational treatments. Events.SDTM 138 Special-purpose domains The CDISC V3.x Submission Data Domain Models include special-purpose domains with a specific structure and cannot be extended with any additional qualifier or timing variables other than those specified. and surgical procedures that are intentionally administered to the subject (with some actual or expected physiological effect) either as specified by the study protocol (e. An optional identifier can be used wherever appropriate.SU Events: . non-extensible special-purpose domains are discussed in the Trial Design model. or other substances self-administered by the subject (such as alcohol.g.2) Special-Purpose Domains: • • • • Demographics . but it should be used consistently where applicable for all domains. “exposure”). ECG testing.g. All datasets based on any of the general observation classes share a set of common Identifier variables and Timing variables. In cases when the topicality may not be as clear. The CDISC standard domain models (SDTMIG 3. tobacco.EX • Substance Use . 'adverse events' or 'disposition') or prior to the trial (e.1. • Demographics includes a set of standard variables that describe each subject in a clinical study • Comments describes a fixed structure for recording free-text comments on a subject.

DS Medical History .SUPPQUAL • Relate Records . cdisc.IE Laboratory Tests .MB Questionnaires .SDTM • • • • • • • • • • • • • • • • • • • • • • • Adverse Events .TS 139 Findings: Trial Design Domains: Special-Purpose Relationship Datasets: • Supplemental Qualifiers .RELREC References • CDISC Study Data Tabulation Model / Submission Data Domain Models.TA Trial Visits .AE Disposition .EG Inclusion/Exclusion Exceptions . cdisc. Version 3.DA ECG Tests . org/ models/ sdtm/ v1.PE Pharmacokinetics Concentrations .TV Trial Inclusion/Exclusion Criteria – TI Trial Summary .1 [1] • CDISC Study Data Tabulation Model SDTM Implementation Guide V3. archive. org/ sdtm .QS Microbiology Susceptibility . cdisc.FA Trial Elements .DV Clinical Events . 1/ index.MS Physical Examinations . org/ web/ 20071027092920/ http:/ / www.CE Drug Accountability .VS Findings About Events or Interventions . html [2] http:/ / web.MH Protocol Deviations .TE Trial Arms . org/ web/ 20080612045554/ http:/ / www.SC Pharmacokinetics Parameters .LB Microbiology Specimens . 1/ index. archive.PP Vital Signs .1 [2] External links • Study Data Tabulation Model [3] at CDISC References [1] http:/ / web.1. html [3] http:/ / www. org/ models/ sds/ v3.PC Subject Characteristics .

SMOs may be either a division of a larger CRO. or else standalone organisations in their own right. In addition the SMO must be careful to negotiate and correctly interpret country specific legislation regarding the practice of commercial clinical research which is often considered a form of specialised medical practice in most countries around the world. Whilst the SMO has maximum control in this situation. In Europe. and other countries like India. Dedicated Research Centres are expensive to create and require the SMO to employ its own dedicated full time research staff to staff the reseach centre. a pharmaceutical company. This can pose an obstacle to SMOs operating a DRC model who wish to expand into other countries. Restrictions on the practice of medicine and ownership of medical practices occur in several countries. this is often done by the Sponsor or CRO • Site initiation and trial close-out operations • Trial-related documents archival and maintenance • Reporting serious adverse events to the Sponsor or CRO and the IRB/IEC • Ensuring protocol compliance • Advising & alerting investigators of potential protocol violations • Advising & alerting investigators of potential ICH-GCP violations Origin SMOs are relatively new entrants into the field of clinical research and have since grown at an explosive rate in the U.Site management organization 140 Site management organization A Site Management Organization (SMO) is an organization that provides clinical trial related services to a contract research organization (CRO). a biotechnology company.a market research firm. The site is usually a hospital or a similar health care institution that has adequate infrastructure and staff to meet the requirements of the clinical trial protocol. Dedicated Research Centres: Dedicated Research Centres are centres which are normally funded. a medical device company or a clinical site. The scope of an SMO's responsibility is limited to the 'site' and hence the eponymous title. Some (but not all) of the responsibilities include: • Contract • Submission for Institutional Review Board or Independent Ethics Committee (IRB/IEC) approval. operated. subsission to Ethics Committee is often done by sponsor or by CRO. not by SMO • Patient Counseling • Patient Recruitment • Patient Follow-up • Informed consent form (ICF) translation into vernacular languages . China and Brazil where clinical trial outsourcing has been at its peak. SMOs may favour the use of a small number of bespoke Dedicated Research Centres (DRCs). or instead prefer to have partnerships with previously existing sites or academic research networks. it is also the option which generates highest overheads for the SMO business. and substantially controlled by the SMO. i. The fledgling SMO industry is currently valued at about $3 billion and is expected to grow further according to recent estimates from R&D Directions . However the same operating principles apply in either case.e. . Some SMOs use a combination of both. In Europe.S. How an SMO Operates The exact method of how an SMO operates is dependant on the local applicable laws of the country it is operating in and how it has been set up.

The SMO has little direct control over the site and relies on fostering very good relationships with key decision makers in the medical practice it has partnered with. This requires the SMO to only provide a small number of personnel to supplement and augment the previously existing operations at site. South Africa. and India DRC . SMOs who operate the site partnership route. however they must tailor their assistance on site in accordance with the extent of approval granted by the medical directorship of the site they wish to work with. benefit from not falling under the classification of a specialised medical practice. List of SMOs by alphabetical order Name Aurum Clinical Research Asia Global Research Cambridge Clinical Research Clinexa Lifesciences Clinfocus Geographical Coverage India Thailand U. as they utilise previously exisiting staff and facilities.K and Ireland India Philippines India Europe.K India India Operating Model Site Partnership Site Partnership Site Partnership Site Partnership Site Partnership Site Partnership Site Partnership Site Partnership DRC and Site Partnership Site Partnership Clinical Development & Support Services India Clinical Conduct Associates Excel Life Sciences Fortitude Clinical Metropolis Synexus U.Site management organization 141 Site Partnerships: Partnerships with previously existing sites or site networks are much lighter on operating costs.

suffering a heart attack after several bouts of fever. each patient received bites from 10 infected mosquitoes[2] . Malaria As the United States military fought battles in the Pacific theater during World War II. For the experiment. In the study. Illinois in the 1940s. The work on this standard began in July 2002—subsequently. Malaria research continued at Stateville Penitentiary for 29 years. SEND v2. The experiments gained much media attention and praise. References http://www. and carcinogenicity studies. These types of studies are typically related to animal testing as part of pre-clinical (pre-Phase 1) clinical trials. . Malaria Research Project The Malaria Research Project was primarily conducted on a floor of the prison hospital in the Stateville Penitentiary. Feedback from this pilot and continuous efforts to more closely align this implementation with the SDTM for human clinical trials led to development of the current version. Life Plus 99 Years[3] . doctors from the University of Chicago bred Anopheles quadrimaculatus mosquitoes. 1945 issue of Life magazine contained an article about this research. repeat-dose.fda. one prisoner died. The study aimed to understand the effect of various antimalarial drugs on relapses of malaria.S. The June 4. Food and Drug Administration pilot project was initiated in July 2003 through a Cooperative Research and Development Agreement (CRADA). The need for human subjects to test new antimalarial drugs was met by taking the research into the prison system. which covers single-dose. Over the course of the experiments. malaria and other tropical diseases hindered their efforts. The study was conducted by the Department of Medicine at the University of Chicago in conjunction with the United States Army and the State Department. a U. primarily from the 8-aminoquinoline group of compounds.gov/oc/datacouncil/send. The researchers insisted that the death was unrelated to their research[4] . 441 inmates volunteered for the study.3. The study marked the first human test of the antimalarial drug primaquine[1] . The study is notable for its impacts on the Nuremberg Medical Trial and subsequent medical experimentation on prisoners.Standard for Exchange of Non-clinical Data 142 Standard for Exchange of Non-clinical Data The Standard for Exchange of Non-Clinical Data (SEND) is an implementation of the Study Data Tabulation Model SDTM for non-clinical studies. The mosquitoes were infected with a plasmodium vivax malaria strain that was isolated from a military patient.html Stateville Penitentiary Malaria Study The Stateville Penitentiary malaria study was a controlled study of the effects of malaria on the prisoners of Stateville Penitentiary near Joliet. This standard was developed by the Clinical Data Interchange Standards Consortium’s (CDISC) SEND Team. which is committed to establishing a standard that can be used for the exchange and submission of non-clinical data collected from animal toxicology studies. Infamous murderer Nathan Leopold participated in the study and later wrote about his experiences in his autobiography.

(http:/ / history. The medical community in the United States largely regarded the Nuremberg Code to be applicable to war criminals and not to the practices of U. pubmedcentral. Andrew Conway Ivy. 1958 (http:/ / www. a set of principles concerning human experimentation. The Green Report was published in the Journal of the American Medical Association and opened the door for legal. Alf S.com/cgi/content/full/315/7120/1437) ." The trial resulted in the formation of the Nuremberg Code.D. it produced the Green report. The malaria study was specifically mentioned. gov/ pagerender. Ivy's testimony at the Medical Trial asserted that the Stateville malaria research was "an example of human experiments which were ideal because of their conformity [with the highest ethical standards of human experimentation]. time. nih. amedd. medical researcher and vice president of the University of Illinois. Alving. served as a witness and consultant for the prosecution.00. mil/ booksdocs/ KOREA/ recad2/ ch5-2. ethically. Ivy encouraged Illinois Governor Dwight H. though the committee never met. Hornblum (http://www. defense attorneys argued that.863292. April 7.S. htm) [2] Procedures Used at Stateville Penitentiary for the Testing of Potential Antimalarial Agents (http:/ / www.bmj. researchers.Stateville Penitentiary Malaria Study 143 Nuremberg medical trial In 1946. Green appointed Ivy to be chair of the committee and. The code includes principles such as informed consent and the absence of coercion. army.9171. David J. during the Nuremberg Medical Trial. ethical experimentation on prisoners in the United States. The report justified the experimentation on the Stateville prisoners. html) [4] Strangers at the Bedside: A history of how law and bioethics transformed medical decision making. Effect on prisoner experimentation Public opposition to medical experimentation on prisoners was scant during the war. M. there was no difference between research conducted in American prisons and the experiments that took place in Nazi concentration camps. Green to form a committee to analyze the ethics of prison research. fcgi?artid=438882& pageindex=2#page) [3] Time Magazine. Allen M. Rothman External links • They were cheap and available: Prisoners as research subjects in twentieth century America. References [1] Clinical Treatment of Malaria. com/ time/ magazine/ article/ 0.

[1] [2] Surrogate markers are used when the primary endpoint is undesired (e. STAR took place at more than 500 centers across the United States. death). so a trial may record the subject sex. body weight or location) or by clinical criteria such as previous or simultaneous medication. a replacement for the true clinical outcome). For example. and many with high cholesterol do not. A clinical trial may show that a particular drug (for example. The National Institutes of Health (USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint". cancer. [6] A commonly used example is cholesterol. [3] A correlate does not make a surrogate. The FDA and other regulatory agencies will often accept evidence from clinical trials that show a direct clinical benefit to surrogate markers.many people with normal cholesterol develop heart disease. Canada. but "cholesterol" is the surrogate marker. It is a common misconception that if an outcome is a correlate (that is. thus making it impractical to conduct a clinical trial to gather a statistically significant number of endpoints. Such a trial would usually ensure that similar proportion of male and female subjects were in each treatment group. "Death from heart disease" is the endpoint of interest. However. . While elevated cholesterol levels increase the likelihood for heart disease. Instead. or when the number of events is very small. descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed. a surrogate endpoint (or marker) is a measure of effect of a certain treatment that may correlate with a real clinical endpoint but doesn't necessarily have a guaranteed relationship. is the partitioning of subjects and results by a factor other than the treatment. and Puerto Rico.g. functions or survives. gov/ clinicaltrials/ digestpage/ STAR/ page1 Surrogate endpoint In clinical trials.. Subjects could be stratified by demographic information (such as sex. simvastatin (Zocor)) is effective in reducing cholesterol. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint. [5] A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels. correlated with the true clinical outcome) it can be used as a valid surrogate end point (that is. Study of Tamoxifen and Raloxifene The Study of Tamoxifen and Raloxifene or STAR is a clinical trial designed determine how the drug raloxifene compares with the drug tamoxifen in reducing the incidence of breast cancer in postmenopausal women who are at increased risk of the disease.Stratify (clinical trials) 144 Stratify (clinical trials) Stratification of clinical trials. male and female patients may respond differently to treatment. The term "surrogate" should not be used in describing end points. proper justification for such replacement requires that the effect of the intervention [4] on the surrogate end point predicts the effect on the clinical outcome—a much stronger condition than correlation. the relationship is not linear . One of the largest breast cancer prevention studies ever. External links • Study of Tamoxifen and Raloxifene (STAR) Trial [1] References [1] http:/ / www.

125(7):605-13 [5] Sobel B. (1998). reviews including systematic reviews. Journal contents The Trials journal publishes several types of articles about trials. commentaries on topics of contemporary interest that are usually commissioned by the journal. (1999). Weiss NS. and Peter Rothwell[2] . org/ archive/ spring 2009/ Pages/ AnImperfectSubstitute.05780. PMID 10463718. and Sensible Public Policy. Faergeman O.CIR. "Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)". "Surrogate end points. 145 Criticism There have been a number of instances when studies using surrogate markers have been used to show benefit from a particular treatment. A regulatory authority's opinion about surrogate endpoints. letter articles.[8] References [1] Controlled Clinical Trials 22:485–502 (2001)) [2] Cohn JN (2004). articles on new experimental or computational methods. JAMA 282 (8): 786–790. and articles in the form of study protocols[3] . Circulation (American Heart Association) 109 (25 Suppl 1): IV20–1. relying instead on surrogate endpoints. Spring 2009 (http:/ / www. Proof of Zocor's efficacy in reducing cardiovascular disease was only presented five years after its original introduction. "Introduction to Surrogate Markers".Surrogate endpoint without showing directly that simvastatin prevents death.[7] In another case. [7] Pedersen TR. doi:10. crmagazine.1d. AstraZeneca has been accused of marketing rosuvastatin (Crestor) without providing hard endpoint data. Edited by Nimmo WS. David D. The journal is published by BioMed Central whose editors in chief are Doug Altman Curt Furberg. tests or procedures. Clinical Measurement in Drug Evaluation. and the drug approval process for the treatment of risk factors for cardiovascular disease". et al. [3] Alexandra Goho. . 1996 Oct 1. or even a harm. Trials (journal) Trials is an open access. including regular research articles (detailing trial results). peer reviewed online journal regarding performance and outcomes of randomized controlled trials[1] . and that its effects should be comparable to the other statins.786. The company counters that it had been tested on larger groups of patients than any other drug in the class. "An Imperfect Substitute" CR Magazine. Circulation 97 (15): 1453–1460. [8] Psaty BM.1161/01.8. and then only for secondary prevention. PMID 15226247. 1997. health outcomes. Semantics. Circulation. PMID 9576425. 1995. Furberg CD.0000133441. Furberg C. a repeat study looking at endpoints has not shown a benefit.1001/jama. doi:10.282. Jeremy Grimshaw. New York: Wiley. but later. Tucker GT. Surrogate End Points in Clinical Trials: Are We Being Misled? Ann Intern Med. The journal encourages both authors and peer reviewers to make use of the CONSORT and QUOROM checklists for randomized trials and systematic reviews. et al. Surrogates. book reviews. aspx) [4] Fleming T.95:1661-1663 [6] Temple RJ. respectively. Olsson AG.

e. reporting and recruitment" (http:/ / www.com/home/) .gov. com/ edboard/ ). trialsjournal. reducing the risk of publication bias in systematic reviews.Trials (journal) 146 Study protocols Trials encourages trialists to publish study protocols in their journal[4] . The CRASH trial collaborators (2001). "Instructions for Trials authors" (http:/ / www. Retrieved 2009-02-15. . BMC Emergency Medicine 1 (1): 1. in BMC Emergency Medicine[5] . trialsjournal. PMC 33506. Retrieved 2009-02-15.g. in general. com/ info/ instructions/ ?txt_jou_id=10096& txt_mst_id=61789). 2009-02-15. [1] [2] [3] [4] External links • Trials journal (http://www. potentially improving the suggested trial. biomedcentral. and finally. biomedcentral. Trials offers to make publication of protocols more easy as such articles will “ [4] usually be published without peer review if the study has received ethics approval and a grant from a major funding body. as a way to improve medical research on at least four areas[6] : Publishing protocols before they're finalised will allow others to provide constructive criticism. Notes "About Trials" (http:/ / www.trialsjournal. BMC News and Views 2: 4. efforts to increase publication of protocols may also improve trial registration in registers such as ClinicalTrials. trialsjournal. [6] Fiona Godlee (2001). .1186/1471-227X-1-1. com/ info/ about/ ). . ” The publication of study protocols has been proposed by some. readers of scientific articles will be able to compare what was intended with the trial to what was actually done. "Editorial board" (http:/ / www. Retrieved 2009-02-15. com/ 1471-8219/ 2/ 4/ ).Study protocol" (http:/ / www. reducing the risk of wasteful duplication of research effort and ensures that results from all trials are published. PMID 11439175. doi:10. com/ info/ instructions/ ). [5] The CRASH trial management group. "Publishing study protocols: making them visible will improve registration. While many of the BMC journals have published trial protocols in the past. including Trials' editor-in-chief Doug Altman. Retrieved 2009-02-15. in order to identify inappropriate data dredging. protocol publication lets people know what is underway. . Retrieved 2009-02-15. trialsjournal. "Instructions for Trials authors . . com/ 1471-227X/ 1/ 1). . "The CRASH trial protocol (Corticosteroid randomisation after significant head injury)" (http:/ / www.

history. including syphilis.[8] . working with the Tuskegee Institute. Alabama by the U. began the study in 1932. Instead. and free burial insurance. In addition. under numerous US Public Health Service supervisors.S. Public Health Service to study the natural progression of untreated syphilis in poor. scientists prevented participants from accessing syphilis treatment programs available to others in the area. By 1947. and 201 without the disease. the men were told they were being treated for "bad blood. communication of [3] diagnosis. rural black men who thought they were receiving free health care from the U. According to the Centers for Disease Control. and children [5] born with congenital syphilis." a local term used to describe several illnesses. Investigators enrolled in the study a total of 600 impoverished. The 40-year study was controversial for reasons related to ethical standards. the men were given free medical care. and accurate reporting of test results.S. For participating in the study.S. until 1972. 399 who had previously contracted syphilis before the study began.[4] The study continued. meals. or splitting off a control group for testing with penicillin. nor were they ever treated for it. when a leak to the press eventually resulted in its termination. primarily because researchers knowingly failed to treat patients appropriately after the 1940s validation of penicillin as an effective cure for the disease they were studying.[7] It also led to federal laws and regulations requiring Institutional Review Boards for the protection of human subjects in studies involving human subjects.Tuskegee syphilis experiment 147 Tuskegee syphilis experiment The Tuskegee syphilis experiment[1] (also known as the Tuskegee syphilis study or Public Health Service syphilis study) was an infamous clinical study conducted between 1932 and 1972 in Tuskegee. anemia and fatigue. Federal agencies which can be kept secret by Executive Order ). law and regulation on the protection of participants in clinical studies. penicillin had become the standard treatment for syphilis. Alabama.S.S."[6] led to the 1979 Belmont Report and the establishment of the Office for Human Research Protections (OHRP). the Tuskegee scientists continued the study without treating any participants and withholding penicillin and information about it from the patients. Now studies require informed consent (with [2] exceptions possible for U. The Office for Human Research Protections (OHRP) manages this responsibility within the US Department of Health and Human Services (HHS). wives who contracted the disease. Revelation of study failures by a whistleblower led to major changes in U. government. They were never told they had syphilis. Choices available to the doctors involved in the study might have included treating all syphilitic subjects and closing the study. A doctor draws blood from one of the Tuskegee test subjects African-American sharecroppers from Macon County. cited as "arguably the most infamous biomedical research study in U. The victims of the study included numerous men who died of syphilis. The Tuskegee Syphilis Study.[1] The Public Health Service.

S. he decided to gain the "consent" of the subjects for spinal taps (to look for signs of neurosyphilis) by depicting the diagnostic test as a "special free treatment". Arkansas. Clark had solicited the participation of the Tuskegee Institute (a historically black college (HBCU) that was well-known in Alabama) and also the inclusion of the Arkansas regional PHS office. Dr. Wenger. doctors and civil servants simply did their jobs. Dr. Nurse Rivers is on the left. was not directly involved in the study. Clark disagreed with the plan to conduct an extended study. was director of the regional PHS Venereal Disease Clinic in Hot Springs. Oliver Wenger . shortly after penicillin had first been shown to be a cure for syphilis. an African American doctor. and then follow up with a treatment phase. a Caucasian. Dr. Taliaferro Clark Dr. [9] — Dr John Heller. Dr. Vonderlehr retired as head of the venereal disease section in 1943. Director of the Public Health Service's Division of Venereal Diseases ” The venereal disease section of the U. Public Health Service (PHS) formed a study group in 1932 at its national headquarters. Vonderlehr was appointed on-site director of the research program and developed the policies that shaped the long-term follow-up section of the project. Wenger and his staff played a critical role in developing early study protocols. Wenger continued to advise and assist the Tuskegee Study when it turned [10] into a long-term. Dr. Reginald D. was head of the John Andrew Hospital at the Tuskegee Institute. He retired the year after the study began. no-treatment observational study. Dr. Oliver C. When he understood the intention of other study members to use deceptive practices. Representing the PHS. James (third to right). For example. Eugene Dibble. a black physician involved with public health work in Macon County. Some merely followed orders. He and his staff took a lead in developing study procedures. Taliaferro Clark was credited with its origin. Some of the Tuskegee Study Group clinicians. Dr. others worked for the glory of science. His initial goal was to follow untreated syphilis in a group of black men for 6 to 9 months. Raymond H.Tuskegee syphilis experiment 148 History Study clinicians “ For the most part.

"[11] 149 Dr. who often could not afford health care. doctors. nurse and study co-ordinator . not sick people. By the late 1940s. Nurse Rivers became the chief person with continuity. During the Great Depression of the 1930s. They were subjects. stating: "The men's status did not warrant ethical debate. was recruited at the start of the study. John Heller Dr. hot meals on examination days. Dr. John R. Patients were to receive free physical examinations at Tuskegee University. as she was the direct link to the community. hospitals and public health centers throughout the country routinely treated diagnosed syphilis with penicillin. an African-American trained at Tuskegee Institute who worked at its affiliated John Andrew Hospital. Raymond Vonderlehr Dr. and researchers. not patients. Heller of PHS still defended the ethics of the study. No one appeared to have reevaluated the protocols of the Tuskegee Study according to the new standards. the revelation of the Holocaust and related Nazi medical abuses brought about changes in international law. Rivers stayed at Tuskegee University. By the 1950s. Dr. Vonderlehr was a strong advocate for her participation. regional and on-site PHS administrators. Nurse Rivers had become pivotal to the study—her personal knowledge of the subjects enabled maintenance of long-term follow up. the Tuskegee Study began by offering lower class African Americans. Western allies formulated the Nuremberg Code to protect the rights of research subjects.Tuskegee syphilis experiment Nurse Eunice Rivers. Eugene Dibble Eunice Rivers. the chance to join "Miss Rivers' Lodge". In the study's later years. free rides to and from the clinic. Unlike the changing state of national. clinical material. Heller led the national division. who gave information to the Washington Star and the New York Times. As the study became long term. and free treatment for minor ailments. doctors. In 1972 the Tuskegee Study was brought to public and national attention by a whistleblower. In the period following World War II. She was the only study staff person to work with participants for the full 40 years.

The disadvantage that these treatments were all highly toxic was balanced by the fact that no other methods were known. however. and bismuth. it was determined afterward that the doctors did harm their subjects by depriving them of appropriate treatment once it had Subjects talking with study coordinator. In the earlier phases of the study this was not inherently unethical since there was nothing the investigators could do therapeutically at the time. and 201 healthy Black men as controls. and non-therapeutic spinal taps. mercurial ointments. This study is known as a retrospective study since investigators pieced together information from the histories of patients who had already contracted syphilis but remained untreated for some time. After penicillin was discovered as a cure. Continuing effects of the Stock Market Crash of 1929 and the beginning of the Great Depression led the Rosenwald Fund to withdraw its offer of funding. Researchers could study the natural progression of the disease as long as they did not harm their subjects. Medical ethics considerations were limited from the start and rapidly deteriorated. subjects were studied for six to eight months and then treated with contemporary methods including Salvarsan. at best. To ensure that the men would show up for the possibly dangerous. provided financial support to pay for the eventual treatment of the patients. The Rosenwald Fund. Nurse Eunice Rivers been discovered. Study researchers initially recruited 399 syphilitic Black men." The US health service Tuskegee study began as a clinical trial of the incidence of syphilis in the Macon County population.[12] The Tuskegee University-affiliated hospital effectively loaned the PHS its medical facilities and other predominantly black institutions and local black doctors participated as well. the doctors sent the 400 patients a misleading letter titled "Last Chance for Special Free Treatment" (see insert). The Tuskegee Institute participated in the study. as its representatives understood the intent was to benefit public health in the local poor population. painful. researchers continued to deny such treatment to many study participants. Study directors issued a final report as they thought this might mean the end of the study once funding to buy medication for the treatment phase of the study was withdrawn. Subject blood draw. The study also required all participants to undergo an autopsy after death in order to receive funeral benefits. They reasoned that the knowledge gained would benefit humankind.Tuskegee syphilis experiment 150 Study details A Norwegian study in 1928 had reported on the pathologic manifestations of untreated syphilis in several hundred white males. The study was characterized as "the [4] longest non-therapeutic experiment on human beings in medical history. Many patients were lied to and . circa 1953 The Tuskegee study group decided to build on the Oslo work and perform a prospective study to complement it. diagnostic. mildly effective. These methods were. Initially. a major Chicago-based philanthropy devoted to black education and community development in the South.

96% of the 90 original test subjects reexamined in 1963 had received either arsenical or penicillin treatments from another health provider. 40 of their wives had been infected and 19 of their children were born with congenital syphilis. [17] formally apologized to Guatemala for conducting these experiments. . When campaigns to eradicate venereal disease came to Macon County. 151 Non-consensual experiments in Guatemala In October 2010 it was revealed that in Guatemala. A total of 696 men and women were exposed to syphilis without the informed consent of the subjects. the U. It was reported that from 1946 to 1948. American doctors deliberately infected prisoners."[13] Despite this. a government researcher involved in the now infamous Tuskegee study. These men were consequently diagnosed as having syphilis at military induction centers and ordered to obtain treatment for syphilis before they could be taken into the armed services. During World War II.[15] Wellesley College's historian Susan Reverby discovered records of the experiment while examining archives of John Charles Cutler. with the cooperation of some Guatemalan health ministries and officials. 250 of the subject men registered for the draft. This was prior to the discovery of penicillin as a safe and effective treatment for syphilis.[14] By 1947 penicillin had become standard therapy for syphilis. study researchers prevented their patients from participating.S. The US government sponsored several public health programs to form "rapid treatment centers" to eradicate the disease. long term progression of the fatal disease. soldiers. in some cases. thus depriving them of chances for a cure.[12] The Tuskegee Study published its first clinical data in 1934 and issued their first major report in 1936.Tuskegee syphilis experiment given placebo treatments so researchers could observe the full. A PHS representative was quoted at the time as saying: "So far. The study was not secret since reports and data sets were published to the medical community throughout its duration. 28 had died of syphilis. Of the original 399 men.[13] PHS researchers attempted to prevent them from getting treatment. only 74 of the test subjects were alive. gonorrhea. Public Health Service doctors went even further. 100 were dead of related complications.[16] In October 2010. When the subjects contracted the disease they were given antibiotics though it is unclear if all infected parties were cured. we are keeping the known positive patients from getting treatment. and patients in a mental hospital with syphilis and. Doctor injects test subject with placebo as part of the Tuskegee Syphilis Study.[13] By the end of the study in 1972.

until all subjects had died and been autopsied.. and Welfare (HEW). founded and edited The Drum. and gained support for the continuation of the study. The Center for Disease Control (CDC). Buxtun finally went to the press in the early 1970s. In 1968 William Carter Jenkins. On May 16. the "whistleblower". the U. Jenkins called for an end to the Tuskegee Study. a newsletter devoted to ending racial discrimination in HEW. an African-American statistician in the PHS. i. The story broke first in the Washington Star on July 25. He did not succeed. It determined the study was medically unjustified and ordered its termination. As a result of public outcry the CDC and PHS appointed an ad hoc advisory panel to review the study. sent a letter to the national director of the Division of Venereal Diseases to express his concerns about the ethics and morality of the extended Tuskegee Study. 1972. Education. As part of the settlement of a class action lawsuit subsequently filed by the NAACP. It became front-page news in the New York Times the following day. 1997. a PHS venereal-disease investigator in San Francisco. survivor Aftermath In 1974 Congress passed the National Research Act and created a commission to study and write regulations governing studies involving human participants. Peter Buxtun. survivor . at which Buxtun and HEW officials testified.Tuskegee syphilis experiment 152 Study termination In 1966 Peter Buxtun.S. government paid $9 million (unadjusted for inflation) and agreed to provide free medical treatment to surviving participants and to surviving family members infected as a consequence of the study. part of the Department of Health. it is not [18] clear who read his work. President Bill Clinton Herman Shaw. In The Drum. reaffirmed the need to continue the study until completion. a PHS venereal disease investigator. the CDC sought. from local chapters of the National Medical Association (representing African-American physicians) and the American Medical Association (AMA).e. Group of Tuskegee Experiment test subjects Charlie Pollard. To bolster its position. Senator Edward Kennedy called Congressional hearings. which by then controlled the study. The cabinet-level department included the CDC.

participants in the study did not receive them. The study may also have contributed to the reluctance of many poor black people to seek routine preventive care. poster advocating early syphilis treatment. But we can end the silence. • Don Byron's debut album.S. it was ended in a day. what the United States government did was shameful. It was a runner-up for the 1992 Pulitzer Prize in drama. In popular culture • Dr. We can stop turning our heads away.[26] Depression-era U. or contracts).Tuskegee syphilis experiment formally apologized and held a ceremony for the Tuskegee study participants: "What was done cannot be undone..[27] • Marvel Comics' limited series Truth: Red.[23] The aftershocks of this study. White & Black reinterpreted the Tuskegee Experiment as part of the Weapon Plus program.[25] and won in four categories. Tuskegee Experiments. when discussing African Americans and science.[24] In 1997 it was adapted for an HBO made-for-TV movie.[21] Two groups of researchers at Johns Hopkins debated the effects that the Tuskegee Study has had on black Americans and their willingness to participate in medical trials. To our African American citizens. The latter requires the establishment of institutional review boards (IRBs) at institutions receiving federal support (such as grants.[20] As a result. I am sorry that your federal government orchestrated a study so clearly racist. After the study and its consequences became front-page news. cooperative agreements. many distrust the medical community and are reluctant to participate in programs such as organ donation."[19] Five of the eight remaining study survivors attended the White House ceremony. takes inspiration from the tragic facts and discrimination related to the study. The Immortal Life of Henrietta Lacks briefly discusses the study.[29] • The book.[22] Distrust of the government because of the study contributed to persistent rumors in the black community that the government was responsible for the HIV/AIDS crisis by introducing the virus to the black community. the study continued for another 25 years without treating those suffering from the disease. The Tuskegee Syphilis Study significantly damaged the trust of the black community toward public health efforts in the United States. 153 Ethical implications After penicillin was found to be an effective treatment for syphilis. David Feldshuh wrote a stage play in 1992 based on the history of the Tuskegee study.[30] . We can look at you in the eye and finally say on behalf of the American people. is named after the study. and other human experiments in the United States.[28] • Carlo Boccadoro's composition Bad Blood. and I am sorry . titled Miss Evers' Boys. The HBO adaptation was nominated for eleven Emmy Awards. Although treatments were available.. led to the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and the National Research Act.

2004. [26] "Awards for Miss Evers' Boys" (http:/ / www. 2009-01-15. Laura (1997-04-28). . tuskegee. gov/ tuskegee/ timeline. Retrieved 2011-01-18. USA Today. Jeffrey St. ISBN 0029166764. news. virginia. . ISBN 0-8261-2025-3. jhu. Department of Health and Humand Services. Code of Federal Regulations. gov/ ohrp/ policy/ ohrpregulations. Tuskegee Syphilis Study Legacy Committee. doi:10. html) on 2008-06-13. [11] "Impact on Health Care" (http:/ / www. [2] "Code of Federal Regulations Title 45 Part 46 Protections of Human Subjects 46. Title 45. guardian. CNN. Boston Globe (Boston. Retrieved 2008-12-04. . hhs. Study Went Untreated for 40 Years. IMDb. Retrieved 2008-12-04. nytimes. NPR. [13] "Doctor of Public Health Student Handbook" (http:/ / www. Quinn SC (November 1991). .S. New York: Free Press. html). boston. P.00. Clair (1998). htm). Guardian UK (Guardian News and Media Limited). com/ article/ idUSTRE6903RZ20101001). . org/ web/ 20080613004659/ http:/ / www. spiked-online. pulitzer. Retrieved 2008-12-04. org/ Portals/ 0/ DoctorofPublicHealth/ Dr. The White House. New York: Springer Pub. ajph. Reuters. com/ 2007/ HEALTH/ 02/ 07/ bone. Entertainment Weekly. com/ 2008/ HEALTH/ 03/ 17/ clinical. hsl.Tuskegee syphilis experiment 154 References [1] "Tuskegee Study . CNN. Retrieved 2008-12-04. [6] Katz RV. Part 46. [24] "The Pulitzer Prizes : Drama" (http:/ / www. 2008-09-28. cnn.1. ap/ index. edu/ about_us/ centers_of_excellence/ bioethics_center/ impact_on_health_care. . "Tuskegee's ghosts: Fear hinders black marrow donation" (http:/ / www. imdb. . com/ articles/ 0000000CA34A. [27] http:/ / www. . Retrieved 2011-01-18. gov/ ohrp/ ). . com/ title/ tt0119679/ awards). com/ news/ science/ articles/ 2010/ 10/ 02/ wellesley_professor_unearths_a_horror_syphilis_experiments_in_guatemala/ ).11. google. Darryl (1997-09-11). cnn. [16] Stephen Smith (2010-10-02). In 1980. where he managed the Participants Health Benefits Program that ensured health services for survivors of the Tuskegee Study. npr. HStudentHandbook. . pp. pdf) (PDF). Retrieved 2010-10-01. ap/ index. CDC. (November 2006). Drugs and the Press (http:/ / books. cdc. . Cornell Chronicle. [20] Thomas SB. Retrieved 2008-12-04.S. edu/ Chronicle/ 97/ 9. html). archive. asp?s=1209852).81. "Syphilis Victims in U. . PMID 1951814.2105/AJPH. "The Tuskegee Legacy Project: willingness of minorities to participate in biomedical research" (http:/ / muse.1353/hpu. cornell. Blumenthal DS (2003). "Wellesley professor unearths a horror: Syphilis experiments in Guatemala" (http:/ / www. Tuskegee University. J Health Care Poor Underserved 17 (4): 698–715. pp.2006. ukcph. The Pulitzer Prizes -. 11. google. org/ programs/ morning/ features/ 2002/ jul/ tuskegee/ ). 97/ Emmys. [9] Cockburn. . [21] Cohen E (2007-02-26). Retrieved 2008-12-04. [19] "Remarks by the President in apology for study done in Tuskegee" (http:/ / clinton4. ew.1(i)" (http:/ / www.390672. . gov/ ohrp/ humansubjects/ guidance/ 45cfr46. 50. edu/ global/ Story.+ others+ worked+ for+ the+ glory+ of+ science+ ). [3] "Final Report of the Tuskegee Syphilis Study Legacy Committee" (http:/ / www. [14] http:/ / www. U. gov/ textonly/ New/ Remarks/ Fri/ 19970516-898. in/ books?id=KN_-9lwSI5oC). uk/ world/ 2010/ oct/ 01/ us-apology-guatemala-syphilis-tests). "US apologizes for '40s syphilis study in Guatemala" (http:/ / www. Department of Health and Human Services. hhs. Kegeles SS. . London: Verso. Retrieved 2009-09-06. ISBN 1859841392.Timeline" (http:/ / www. Whiteout: The CIA. . NCHHSTP. 67. US Department of Health and Human Services. . com/ ew/ article/ 0. doi:10. nara. reuters. Retrieved 2010-02-22. Alexander. . [8] "Office for Human Research Protections" (http:/ / www. org/ bycat/ Drama). edu/ cgi-bin/ resolve_openurl. 1996-05-20. [7] Office for Human Research Protections (OHRP) (2005-06-23). he joined the CDC Division of Sexually Transmitted Diseases. html). trials. Archived from the original (http:/ / www. "Remembering the Tuskegee Experiment" (http:/ / www. [4] Jones J (1981). et al. . [12] Parker. Community-based health research: issues and methods (http:/ / www. "The Tuskegee Syphilis Study. [18] Bill Jenkins left the PHS in the mid-1970s for doctoral studies. 2008-03-17. cgi?issn=1049-2089& volume=17& issue=4& spage=698& aulast=Katz). com/ albums/ tuskegee-experiments [28] Black in Action (http:/ / www. Retrieved 2011-02-26. Kressin NR. . cfm). [22] "Did Tuskegee damage trust on clinical trials?" (http:/ / web.1498. New York Times (Associated Press). tuskegee. "Protection of Human Subjects" (http:/ / www. .com). 2008-06-25. [25] Geddes. html?res=F40616F6345A137B93C4AB178CD85F468785F9). Retrieved 2008-12-04.. co.Columbia University. marrow/ index. Am J Public Health 81 (11): 1498–505. com/ 2008/ HEALTH/ 03/ 17/ clinical. . htm [15] Chris McGreal (2010-10-01). [23] Chadwick A (2002-07-25). edu/ historical/ medical_history/ bad_blood/ report. hhs. 1932 to 1972: implications for HIV education and AIDS risk education programs in the black community" (http:/ / www.0126. Retrieved 2008-12-04. com/ ?id=s5qIj_h_PtkC& pg=PA67& lpg=PA67& dq="some+ merely+ followed+ orders. PMC 1780164. htm). [10] DiClemente RJ. html). com/ gst/ abstract. [5] Heller J (1972-07-26). pp. aspx). "HBO's adaptation of Feldshuh's play Miss Evers' Boys is up for 12 Emmys" (http:/ / www. 17. PMID 17242525. pdf) (PDF). cnn. Retrieved 2008-12-04. trials. nonesuch. html). [17] Maggie Fox (2010-10-01). Syphilis Victims Got No Therapy" (http:/ / select. org/ cgi/ pmidlookup?view=long& pmid=1951814). . . co. Office of the Press Secretary. 1997-05-16. Bad Blood: The Tuskegee Syphilis Experiment. "US says sorry for 'outrageous and abhorrent' Guatemalan syphilis tests Experiments in 1940s saw hundreds of Guatemalan prisoners and soldiers deliberately infected to test effects of penicillin" (http:/ / www. "'Bad Blood' Still Flows In Tuskegee Study" (http:/ / www. PMC 1405662. University of Kentucky College of Public Health.

PMID 4610772. • Rockwell. Christ Century 90 (43): 1174–6. PMC 2024316. et al. R. "Final report on the "Tuskegee syphilis study". background and current status of patients in the Tuskegee study. South Med J 67 (11): 1349–53. requesting that after test subjects die. Photocopied documents from the study The Tuskegee Study Group Letter inviting subjects to receive "special treatment". • Schuman. (1954). D.Tuskegee syphilis experiment [29] http:/ / www. H. p.. H. page 2 . J. R. L. Public Health Rep 69 (7): 691–8. • Kampmeier. 135.1016/0021-9681(73)90089-1. PMID 14211593. et al. (1972). 155 Further reading Primary sources • Caldwell. E. org/ multimedia/ audio [30] Rebecca Skloot (16 August 2011). Document from Tuskegee Syphilis Study. Simpson.". R. S. (1973). "Aortic regurgitation in the Tuskegee study of untreated syphilis". "Untreated syphilis in the male negro. V. • Kampmeier. G. J Chronic Dis 2 (5): 543–58. PMID 13177831. PMID 13263393. Crown Books. "The Tuskegee study of untreated syphilis". an autopsy be performed. et al. the 30th Year of Observation". Arch Intern Med 114: 792–8. J Chronic Dis 26 (3): 187–94. "The Tuskegee Syphilis Study under review".1016/0021-9681(55)90153-3. page 1 Draft report of study results up to 1949. (1964).. S. • Hiltner. • Olansky. PMID 11662609. The Immortal Life of Henreitta Lacks. (1955). "Environmental factors in the Tuskegee study of untreated syphilis". Price. "The Tuskegee Study of Untreated Syphilis. H. S. et al. PMID 5074095. H. S.. South Med J 65 (10): 1247–51. doi:10. actually a diagnostic lumbar puncture. (1974). PMID 4695031. Yobs. A. sentieriselvaggi. and the results sent to the National Institutes of Health Draft report of study results up to 1949. doi:10. (1973). Olansky.

Tuskegee's Truths: Rethinking the Tuskegee Syphilis Study. "Syphilis Victims in the U. Fred D. doi:10.php?film_id=6341) • Reverby. Sandra Crouse Quinn (1991). Research Nurse. (1981). PMC 1405662. 1993. "History of an Apology: From Tuskegee to the White House". Susan M. 1932–1972: Implications for HIV Education and AIDS Risk Programs in the Black Community". (2000). by Denisce DiAnni. • Carlson. • Jones.1498. Times of triumph. PMID 1951814. Stephen B. Examining Tuskegee: The Infamous Syphilis Study and its Legacy. University of North Carolina Press.Tuskegee syphilis experiment 156 Table depicting number of subjects with syphilis and number of controlled non-syphlitic patients. (2009). Susan M. Bad Blood: The Tuskegee Syphilis Experiment. • Jean Heller (Associated Press). (http://www. University of North Carolina Press. Montgomery. (2007). ISBN 0-87969-805-5. New York: Free Press. "The Oslo study of untreated syphilis: an epidemiologic investigation of the natural course of the syphilitic infection based upon a re-study of the Boeck-Bruusgaard material". • Washington. (1998). Acta Derm Venereol 35 (Suppl 34): 3–368. . Alabama: NewSouth Books. • Reverby.2105/AJPH. "The Tuskegee Syphilis Study. 1972: 1. unc. Harriet A. 1969 Memo ordering termination of the study Secondary Sources • Gjestland T (1955). and how many of the subjects have died during the experiments. Cold Spring Harbor Press. • Thomas. Study Went Untreated for 40 Years" New York Times. PBS/WGBH NOVA documentary video. • Gray.11. 8.81. Medical Apartheid: The Dark History of Medical Experimentation on Black Americans From Colonial Times to the Present. • The Deadly Deception. times of doubt : science and the battle for the public trust. July 26.S. • Reverby.lib. American Journal of Public Health 81 (1503).edu/house/mrc/films/full. The Tuskegee Syphilis Study: The Real Story and Beyond. Elof Axel (2006). (1998). James H. Susan M.

org/templates/story/story.democracynow.jsp?id=h-1116) • New York Times review (http://movies2.php) • Tuskegee Syphilis Study article. In particular.washingtonpost. author of Examining Tuskegee (http://www.encyclopediaofalabama.archive.ogg).democracynow.Tuskegee syphilis experiment 157 External links • CDC Tuskegee Syphilis Study Page (http://www. stroke. National Institutes of Health (NIH) in 1991.com/wp-dyn/content/article/2006/08/ 04/AR2006080401492.gov/southeast/finding-aids/tuskegee. plus progestin (Prempro. All 4 of the randomized components overlap with each other to some extent (and a few even overlap with the observational study).org/face/ Article.org/article.html) • Mary Harper.html) • Interview at Democracy Now!: Ogg Vorbis recording (http://www.htm) • Patient medical files held at National Archives and Records Administration Southeast Region. Study components There are actually 4 different randomized interventions and a separate observational-only cohort in the WHI.com/articles/2007/01/24/features/ bookjeu. breast cancer.archives.gov/nchstp/od/tuskegee/) • Excellent review of the TSS (http://www.npr. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women. and pulmonary embolism than the subjects .iht. GA (http://www. Leader in Minority Health (http://www. Morrow. Wyeth) compared to placebo (the "WHI-E+P" trial).video interview by Democracy Now! Women's Health Initiative The Women's Health Initiative (WHI) was initiated by the U. Encyclopedia of Alabama (http://www.S. The 4 interventions and their abbreviated terminology are: Estrogen-progestin versus placebo This phase studied estrogen. among healthy postmenopausal women.org/download/dn2007-0119/ dn2007-0119-1. interview transcript (http://www. randomized controlled trials were designed and funded that address cardiovascular disease.msu. compared with placebo.pl?sid=07/01/19/1432231) • Interview at NPR: 'Medical Apartheid' Tracks History of Abuses (http://www. cancer.edu/course/hm/546/tuskegee. and osteoporosis.org/2010/10/5/ the_dark_history_of_medical_experimentation) . specifically conjugated equine estrogen.cdc.com/gst/movies/movie. including deep venous thrombosis (DVT) and pulmonary embolism (PE) increased risk of breast cancer decreased risk of colorectal cancer fewer fractures The trial was ended early in 2002 when the researchers found that the subjects with estrogen plus progestin had a greater incidence of coronary heart disease. php?storyId=7046077) • IHT book review: Book Review: Medical Apartheid (http://www. This trial found that.html?v_id=161965) of HBO movie "Miss Evers' Boys" • Susan Reverby.nytimes. women receiving estrogen plus progestin experienced:[1] • • • • • • increased risk of myocardial infarction ("heart attack") increased risk of stroke increased risk of blood clots.

Two hormone clinical trials were designed and conducted: The estrogen that was administered in the WHI studies was conjugated equine estrogen (CEE). followed by a decline in breast cancer.[2] Hormone replacement therapy use declined in the U. alone versus placebo (the "WHI-CEE" trial) in women with prior hysterectomy.[5] A secondary endpoint was postmenopausal weight gain. compared with placebo.[4] • Fracture endpoint: Long term daily supplementation of calcium with vitamin D resulted in a small but significant improvement in hip bone density. and increased the risk of kidney stones. Both studies were randomized. women receiving estrogen alone experienced: • • • • • • no difference in risk for myocardial infarction an increased risk of stroke an increased risk of blood clots an uncertain effect on breast cancer risk no difference in risk for colorectal cancer a reduced risk of fracture [1] Calcium and vitamin D versus placebo This trial compared calcium plus vitamin D versus placebo ("WHI-CalcVitD"). many physicians had come to interpret results from previous clinical trials and studies using experimental animals as indicating that administration of an estrogen supplement to postmenopausal women would lower the incidence of cardiovascular disease.S. placebo-controlled studies. Some benefits of using an estrogen supplement such as reduced risk of .[3] 158 Conjugated estrogen versus placebo This trial studied estrogen. Both studies were terminated early because a reduction in cardiovascular disease was not observed for most women and some women had dangerous side-effects. and around the world. In particular. Wyeth). It had two primary endpoints: • Colorectal cancer endpoint: Long term daily supplementation of calcium with vitamin D had no effect on the incidence of colorectal cancer among postmenopausal women. a type of progestin) with CEE was associated with a slightly increased risk of breast cancer. In women with a uterus.Women's Health Initiative receiving placebo. a progestin is needed to counteract the risk of endometrial cancer posed by unopposed estrogen. Major results of this study were that. co-administration of MPA (medroxyprogesterone acetate. Half the women were given an inactive placebo rather than hormone(s). The WHI Postmenopausal Hormone Therapy Trials were part of the effort to address the high risk of cardiovascular disease in older women. an increased risk of dangerous blood clotting is associated with oral administration of CEE. but did not significantly reduce the number of hip fractures. specifically conjugated equine estrogen (Premarin.000 women drawn from the same national clinical coordinating centers (many epidemiology studies conducted within this observational component of the WHI). A review of the observational and WHI estrogen trial results [7] describes potential explanations for the conflicting results. The CEE was administered orally. In addition. The trial was conducted among women with hysterectomy so that estrogen could be administered without a progestin. Long term daily supplementation of calcium with vitamin D resulted in a small prevention of weight gain. By the early 1990s.[6] Non-intervention cohort The non-interventional observational cohort study ("WHI-OS") observed 93. This consists of a mixture of estrogens isolated from horse urine (Premarin).

"Prothrombotic mutations. PMID 16301339. Jackson RD.1001/jama. org/ cgi/ content/ full/ 360/ 6/ 573).[12] Footnotes [1] "Questions and Answers About WHI Postmenopausal Hormone Therapy Trials. [3] Chlebowski. "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial" (http:/ / jama.105. Caan B. N Engl J Med. the mechanism of disease of developing breast cancer may have a significantly longer time course than the duration of the study. [6] Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. sleep disturbance and urinary/vaginal atrophy are still candidates for hormone replacement therapy. gov/ whi/ whi_faq. WHI" (http:/ / www. "The women's health initiative--curse or blessing?". Circulation 112 (22): 3495–500. 2007 May 14. Med. (2007). other forms of estrogen (such as esterified estrogens) or topical administration of estradiol may reduce the risk of blood clotting compared to that for oral CEE. Majure DT (2006). NEJM 360 (6): 573.3. org/ cgi/ content/ abstract/ 288/ 3/ 321). [2] Writing Group for the Women's Health Initiative Investigators (2002). .321. .167(9):893-902. doi:10. Alternatives to orally administered CEE and MPA are being increasingly used by women since the termination of the WHI studies. Oger E. hsph.296. Manson JE. PMID 17442911. html). ama-assn.280-a. Retrieved 2008-03-28. nih. RT. Engl. PMID 16847020. JAMA 288 (3): 321–333. Retrieved 2010-01-15. et al. Gass M.[8] Finally. For example. . both internal (the desired endpoint for fat reduction in diet was not fully achieved)[9] as well as external (a group of post menopausal women is not generalizable to all women). nhlbi. 159 Criticisms The dietary trial has been criticized by epidemiologists for its lack of validity. [10] Aberegg SK. doi:10.1093/ije/dyl133. et al. "The decrease in breast-cancer incidence in 2003 in the United States". "Breast cancer after use of estrogen plus progestin in postmenopausal women" (http:/ / content.288. Women's Health Initiative Investigators. Stefanick ML.[11] and intervention may have been most effective prior to menopause.1001/jama. . doi:10. .565556. et al.1056/NEJMoa0807684. [12] Michels KB (2006). [11] Ravdin PM.1161/CIRCULATIONAHA. NHLBI.1056/NEJMsr070105. J. N Engl J Med. "Low-fat diet and cardiovascular disease". harvard. [7] http:/ / www. Howlader N. However. Cronin KA. org/ 2006/ 10/ resolving-differences-of-studies-of. (2009). However. Int J Epidemiol 35 (4): 814–6. JAMA 296 (3): 280. 2006 Feb 16. nejm. epidemiologic. Arch Intern Med. doi:10. htm). Younger postmenopausal women seeking relief from conditions such as hot flashes. 2006 Feb 16. et al. et al. html [8] Straczek C. [5] Calcium plus vitamin D supplementation and the risk of fractures. the WHI trial has been argued as unnecessary by many scientists. N.Women's Health Initiative bone fractures were confirmed by these studies. doi:10. PMID 16849659. [9] "Low-Fat Diet Not a Cure-All: Nutrition Source. Harvard School of Public Health" (http:/ / www. for the older postmenopausal women who were recruited for this study. (2005). the undesirable side-effects of treatment generally were greater than the health benefits. CEE and MPA are no longer given to women in order to try to prevent cardiovascular disease in older women. doi:10. Yon de Jonage-Canonico MB. Wactawski-Wende J. Women's Health Initiative Investigators. Kuller LH. Based on the results of these studies.[10] Finally. edu/ nutritionsource/ low_fat. Prentice RL. author reply 280–1. and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration". [4] Calcium plus vitamin D supplementation and the risk of colorectal cancer.354(7):669-83.3. hormone therapy. PMID 12117397.354(7):684-96. the low fat dietary pattern trial of the WHI yielded conflicting and controversial results. et al. 356 (16): 1670–4. who already knew a full decade ago that total fat intake is not related to cardiovascular risk nor postmenopausal breast cancer risk. PMID 19196674.

PMID 15082697.291. Prentice RL.14. et al. Anderson GL.nhlbi. "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". External Links • National Health Lung and Blood Institute's WHI website (http://www. PMID 12117397. JAMA 291 (14): 1701–12. JAMA 288 (3): 321–33. doi:10.1001/jama. (2004). (2002).gov/whi/) .3.1001/jama. Limacher M.288. et al. • Anderson GL.1701. doi:10. Assaf AR.Women's Health Initiative 160 References • Rossouw JE. "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial".nih.321.

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Hamiltondaniel. David Eppstein. 18 anonymous edits Confirmatory trial  Source: http://en. TheChairman101. ZayZayEM. 162 . Nolelover. Redthoreau. Hydrargyrum. MakeRocketGoNow. J.php?oldid=438075006  Contributors: Bwpach. TruthbringerToronto. Ace111. Gultepe. Lindsay658.wikipedia. Sarwicked.wikipedia. Mr pand. Sam Spade.andrew. Waladkhani Clinical significance  Source: http://en. Will Beback.org/w/index. Simonxag. Paul144.php?oldid=386555311  Contributors: De728631. JeffreyGomez.php?oldid=447403532  Contributors: Bearcat.org/w/index. Ukexpat. Owen. Former user. Arcadian.org/w/index. G716. Ehusman. Grijze poes. Physicistjedi. Cacycle. Jheald. 1 anonymous edits Kano trovafloxacin trial litigation  Source: http://en. FourteenDays. Betacommand.wikipedia. MastCell. Ph. Mozii2009.org/w/index. Kylelovesyou. Daksya. Mote.org/w/index.wikipedia. John Nevard. Freakofnurture. Pparazorback. Stepshep. CWDURAND. Lshamseer. StaticGull.php?oldid=443802936  Contributors: Bearcat. Shopewell. Sweikart. PrevMedFellow. PaulinSaudi. Nurg. LilHelpa. Martarius. Colonies Chris. Vikingstad. PeregrineAY. Dirkbb. David Latapie. G716. Edward. NMarkRoberts.g. Pigman. FeydHuxtable. Lukeasrodgers. JHP. WaysToEscape. Koolkao. Everyking. Jlray. Mo-Al. Riya bathia. Ivesiana. Bsherr. Elonka.wikipedia. Wingman4l7. Robma.org/w/index.org/w/index. 3 anonymous edits European Forum for Good Clinical Practice  Source: http://en. Petersam. Candlewicke. Itinerant1. Lindsay658. RB972. Proserepair. M1ss1ontomars2k4. Ciphers. 6 anonymous edits JUPITER trial  Source: http://en. Rich Farmbrough.php?oldid=441875705  Contributors: A2Kafir. Pigsonthewing. Zeamays. Communisthamster. Drbreznjev. Sofia Roberts. Rjwilmsi. Rich Farmbrough. Rjwilmsi. Rjwilmsi Intersalt study  Source: http://en. Corti. ShelfSkewed. Diannaa. Ironholds. Jeruckle. Hemlock Martinis. Sssuuuzzzaaannn. Bsadowski1.org/w/index. Gary King. Icarusgeek. Shoy. Laurel Lodged. Richard Arthur Norton (1958. Cat2020. 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Raimundo Pastor Jesse Gelsinger  Source: http://en. A3 nm. Isnow.wikipedia. Simplyph. John Richard Heath. Malcolma. Kurieeto.php?oldid=415197419  Contributors: Alshamsi2000. Fæ.wikipedia.wikipedia. Mingramh. Melesse. DerHexer. Zloyvolsheb.wikipedia. Graham87. Jmlk17. Colorbynumber96.org/w/index.php?oldid=445313613  Contributors: Alan Liefting.G. 280 anonymous edits Clinical trial protocol  Source: http://en. Stevertigo. Avala. 11 anonymous edits International Studies of Infarct Survival  Source: http://en. Rbean.org/w/index. BinaryTed. Bertrc. Cpujolas. Mar4d.php?oldid=432101209  Contributors: 4wajzkd02. Rjwilmsi. Conscious.e. Roidna. Blindleaf. Hordaland.eyes. Dfrg. Wpharm1. Treybien.php?oldid=448222057  Contributors: 564dude. Jkpjkp. FF2010.org/w/index. Montie5.wikipedia.php?oldid=399217521  Contributors: Alfie66. Michal Nebyla. Para. Kathaz. Casscoburn. SplendidConfusion. BlackTerror.wikipedia.wikipedia. Janka1. Hébus. Rod57. Melcombe. Qwfp. MattKingston. SlackerMom. Reddi. 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Solotaig.php?oldid=423575830  Contributors: BillC.php?oldid=412149296  Contributors: Bwpach. Yilloslime.org/w/index. Moonksy29. Crimson Observer. BrassRat. Ecrin. Henrymrx. 40 anonymous edits Guatemala syphilis experiment  Source: http://en. Rich Farmbrough. Tim! End point of clinical trials  Source: http://en. WAS 4. Paalappoo.php?oldid=446733143  Contributors: Bearcat. JoeSmack. HamburgerRadio.org/w/index. Shoefly. Gabi bart. BorgQueen. Mu Mind. Smalljim. Calog001. Consort-ottawa. DynamoDegsy. Waladkhani Dose-ranging study  Source: http://en. Crt. Cocoaguy. TheFifthSmith. Welsh. Rjwilmsi. Wpharm2.org/w/index. Leesh84. Cobaltcigs. Quietly. Erianna. PimRijkee.wikipedia. Lvcarlin. T@nn. Alphachimp. Billf12.org/w/index. RHaworth. Melcombe. AndreasPDemetriou.php?oldid=394010347  Contributors: Bearian. Frazzydee. Crl620. Leah-kalinda. Gurch.

php?oldid=220205167  Contributors: Lilac Soul. AEMoreira042281. Mattisse N of 1 trial  Source: http://en. Gearspring.php?oldid=437767689  Contributors: Blackise. JWSchmidt. Matthias92. Scarlet Lioness. David Legrand. Dancter. MarcoTolo. Dancanm. Gobonobo. Dougdp. Ceyockey. Dale Arnett. Dkearney54. U+003F. Yakushima. Adjusting. AdamProcter. Bobo192. Pearle. Goldenrowley. NawlinWiki.php?oldid=409735267  Contributors: Adammarklenny. Abune. Kpjas.wikipedia. Gabitea. Natl1. Mcstrother. VeryVerily. Norsiegirl. Sabishii.wikipedia. G716. Fences and windows. Get-back-world-respect.org/w/index. Tracy2214. Katnap01.php?oldid=404718820  Contributors: Af1523. Muboshgu. Littledw. Eqdoktor. Woohookitty. JAKiernan. 1 anonymous edits Tuskegee syphilis experiment  Source: http://en. MGFanJay. Quebec99. M. MastCell. Ibby. Piotrus. Malik Shabazz. DBaba. Thingg. Paul Barlow. Jsmaster24. Ozgod. FilmFemme. DocendoDiscimus. Mikael Häggström. Synchronism. Jojojigamobo. Ygfperson. Ground Zero. Chris CII. J. Decstop. Khatru2. Jayen466. Sir Tobek. KeithTyler. Cgingold. Jkp1187. Pinethicket. Cburnett. Eluchil404.org/w/index. Airconswitch.org/w/index.org/w/index. Delphii.php?oldid=368516952  Contributors: Decstop. LuckyNoSlevin.wikipedia. Marsvin. Nirmos. 10 anonymous edits Potentially all pairwise rankings of all possible alternatives  Source: http://en.php?oldid=447604787  Contributors: Abc518.wikipedia. Squandermania. Futurebird.php?oldid=334909146  Contributors: Addison2008. Bcgh345. Astronautics.php?oldid=447388532  Contributors: Grafen. Jojalozzo. Louis Waweru. Viriditas. Bcatah11. Rjwilmsi. Graeme Bartlett. CanadianLinuxUser. Skomorokh. Salad Days. Johnfos. MK. EdC. Maximus Rex. The Anome. Lmcelhiney.wikipedia. Good Olfactory. PhilBradley. A J Luxton. Doldrums. Plantwater. Kbh3rd. Jcmo. Mike Selinker. NuclearWarfare. Bsherr. 74 anonymous edits Rule of three (medicine)  Source: http://en. Wickey-nl Patient recruitment  Source: http://en. Giantnegro. Glacier Wolf. TygerDawn. Saxsux. 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Tide rolls. 467 anonymous edits Women's Health Initiative  Source: http://en. Janlcc. Rsabbatini Stateville Penitentiary Malaria Study  Source: http://en. THB. Emperor. Flowanda.php?oldid=388164781  Contributors: Cgingold. G716. Greatislander. Scorpios. Richi. Ravendon. Nishkid64. MusicMaker5376. Germán E. LittleHow. Caltas.org/w/index. Xpanzion. Zntrip. Rich Farmbrough.wikipedia. Kazenwil. Aurorae borealis. DDima. Chowbok. Ground Zero. Littlealien182. Iain99. Mfranck. Eaefremov.wikipedia. Lisasmall. Justinep. Kickyandfun. Slicing.org/w/index. Richard Arthur Norton (1958. Mohamedha. 18 anonymous edits Per-protocol analysis  Source: http://en. Bearcat.wikipedia. Ohwell32. PatRec. Khazar. Dara Koper. Redthoreau. JodyB. Infrogmation. Qwfp.org/w/index. 3 anonymous edits Scandinavian Simvastatin Survival Study  Source: http://en. Tassedethe. NoahB. DragonflySixtyseven. NekoDaemon. Rich Farmbrough.Article Sources and Contributors Werty8472. Thue. Pharaoh of the Wizards. Mandarax. Hs956. Mulad. Levineps. Gak. GoingBatty. Nunh-huh.B. Kvdveer.php?oldid=253183770  Contributors: Daveswagon. ShelfSkewed. AuburnPilot. Hassantheharelippedkiterunner. Otheus. Pdcook. Juliand. Gabbe. Grshaw. SandyGeorgia. Cristan.php?oldid=367332503  Contributors: Christopher Kraus.org/w/index. Zandperl. Lmoench. Swood96. Rich Farmbrough. MichaelMaggs. MrOllie. Saforrest. Danny-w. Prasad kvr. Alomakya. Adashiel. Hallmark. Ward20. GJeffery. 7 anonymous edits Stratify (clinical trials)  Source: http://en. Wxlfsr. Billyo516. Mh7719. David Tornheim. FreplySpang. Paul A. Udansk. Slipperyweasel. Marcus Brute. Dodiad. John Nevard.org/w/index. Rrburke. IbLeo. Melcombe. Melcombe. Humus sapiens. Thesis4Eva. Fastfission. Vendavel. Niku. Otto4711. Wouterstomp. JohnCD. Funandtrvl. Uthbrian. Minimac. Malcolma. WhatamIdoing. Mirrormundo. Husond. Hmains. Bueller 007. MartinezMD. Oleg Alexandrov. Jfdwolff. Jclemens. Melcombe. G716. Rainprancer068. Todd661. Veinor. Zzuuzz. Sift&Winnow. Rl. G716. 7 anonymous edits Natural history group  Source: http://en. TomTheHand. Notenderwiggin. WolfmanSF. Lokifer. Sbhardy. Malcolma. Xtrump. Yworo. Michaelbusch.org/w/index. Anupam. Joel7687. ROxBo. Noah Salzman. 22 anonymous edits Length time bias  Source: http://en. Johnfos. Satoris11. Edratzer. Brianfrielfan. Koveras. Jrtayloriv. Cybercobra.wikipedia. Rhino051005. Sherurcij. Johnpseudo. Uthbrian. Qwfp. Malcolma. PhilipMW. Whosasking. Ian Pitchford. Hroðulf. Mlivesey. Auric. Pigman. Equazcion. 5 anonymous edits SDTM  Source: http://en. G716. Veriss1. PrevMedFellow. Giraffedata.wikipedia.wikipedia.).eyes. Jatkins. 16 anonymous edits 163 . Sunfever. Runjmb. Taco325i. Mxpule.org/w/index. Proud Tuskeegee Airmen. Sango123.delanoy. Another Philosopher. Winston365.O.org/w/index. GravityIsForSuckers. Malcolma. Parkwells. Jeff Silvers. Otolemur crassicaudatus. Timwi. Falcorian. CecilWard. J. Jmh649. Tpruane. Soapy1. Jonkerz. Jrtayloriv. Vik2. Diberri. Jfdwolff. 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Jrtayloriv.php?title=File:Eunice_Rivers.wikipedia.jpg  Source: http://en.wikipedia.wikipedia Image:vonderle. Health Services and Mental Health Administration.gif  Source: http://en.php?title=File:Tuskegee-syphilis-study_termination-memo.org/w/index.JPG  License: unknown  Contributors: Skier Dude.gif  Source: http://en.wikipedia.wikipedia .jpg  Source: http://en.wikipedia. 2 anonymous edits Image:Tuskegeeletter. Avicennasis Image:ClearTrial logo.jpg  License: Public Domain  Contributors: Original uploader was ROxBo at en.org/w/index.1973).wikipedia File:Herman Shaw.jpg  License: Public Domain  Contributors: Dethomas. File:Charlie Pollard.jpg  License: Fair Use  Contributors: Mikematurin File:CTD-img004.1973) Image:Tuskegee-syphilis-experiment draft report 2.wikipedia.php?title=File:Tuskegeegroup.wikipedia. Mxpule.php?title=File:USSupremeCourtWestFacade.wikipedia.wikipedia.jpg  Source: http://en. 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