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A Practical Guide to Study Directing

A Practical Guide to Study Directing

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A Practical Guide to Study Directing
Alan P. Brown
Ã
Drug Safety Research & Development, Pfizer Global Research & Development, Ann Arbor, Michigan48105, USA
Summary
The Good Laboratory Practice (GLP) regulations are designed to provide regulatoryguidance and oversight of nonclinical studies that prospectively study the effects oftest articles in test systems under laboratory conditions to determinetheir safety. Theseregulations are designed to assure quality, accountability, and reliability of safety data,and provide guidelines for improving the scientific validity of the studies. A key ele-ment of the GLP regulations is with respect to the role of the Study Director, who is theindividual assigned as the single point of study control and has overall responsibilityfor the entire nonclinical study. Experience has shown that unless responsibility for theproper conduct of a study is assigned to a single individual, the potential exists forpersonnel to receive conflicting instructions, and for study events and issuance of thefinal report to occur in an uncoordinated fashion. While serving as the Study Directorcan be a challenging position with numerous demands and expectations, it is a rolethat allows an individual the opportunity to combine project management withtechnical and scientific skills in the pursuit of a single goal. Individuals who serve asStudy Directors in the nonclinical laboratory typically represent a diverse range ofeducational and professional backgrounds, and oftentimes learn to become StudyDirectors on the job. The goal of this paper is to provide a concise description of theStudy Director’s responsibilities and give guidance for planning, initiating, and com-pleting a nonclinical study. While this paper focuses on test articles that are evaluatedin the pharmaceutical/biotechnology industry and regulated by the US Food and DrugAdministration (FDA) GLPs, much of the information presented should apply to otherGLP and non-GLP studies. Copyright
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2009 John Wiley & Sons, Ltd.
Key Words:
Study Director; GLP; Good Laboratory Practices; nonclinical laboratory;toxicology; US FDA
Introduction and Responsibilities
The US FDA Good Laboratory Practice (GLP)regulations (Section 58.33) state the following.‘For each nonclinical laboratory study, ascientist or other professional of appropriateeducation, training, and experience, or combi-nation thereof, shall be identified as the StudyDirector. The Study Director has overallresponsibility for the technical conduct of thestudy, as well as for the interpretation, analysis,documentation and reporting of results, andrepresents the single point of study control. TheStudy Director shall assure that:
*Correspondence to: Alan P. Brown, PhD, DABT,NAMSA Inc., 6750 Wales Road, Northwood, Ohio,USA. E-mail: abrown@namsa.com
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a) The protocol, including any change, isapproved as provided in 58.120 and isfollowed.b) All experimental data, including observa-tions of unanticipated responses of the testsystem are accurately recorded and veri-fied.c) Unforeseen circumstances that may affectthe quality and integrity of the nonclinicallaboratory study are noted when theyoccur, and corrective action is taken anddocumented.d) Test systems are as specified in the proto-col.e) All applicable Good Laboratory Practiceregulations are followed.f) All raw data, documentation, protocols,specimens, and final reports are transferredto the archives during or at the close of thestudy.’’ [1]The role of the Study Director in the conductof nonclinical studies designed to assess safetyof various test articles is oftentimes challengingand dependent upon that individual’s manage-rial, technical, and scientific capabilities. In-dividuals who serve as Study Directors typicallyhave not received formal education in thisendeavor, and many times have other profes-sional responsibilities within an organization.Training and mentoring of Study Directorsusually occurs ‘‘on the job’’ and is dependentupon the level of organization and experienceof the laboratory personnel interacting withthat individual.This paper is intended to serve as a practicalresource to provide guidance to Study Directorsfor the initiation, conduct, and completion of nonclinical studies. This guide is intended to beuseful to all Study Directors, regardless of ex-perience level, and is applicable for the majorityof studies conducted in a nonclinical labora-tory, irrespective of scientific discipline or studydesign. Although emphasis is placed on theconduct of nonclinical studies for the bio-pharmaceutical industry and regulated by theUS Food and Drug Administration (all citedreferences to GLP refer to these regulations),the guidance provided here is consistent withthe role and responsibilities of the StudyDirector in GLP studies as described in theOECD (Organization for Economic Coopera-tion and Development) Principles of GLP [2].Although the qualifications and trainingrequired for an individual to serve as a StudyDirector may vary and are the responsibility of test facility management to determine, generalguidances should be considered. In regard toformal education, a degree in the biologicalsciences (e.g. BS, MS, DVM, PhD, MD) isgenerally required although in certain circum-stances appropriate training and professionalexperience may be sufficient for an individualwithout a degree in the biological sciences.Management should assess prior professionalexperience when determining which aspects of a formal training program are most applicablefor an individual becoming a Study Director.This individual should clearly document intheir training record or file the ability to collect,interpret, evaluate, and report experimentaldata as evidenced by formal education, aca-demic and/or industrial research, publications,certifications, professional experience, andcompletion of any relevant training programs.In addition to understanding the regulatory andscientific requirements for directing studies,Study Directors also need to successfully man-age, communicate, and interact with numerousindividuals who are involved with the designand conduct of the study. The various man-agerial and interpersonal skills necessary forsuccessful study directing have been describedelsewhere [3].As per Section 58.31 of the GLP regulations,‘‘For each Nonclinical laboratory study, testingfacility management shall: (a) Designate aStudy Director as described in 58.33, before thestudy is initiated. (b) Replace the Study Direc-tor promptly if it becomes necessary to do soduring the conduct of a study.’[1] Forboth assignment and replacement of a StudyDirector, management should ensure that theassigned person has the appropriate qualifica-tions, training, interest, and resources to directthe study. Management has the ultimate re-
A PRACTICAL GUIDE TO STUDY DIRECTING 41
Copyright
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2009 John Wiley & Sons, Ltd.
Qual Assur J 
2009;
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sponsibility for ensuring that the testing facilityis effectively organized and that work is carriedout to a high standard, in accordance with GLPregulations and facility standard operatingprocedures (SOPs) and practices.Before any study activity is undertaken, theStudy Director should ensure that managementhas committed adequate resources, in terms of personnel and equipment, to perform andcomplete the study in a timely fashion. SOPsshould be in place for procedures/operations tobe conducted in the study. The laboratory’sSOPs should be detailed enough to adequatelydescribe/instruct how to perform the intendedtask, yet clearly written to avoid confusion andallow efficient work to occur [4]. Facilitymanagement should ensure that personnel in-volved in the study are adequately trained toperform the tasks expected of them and that theequipment to be used in the study has beenappropriately calibrated, serviced, and main-tained. Although the Study Director is not di-rectly responsible for instituting theseconditions for the study, he/she accepts re-sponsibility for the study following issuance of the protocol.
Initiating and Directing the Study
Study Objectives
The Study Director, in consultation with theSponsor or project team representative shoulddiscuss the objective(s) of the study, whetherGLP compliance is required, and the appro-priate study design. Section 58.3 of the GLPregulations state: ‘‘Nonclinical laboratory studymeans in vivo or in vitro experiments in whichtest articles are studied prospectively in testsystems under laboratory conditions to deter-mine their safety. The term does not includestudies utilizing human subjects or clinicalstudies or field trials in animals. The term doesnot include basic exploratory studies carriedout to determine whether a test article has anypotential utility or to determine physical orchemical characteristics of a test article.’’[1]Studies intended to support safety andcharacterize the toxicity of a test article need tocomply with GLP regulations. This includes themajority of genetic toxicology, safety pharma-cology, and general toxicology studies per-formed in support of applications for researchor marketing permits of biopharmaceuticalagents. Exceptions to this rule may includescreening genetic toxicology studies, doserange-finding studies, and investigative or ex-ploratory studies.Study design and rationale, parameters to beevaluated, and doses to be tested should bediscussed between the Study Director, Sponsor,project team representative, and other relevantindividuals. If unique assays or procedures areto be included, planning should occur to ensurethat appropriate resources, training, and pro-cedures are available to properly conduct thestudy. Dose-level selection is a key aspect inprotocol preparation and should be determinedas soon as possible so that test/control articlerequirements can be determined, materialsordered, and appropriate analytical methods/ information made available.
Test and Control Articles
The test article is commonly referred to as testsubstance and is typically the drug or experi-mental compound under study. Oftentimes, thetest article is the most variable element to thenonclinical study and it is common for the testfacility and Study Director to have variousquestions regarding this aspect of the study.The control article is also referred to as controlsubstance and is administered to the test systemfor establishing a basis for comparison with thetest article. Typically, the control article is thevehicle that is used to formulate and deliver/ apply the test article to the test system.Adequate supplies of the test and controlarticles for completion of the study should beavailable in the test facility at least several daysprior to initial use of the material.Documentation of identity, strength, purity,and composition of the test article is requiredby the GLPs (Section 58.105), and should be
A. P. Brown42
Copyright
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2009 John Wiley & Sons, Ltd.
Qual Assur J 
2009;
12
, 40–50DOI: 10.1002/qaj

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