Randomized controlled trial

A randomized controlled trial (RCT) is a type of scientific experiment most commonly used in testing the efficacy or effectiveness of healthcare services (such as medicine or nursing) or health technologies (such as pharmaceuticals, medical devices or surgery). RCTs are also employed in other research areas, such as judicial, educational, and social research. As their name suggests, RCTs involve the random allocation of different interventions (treatments or conditions) to subjects. As long as numbers of subjects are sufficient, this ensures that both known and unknown confounding factors are evenly distributed between treatment groups.

Types of trials
Trials may be open, blind or double-blind.Open trial In an open trial, also called an open-label trial, the researcher knows the full details of the treatment, and so does the patient. These trials are open to challenge for bias, and they do nothing to reduce the placebo effect. However, sometimes they are unavoidable, as placebo treatments are not always possible (see Blinding).Usually this kind of study design is used in bioequivalence studies.

[edit] Blind trials

[edit] Single-blind trial

In a single-blind trial, the researcher knows the details of the treatment but the patient does not. Because the patient does not know which treatment is being administered (the new treatment or another treatment) there might be no placebo effect. In practice, since the researcher knows, it is possible for the researcher to treat the patient differently or to subconsciously hint to the patient important treatment-related details, thus influencing the outcome of the study.[edit] Double-blind trial In a double-blind trial, one researcher allocates a series of numbers to 'new treatment' or 'old treatment'. The second researcher is told the numbers, but not what they have been allocated to. The second researcher does not know which treatment is being administered, and so cannot possibly tell the patient, directly or otherwise. Also, the patient cannot provide pressure to be given the new treatment. In this system, there is also often a more realistic distribution of sexes and ages of patients. Therefore double-blind trials are preferred, as they tend to give the most accurate results.[edit] Triple-blind trial Some randomized controlled trials are considered triple-blinded, although the meaning of this may vary according to the exact study design. The most common meaning is that the subject, researcher and person administering the treatment (often a pharmacist) are blinded to what is being given. Alternately, it may mean that the patient, researcher and statistician are blinded. The team monitoring the response may be unaware of the intervention being given in the control and study groups. These additional precautions are often in place with the more commonly accepted term "double blind trials", and thus the term "triple-blinded" is infrequently used. However, it connotes an additional layer of 1

security to prevent undue influence of study results by anyone directly involved with the study.

[edit] Trials in healthcare
In the hierarchy of evidence that influences healthcare policy and practice, RCTs are considered by most to be the top individual unit of research. They are considered the most reliable form of scientific evidence because they eliminate spurious causality and bias[1].Sellers of medicines throughout the ages have had to convince their consumers that the medicine works. As science has progressed, public expectations have risen, and government health budgets have become ever tighter, pressure has grown for a reliable system to do this. Moreover, the public's concern for the dangers of medical interventions has spurred both legislators and administrators to provide an evidential basis for licensing or paying for new procedures and medications. In most modern health-care systems all new medicines and surgical procedures therefore have to undergo trials before being approved. Trials are used to establish average efficacy of a treatment as well as learn about its most frequently occurring side-effects. This is meant to address the following concerns. First, effects of a treatment may be small and therefore undetectable except when studied systematically on a large population. Second, biological organisms (including humans) are complex, and do not react to the same stimulus in the same way, which makes inference from single clinical reports very unreliable and generally unacceptable as scientific evidence. Third, some conditions will spontaneously go into remission, with many extant reports of miraculous cures for no discernible reason. Finally, it is wellknown and has been proven that the act of administering the treatment itself may have direct, sometimes very powerful, psychological effects on the patient, which is known as the placebo effect.

[edit] Aspects of control in clinical trials
Traditionally the control in randomized controlled trials refers to studying a group of treated patients not in isolation but in comparison to other groups of patients, the control groups, who by not receiving the treatment under study give investigators important clues to the effectiveness of the treatment, its side effects, and the parameters that modify these effects. Other aspects of control include having other members of the research team, who will typically review the test to try to remove any factors which might skew the results. For example, it is important to have a test group which is reasonably balanced for ages and sexes of the subjects (unless this is a treatment which will never be used on a particular sex or age group). Additionally, peer review and/or review by government regulators can be seen as another source of control. These bodies examine the trial results when they are presented for publication or when the drug manufacturer applies for a licence for the drug.

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The importance of having a control group cannot be overstated. Merely being told that one is receiving a miraculous cure can be enough to cure a patient²even if the pill contains nothing more than sugar. Additionally, the procedure itself can produce ill effects. For example, in one study[citation needed] on rabbits where these subjects were receiving daily injections of a drug, it was found that they were developing cancer. If this was a result of the treatment, it would obviously be unsuitable for testing in humans. Because this result was reflected equally between the control and test groups, the source of the problem was investigated and it was shown in this case that the administration of daily injections was the cancer risk²not the drug itself. The analysis of the trial results requires knowledge of medicine, epidemiology, and in particular statistics. The branch of statistics that deals specifically with biomedical research is biostatistics. Pharmaceutical firms employ groups of biostatisticians to try to make sense of the data. Likewise, regulators pay keen attention to the appropriateness of statistical methods used to analyze trial results.

[edit] Types of control groups
y y y y y

Placebo concurrent control group Dose-response concurrent control group Active concurrent control group No treatment concurrent control group Historical control

[edit] Randomization in clinical trials
There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate a random and unpredictable sequence of allocations. This may be a simple random assignment of patients to any of the groups at equal probabilities, or may be complex and adaptive. A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed to the study investigators prior to definitively allocating them to their respective groups.

[edit] Randomization procedures
There are a couple of statistical issues to consider in generating the randomization sequences[1].:
y

y

Balance: since most statistical tests are most powerful when the groups being compared have equal sizes, it is desirable for the randomization procedure to generate similarly-sized groups. Selection bias: depending on the amount of structure in the randomization procedure, investigators may be able to infer the next group assignment by guessing which of the groups has been assigned the least up to that point. This

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will depend on the randomization procedure. In addition to promoting group balance at the end of the trial. In practice. in which the entire sample is treated as one block. for small block sizes this may become infeasible. ECCE. Strictly speaking. Permuted block randomization has several advantages. permuted block randomization should be followed by statistical analysis that takes the blocking into account. The potential magnitude of that bias. predicting future group assignment becomes progressively easier. For instance. However. A special case of permuted block randomization is random allocation. let E stand for experimental group and C for control group. CECE. Accidental bias: if important covariates that are related to the outcome are ignored in the statistical analysis.y breaks allocation concealment (see below) and can lead to bias in the selection of patients for enrollment in the study. estimates arising from that analysis may be biased. [edit] Urn randomization 4 . The remedy for this bias is to blind investigator from group assignments and from the randomization procedure itself. permuted block randomization is particularly susceptible to selection bias. each patient is effectively randomly assigned to any one of the groups. if any. That is. ECEC. [edit] Complete randomization In this commonly used and intuitive procedure. This is particularly important because clinical trials enroll patients sequentially. it also promotes periodic balance in the sense that sequential patients are distributed equally between groups. In practice it is recommended that intra-block correlation be examined as a part of the statistical analysis. imbalance is only a concern for small sample sizes (n < 200). such that there may be systematic differences between patients entering at different times during the study. with equal probabilities of 1/6 each. since toward the end of each block the investigators know the group with the least assignment up to that point must be assigned proportionally more of the remainder. However. CEEC. by enforcing within-block balance. its main drawback is the possibility of imbalances between the groups. Unfortunately. blocks of k patients are created such that balance is enforced within each block. then a block of k = 4 patients may be assigned to one of EECC. and CCEE. [edit] Permuted block randomization In this form of restricted randomization. It is simple and optimal in the sense of robustness against both selection and accidental biases. Note that there are equal numbers of patients assigned to the experiment and the control group in each block.

the investigator must believe before the trial begins that all treatments under consideration are equally desirable. This can be done with a separate list of randomization blocks for each combination of values . Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient[2]. one treatment may be selected as superior if a statistically significant difference was discovered. Outcome-adaptive randomization is a variation on traditional randomization designed to address the ethical issue raised above. clinical investigators often find it difficult to maintain impartiality. This introduces selection bias and confounders and distorts the results of the study. evidence may accumulate that one treatment is superior. in taking care of individual patients. gender or previous treatments) it is desirable to ensure a balance across each of these variables. Randomization probabilities are adjusted continuously throughout the trial in response to the data. The probability of a treatment being assigned increases as the probability of that treatment being superior increases. patient age. Sealed Envelopes (SNOSE) Sequentially-numbered containers Pharmacy controlled Central randomization Great care for allocation concealment must go into the clinical trial protocol and reported in detail in the publication. [edit] Allocation concealment In practice.[edit] Covariate-adaptive randomization When there are a number of variables that may influence the outcome of a trial (for example. Opaque. Some standard methods of ensuring allocation concealment include: y y y y Sequentially-Numbered. When the number of variables or possible values are large a statistical method known as Minimisation can be used to minimise the imbalance within each of the factors. Breaking allocation concealment in randomized controlled trials is that much more problematic because in principle the randomization should have minimized such biases. Between the beginning and end of the trial is an ethical grey zone. [edit] Outcome-adaptive randomization For a randomized trial in human subjects to be ethical. Recent studies have found that not only do most publications 5 .although this is only feasible when the number of lists is small compared to the total number of patients. while on average more patients are assigned to superior treatments. and yet patients are still randomized equally between all treatments until the trial ends. At the end of the trial. The statistical advantages of randomization are retained. As patients are treated.

6 . [edit] New chemical entity (NCE) development New chemical entities (NCEs) are compounds which emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease.g. based on the facts. preclinical research(microorganisms/animals) and Clinical trials (on humans).. [edit] Statistical error Most studies start with a 'null hypothesis' which is being tested (usually along the lines of 'Our new treatment x cures as many patients as existing treatment y') and an alternative hypothesis ('x cures more patients than y').. little will be known about the safety. Few people still refer to the drug developent as mere preclinical development. pharmacokinetics and metabolism of this NCE in humans. dieting) Thus. however. so if 200 trials are done (often the case for contentious matters) about 2 will show contrary results.. There is a tendency for these two to be seized on by those who need that proof for their point of view. of whether the null hypothesis can be safely rejected (saying that the new treatment does. so false negatives and false positives are possible. It is the function of drug development to assess all of these parameters prior to human clinical trials. result in more cures). studies should be blinded (see above) by giving placebo treatments. for some treatments placebos are not possible. most of the publications that do not report also have unclear concealment procedures in the protocols[3][4]. The analysis at the end will give a statistical likelihood. [edit] Blinding Ideally. this risk is cumulative. 1% chance that it was a false result). However.not report their concealment procedure. Examples: y y treatments where a convincing placebo treatment would be too dangerous to be ethically acceptable (e. However. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-inman" (FIM) or First Human Dose (FHD)). in fact. physical therapy. Drug development Drug development is a blanket term used to define the entire process of bringing a new drug or device to the Market.g. toxicity. Nevertheless this is only a statistical likelihood. These are generally set an acceptable level (e.g. It includes Drug discovery / product development. surgery) treatments where active participation of the patient is necessary (e. to avoid bias caused by placebo effects. some treatments can by their nature not be subjected to blinded studies.

it can be manufactured on the kilogram and then on the ton scale. components of experimentation and components that involve set routines. The early phase of drug discovery actually has components of real innovation. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. etc). liver and digestive system). as well as effects on other parts of the body that might be affected by the drug (e. subcuteneous injectable. Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. as well as effects on systems not previously monitored (fertility. or because they simply do not work in clinical trials. reproduction. The compound will also be tested for its ability to cause cancer (carcinogenicity testing). Manufacturing and Control. Experimentation. [edit] Cost 7 . This model also allows the discipline to use appropriate internal and external resources for the right work. tablets. or intravenous formulations. stability. the skin if the new drug is to be delivered through the skin). This model of Innovation. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a synthetic chemist. While. increasingly. solubility. One approach to improve efficiency is to recognize that there are many steps requiring different levels of experimentation. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs. these tests can be made using in vitro methods (e. immune system. either because they have some unacceptable toxicity.In addition. Most NCEs. then it can be submitted for marketing approval in the various countries where it will be sold. Together these processes are known in preclinical development as CMC: Chemistry. and Commoditization ensures that new ways to do work are adopted continually. intramuscular injectable. As this drug discovery process becomes more expensive it is becoming important to look at new ways to bring forward NCEs. and it can further be demonstrated to have the desired effect in clinical trials. kidney. with isolated cells). If a compound emerges from these tests with an acceptable toxicity and safety profile. however.g. this process is called a New Drug Application or NDA.g. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined. drug development is required to establish the physicochemical properties of the NCE: its chemical makeup. In the US. since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined. aeresol. brain. The process of drug development does not stop once an NCE begins human clinical trials. fail during drug development. many tests can only be made by using experimental animals. It will be further examined for its suitability to be made into capsules.

Good Clinical Practice guidelines include protection of human rights as a subject in clinical trial. 2003: 26. [edit] Need for a DMC Many randomized clinical trials are double blind. 2004: 24. only about 26 such drugs enter the market (2005: 26.Studies published in 2003 report an average pre-tax cost of approximately $800 million to bring a new drug (i. these trials may go for years and there is justifiably concern about enrolling participants and exposing them to an unproven treatment without someone overseeing results.The consumer advocacy group Public Citizen suggests on its web site that the actual cost is under $200 million. and even the study personnel at the company that is sponsoring the trial. This includes the participant. In the pharmaceutical industry monitors are often called Clinical Research Associates. The $800 million quoted include the cost of all drug development which did not result in a new drug. about 29% of which is spent on FDA-required clinical trials Good clinical practice Good Clinical Practice is an international quality standard that is provided by International Conference on Harmonisation (ICH). worldwide. The development cost of the thousands of other drugs are much smaller. innovative drugs (drugs with a New Chemical Entity NCE. 2002: 28).e. a drug with a New Chemical Entity) to market. they would be in an awkward position between concern for their corporate interests and concern for the trial participants. Data monitoring committees A Data Monitoring Committee (DMC) ² sometimes called a Data and Safety Monitoring Board (DSMB) ² is an independent group of experts who monitor patient safety and treatment efficacy data while a clinical trial is ongoing. The company sponsoring the trial is blinded. Even if they had some people who were unblinded to the results.e. 8 . It also includes some 400 million $ of opportunity costs. an international body that defines standards.[3] These figures relate only to new.However. which governments can transpose into regulations for clinical trials involving human subjects. There are many extremely good reasons to conduct a trial in this manner and only after the trial database is finalized is the blind broken and the true treatment assignments disclosed. Each year. so they can't perform this service.[1][2] A study published in 2006 estimates that costs vary from around 500 million to 2. define the roles and responsibilities of clinical trial sponsors. i. no one involved with the trial knows what treatment was given to the trial participant.000 million dollars depending on the therapy or the developing firm.Good Clinical Practice Guidelines include standards on how clinical trials should be conducted. clinical research investigators. and monitors. also called New Active Substance NAS). their doctor. It also provides assurance of the safety and efficacy of the newly developed compounds.

As an example.The DMC is a group (typically 3 to 7 members) who are independent of the company sponsoring the trial. The DMC has the power to recommend termination of the study based on the evaluation of these results. Institutional review board An institutional review board (IRB). the experimental arm could cause serious adverse events (chemotherapy. current and potential trial participants could be freed to take other treatments.e. Also. but the resulting improvement in survival outweighs these adverse events. It is extremely unlikely that the trial. such as collecting more long-term safety data. but actually can be the most common reason to stop a trial. should it continue to its normal end. At least one DMC member will be a statistician. If adverse events of a particularly serious type are more common in the experimental arm compared to the control arm. Clinicians knowledgeable about the disease indication should be represented. A few long. nephrology. as well as clinicians knowledgeable in the fields of any major suspected safety effects (e. and futility. also known as an independent ethics committee (IEC) or ethical review board (ERB) is a committee that has been formally designated to 9 . [edit] Overwhelming benefit In the rare. would have the statistical proof needed to convince a regulatory agency to approve the treatment. rather than this experimental treatment which is unlikely to benefit them. This evaluation has to be made in consideration of risk/benefit. suppose a trial is one-half completed. There are typically three reasons a DMC might recommend termination of the study: safety concerns. The company sponsoring the study could save money for other projects by abandoning this trial. situation that the experimental arm is shown to be undeniably superior to the control arm the DMC may recommend termination of the trial. but fortunate. there might be other reasons to continue. Safety concerns The primary mandate of the DMC is to protect patient safety. outstanding benefit. There are cautions here though. [edit] Futility Futility is not as widely recognized as safety and benefit. In many cases. cardiology). for example). Also.g. then the DMC would have to strongly consider termination of the study. results split by experimental and control arms. The statistical proof needs to be very high indeed. but the experimental arm and the control arm have nearly identical results. The DMC will convene at predetermined intervals (three to six months typically) and review unblinded results. i. This would allow the company sponsoring the trial to get regulatory approval earlier and to allow the superior treatment to get to the patient population earlier. It's likely in no one's interest to have this trial continue. visible trials may include an ethicist or even a representative from a patient advocacy group.

employability.approve. and 2. or 2. a project conducted between 1932 and 1972 by the U. research on regular and special education instructional strategies. directly or through identifiers linked to the subjects. IRBs were developed in direct response to research abuses earlier in the twentieth century. 2. [edit] Exemptions While IRBs can be more inclusive or restrictive. and Welfare at the time. involving normal educational practices. and regulatory.S. ethical. and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects. research on the effectiveness of or the comparison among instructional techniques. from what was the Department of Health. aptitude. require modifications in planned research prior to approval. the Food and Drug Administration (FDA) and Department of Health and Human Services (specifically Office for Human Research Protections) regulations have empowered IRBs to approve. An IRB performs critical oversight functions for research conducted on human subjects that are scientific. 10 . interview procedures or observation of public behavior. Research conducted in established or commonly accepted educational settings. mandate In the United States. Education. In the United States. IRBs are governed by Title 45 CFR (Code of Federal Regulations) Part 46. such as 1. achievement). directly or indirectly. Two of the most notorious of these abuses were the experiments of Nazi physicians that became a focus of the post-World War II Doctors' Trial. monitor.[1] This National Research Act of 1974 defines IRBs and requires them for all research that receives funding. survey procedures. Research involving the use of educational tests (cognitive. IRBs are themselves regulated by the Office for Human Research Protections (OHRP) within HHS. curricula. and the Tuskegee Syphilis Study. or reputation. exemptions to IRB approval include research activities in which the only involvement of human subjects will be in one or more of the following categories: 1. or disapprove research. Public Health Service on black men in rural Alabama. unless: 1.S. any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing. information obtained is recorded in such a manner that human subjects can be identified. under the statute. Title 21 part 56 has additional requirements for IRBs that oversee clinical trials of drugs involved in New drug applications. or classroom management methods. and is now the Department of Health and Human Services (HHS). diagnostic. [edit] U.

aptitude. public benefit or service programs. or agricultural chemical or environmental contaminant at or below the level found to be safe. and which are designed to study.[edit] Naming and composition Although "IRB" is a generic term used by the FDA and HHS. 4. the IRB is subject to the FDA's IRB regulations when studies of FDA-regulated products are reviewed and approved. or possible changes in methods or levels of payment for benefits or services under those programs. federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. primarily to minimize or avoid ethical problems. or diagnostic specimens. diagnostic. records. each institution that establishes an IRB may use whatever name it chooses. 5. or otherwise examine: 1. Originally. or observation of public behavior that is not exempt under paragraph (b)(2) of this section. possible changes in or alternatives to those programs or procedures. Research involving the collection or study of existing data. survey procedures. 2. and they are governed by the same federal 11 . pathological specimens. directly or through identifiers linked to the subjects. Today some IRB reviews are conducted by for-profit organizations known as independent or commercial IRBs. Regardless of the name chosen.S. achievement). 4. if: 1. Department of Agriculture. documents. Research involving the use of educational tests (cognitive. 6. if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified. evaluate.3. by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U. procedures for obtaining benefits or services under those programs. interview procedures. 3. Taste and food quality evaluation and consumer acceptance studies. the human subjects are elected or appointed public officials or candidates for public office. Research and demonstration projects which are conducted by or subject to the approval of department or agency heads. (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe. The responsibilities of these IRBs are identical to those based at academic or medical institutions. IRBs were committees at academic institutions and medical facilities to monitor research studies involving human participants. 2.

informed permission given by a suitable proxy) and to maximize the safety of subjects once they are enrolled in the project.107.[2] (a)2 The members must have enough experience. informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research. but only actual IRB members may vote. (f) The IRB may include consultants in their discussions to meet requirements for expertise or diversity. 12 . (a)1 The IRB must have at least five members. (d) The IRB must include at least one person who is not affiliated with the institution or in the immediate family of a person affiliated with the institution. These terms are not defined in the regulations. more than half of the members of the board must be present and there must be a non-scientist present. sociology. In order to vote on a proposal. (b)2 The members of the IRB must not be all of the same profession. if that is not possible. To accomplish this purpose. The purpose of an IRB review is to assure. (a)3 If the IRB works with studies that include vulnerable populations. or they may be studies of how health care is delivered and might be improved.regulations.g. as long as they aren't chosen specifically for their gender. opinions or attitudes. informed consent is sufficient.." (e) IRB members may not vote on their own projects. both in advance and by periodic review. and psychology. but these are relatively narrow. and diversity to make an informed decision on whether the research is ethical. to promote fully informed and voluntary participation by prospective subjects who are themselves capable of making such choices (or. they may be studies of personal or social behavior. [edit] Purpose and use IRBs are most commonly used for studies in the fields of health and the social sciences. The chief objectives of every IRB protocol review are to assess the ethics of the research and its methods. and appropriate safeguards have been put in place. The composition of an IRB for the FDA's requirements is set in 21 CFR 56. These are commonly called "Community Members. the IRB should have members who are familiar with these groups. IRBs review research protocols and related materials (e. including anthropology. It is common for an IRB to include an advocate for prisoners when considering research that involves them. There are exceptions for expedited review. (b)1 The IRB should include both men and women. Such studies may be clinical trials of new drugs or devices. expertise. where only the chair of the committee or a designee reviews research. (c) The IRB must include at least one scientist and at least one non-scientist. that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study.

Broad complaints range from the legitimacy of IRB review. The way payment will be prorated should be specified. [edit] Problems with IRB review of social science The Common Rule regulations and Belmont principles were formulated with biomedical and laboratory science methods in mind. the lack of physical risks in social science (e. modifications required prior to its approval/favourable opinion. disapproval/negative opinion.10 be given to subjects when.g. When a non-therapeutic trial is to be carried out with the consent of the subject's legally acceptable representative (see 4. is set forth in the written informed consent form and any other written information to be provided to subjects.8. unneeded. the documents reviewed and the dates for the following: y y y y approval/favourable opinion. The IRB/IEC may request more information than is outlined in paragraph 4.. According to ICH GCP the IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects. including the methods. the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials. clearly identifying the trial.14). and schedule of payment to trial subjects. amounts.The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing.8. the additional information would add meaningfully to the protection of the rights. in emergency situations).e. 13 . in the judgment of the IRB/IEC. According to ICH GCP (good clinical practice) the IRB/IEC should ensure that information regarding payment to subjects. but at least once per year.. There have been numerous complaints by investigators about the fit between the federal regulations and its IRB review requirements as they relate to social science research. as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests. and termination/suspension of any prior approval/favourable opinion. Where the protocol indicates that prior consent of the trial subject or the subject's legally acceptable representative is not possible (see 4. the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.12. According to ICH GCP the IRB/IEC should consider the qualifications of the investigator for the proposed trial. 4. The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. safety and/or well-being of the subjects.8.15).8. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.

. Formed in the aftermath of the Tuskegee Experiment scandal. to IRBs failing to understand qualitative research such as ethnography. Education. Education. The commission produced their Reports and Recommendations on the following areas of research: y y y y y y y y y y y Research on the Fetus (1975) [1] Research Involving Prisoners (1976) [2] Research Involving Children (1977) [3] Psychosurgery Report and Recommendations (March 1977) [4] Disclosure of Research Information Under the Freedom of Information Act (April 1977) [5] Research Involving Those Institutionalized as Mentally Infirm (1978) Ethical Guidelines for the Delivery of Health Services by DHEW (1978) [6] Appendix to Ethical Guidelines for the Delivery of Health Services by DHEW (1978) [7] Institutional Review Boards (1978) Implications of Advances in Biomedical and Behavioral Research (1978) The Belmont Report: Ethical Principles and Guidelines for Protection of Human Subjects of Biomedical and Behavioral Research (1979) [8] 14 .e. especially the National Science Foundation. collecting anecdotes. and were never intended to be covered by clinical research rules. and similar free speech activities do not constitute IRB-qualified research. and Welfare and Congress for the protection of Human subjects. the Commission was created in 1974 as Title II of the National Research Act. OHRP. and Welfare (DHEW) until 1978. unstructured interviews (as if for a piece of journalism). It was part of the United States Department of Health.[3] Other federal agencies supporting social science have attempted to provide guidance in this area. issued a formal statement that taking oral histories. In general. the FAQ assures IRBs that the regulations have some flexibility and rely on the common sense of the IRB to focus on limiting harm. maximizing informed consent. In 2003. The Commission was tasked with studying the ethical principles underlying biomedical and behavioral research on human subjects and to make recommendations to the Secretary of Health. consent forms). participants' consent documentation (i. in conjunction with the Oral History Association and American Historical Association. and limiting bureaucratic limitations of valid research National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was the first public national body to shape bioethics policy in the United States.over-burdensome requirements).

These reports contained their recommendations. The IRB or IEC will review not only the protocol of the trial but also the way that subjects are recruited and the consent form that they sign. the underlying deliberations and conclusions. or the standard medical treatment for a patient's condition. prisoners. in Europe they are typically called Independent Ethics Committees (IEC). all trials involving unapproved medical treatments are reviewed for ethics before the study begins. versus a placebo (inactive look-a-like). researchers can seek consent from the patient's legally authorized representative. These approving groups are typically called Institutional Review Boards (IRB) in the United States. a clinical trial is a comparison test of a medication or other medical treatment (such as a medical device). To approve the trial. and the mentally ill. An appendix was also included which contained complete text reports and papers prepared for the commission on the ethical. Ethical problems using children in clinical trials In health care. 15 . Food and Drug Administration (FDA) and Office for Human Research Protections regulations require the IRB to make specific "Subpart D" determinations [1] regarding children. These groups include minors. it must meet all of the following conditions: y y The trial must involve no more than a minor increase over minimal risk.S. researchers must obtain the full and informed consent of participating human subjects. The treatments must be appropriate to the condition or to medical care that the child would otherwise receive. [edit] International standards According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good clinical practice. To be ethical. If the patient is unable to consent for him/herself. legal and medical aspects of the different research areas examined and other material reviewed by the commission in its deliberations. other medications or devices. For a minor child this is typically a parent or guardian since the child cannot legally give consent. The Commission was succeeded by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The World Medical Association's Declaration of Helsinki requires researchers to take special care with consent involving vulnerable subject populations which have barriers to informed consent. a dissenting statement and additional statement by commission members and summaries of materials presented to the Commission. These groups also examine the incentives given for participation in the trial to ensure that they are not coercive. [edit] In the United States U.

clinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices.y The treatment must either yield "generalizable knowledge" about the specific condition that is vital for understanding or treatment. These trials can only take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety. children. prevention. Additional safeguards exist for "wards of the state" such as orphans. Patent term extensions were offered to manufacturers that conducted trials of drugs that would be used in children. or alleviation of a serious problem that specifically affects children. The Pediatric Research Equity Act of 2003. for example.[3] Clinical trial In medical research. They are also expected to evaluate the compensation given to ensure that participants are not coerced by the lure of payment. If not all of those criteria are met. is a potentially fatal complication of aspirin therapy in children that is very rare in adults. The 2002 Best Pharmaceuticals for Children Act. [edit] Ethical concerns Since parents often receive compensation for their children's participation in research. allowed the FDA to request National Institutes of Health-sponsored testing for pediatric drug testing. Reye's syndrome. [2]. "Sound ethical principles" are used. 16 . "adequate provisions" must be made to allow the child to decide if they want to participate in the trial. Many drugs work differently in children. The IRB or IEC is expected to evaluate both the consent and assent process to ensure that children are not coerced into participation. there are concerns that the payments received may be coercive and lead them to participate in trials which are not in their child's best interest. The IRB must ensure that the assent process is appropriate for children. although these requests are subject to NIH funding constraints. In either case. A child cannot legally give Informed Consent but they must be given the opportunity to decline. Congress codified the FDA's authority to mandate manufacturer-sponsored pediatric drug trials for certain drugs as a "last resort" if incentives and publicly funded mechanisms proved inadequate. A parent or guardian legally consents to the child's participation. [edit] Problems for the practice of medicine Partially because of these issues many drugs that are used in children have never been formally studied in children. the FDA commissioner or the Secretary of Department of Health and Human Services must then consult appropriate experts and can approve the trial if both: y y The study is a reasonable opportunity to further the understanding.

one or more pilot experiments are conducted to gain insights for design of the clinical trial to follow. administer the treatment(s). amount of study drug in the blood. In medical jargon.S. In the U. effectiveness is how well a treatment works in practice and efficacy is how well it works in a clinical trial. followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. Some examples of what a clinical trial may be designed to do: y assess the safety and effectiveness of a new medication or device on a specific kind of patient (e. Due to the sizable cost a full series of clinical trials may incur. These data include measurements like vital signs. During the clinical trial. [edit] Overview In planning a clinical trial. the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo). Women.[1] Despite this. the elderly comprise only 14% of the population but they consume over one-third of drugs. As positive safety and efficacy data are gathered. and whether the patient's health gets better or not. often a clinical trial is managed by an outsourced partner such as a contract research organization (CRO). Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries. the number of patients is typically increased.[2] In coordination with a panel of expert investigators (usually physicians well-known for their publications and clinical experience). and what kind of patients might benefit from the medication/device. the investigators: recruit patients with the predetermined characteristics.and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place. the burden of paying for all the necessary people and services is usually borne by the sponsor who may be the pharmaceutical or biotechnology company that developed the agent under study. The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests. If the sponsor cannot obtain enough patients with this specific disease or condition at one location.g. then investigators at other locations who can obtain the same kind of patients to receive the treatment would be recruited into the study. Depending on the type of product and the stage of its development. the sponsor or investigator first identifies the medication or device to be tested. they are often excluded from trials because their more frequent health issues and drug use produces more messy data. investigators enroll healthy volunteers and/or patients into small pilot studies initially. Usually. and collect data on the patients' health for a defined time period. children. Since the diversity of roles may exceed resources of the sponsor. patients who have been diagnosed with Alzheimer's disease) 17 . and people with common medical conditions are also frequently excluded..

Beginning in the 1980s. biologics. or devices against each other. Because the clinical trial is designed to test hypotheses and rigorously monitor and assess what happens. research protocols and clinical research. These activities are pursued in the interest of the consumer and public health. Therapy A vs.y y y y assess the safety and effectiveness of a different dose of a medication than is commonly used (e. Therapy B) Note that while most clinical trials compare two medications or devices. Clinical trials may be required before the national regulatory authority[3] approve marketing of the drug or device.e. medical devices (like a new catheter). 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.g. in which he laid down rules for the experimental use and testing of drugs and wrote a 18 . some trials compare three or four medications. Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ICH HARMONISED TRIPARTITE GUIDELINE Currently. Device B. coordination between Europe.Synonyms for 'clinical trials' include clinical studies. Except for very small trials limited to a single location.g. clinical trials can be seen as the application of the scientific method to understanding human or animal biology.. safe and effective medicines are developed and registered in the most efficient and cost-effective manner. doses of medications. i." History Clinical trials were first introduced in Avicenna's The Canon of Medicine in 1025 AD. Device A vs. aimed at "ensuring that good quality.The most commonly performed clinical trials evaluate new drugs. At the same time. or a new dose of the drug.. psychological therapies. to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory [4] obligations of safety and effectiveness. the clinical trial design and objectives are written into a document called a clinical trial protocol.) A protocol is always used in multicenter trials. The protocol is the 'operating manual' for the clinical trial. for use on patients. harmonization of clinical trial protocols was shown as feasible across countries of the European Union. (This uniformity is designed to allow the data to be pooled. most clinical trial programs follow ICH guidelines. and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics. 10 mg dose instead of 5 mg dose) assess the safety and effectiveness of an already marketed medication or device for a new indication. 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. or other interventions.

The researchers do not actively manage the experiment. In an interventional study. not a composite." 4. Another way of classifying trials is by their purpose. An example is the Nurses' Health Study. on groups of afflicted sailors. who worked at Guy's Hospital in London. "The effect of the drug must be seen to occur constantly or in many cases. which still form the basis of modern clinical trials:[6][7] 1." 2." 7. For example. so that they would have no effect on them. ranging from vinegar to cider." 6." 3. Frederick Akbar Mahomed (d. the investigators give the research subjects a particular medicine or other intervention. "The quality of the drug must correspond to the strength of the disease. 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.[5] He laid out the following rules and principles for testing the effectiveness of new drugs and medications. y y In an observational study.S. "The time of action must be observed. Then the researchers measure how the subjects' health changes. disease. for if this did not happen."[10] [edit] Types One way of classifying clinical trials is by the way the researchers behave. the investigators observe the subjects and measure their outcomes. where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. because sometimes a drug cures one disease by its essential qualities and another by its accidental ones.[8] He compared the effects of various different acidic substances. Usually. this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials. it was an accidental effect. National Institutes of Health (NIH) organizes trials into five (5) different types:[11] 19 . "The drug must be free from any extraneous accidental quality. The U. This is also called a natural experiment.[9] made substantial contributions to the process of clinical trials during his detailed clinical studies. so that essence and accident are not confused. "The experimentation must be done with the human body. "The drug must be tested with two contrary types of diseases. 1884)." He also founded "the Collective Investigation Record for the British Medical Association. "It must be used on a simple.precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances. there are some drugs whose heat is less than the coldness of certain diseases." One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvy." 5. they compare the treated subjects to subjects who receive no treatment or standard treatment.

In other words. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment. Quality of life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness (a. new combinations of drugs. or new approaches to surgery or radiation therapy. or lifestyle changes. These approaches may include medicines. Usually. the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. [edit] Design A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. 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. Compassionate use trials: provide experimental therapeutics prior to final FDA approval to patients whose options with other remedies have been unsuccessful. double blind. In this kind of study. 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. Of note. Blind: The subjects involved in the study do not know which study treatment they receive.k. In addition. when 20 . Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition. y y y Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. vitamins. Screening trials: test the best way to detect certain diseases or health conditions. vaccines. since if a physician knew which patient was getting the study treatment and which patient was getting the placebo.Currently. during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. all patients are given both placebo and active doses in alternating periods of time during the study. This 'blinding' is to prevent biases. case by case approval must be granted by the FDA for such exceptions. Treatment trials: test experimental treatments. and placebo-controlled.a. minerals. Supportive Care trials). he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it.y y y y y y Prevention trials: look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. the researchers also do not know which treatment is being given to any given subject. some Phase II and most Phase III drug trials are designed as randomized. If the study is double-blind. a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. In observational studies.

statistical considerations. methodology. The study would compare the 'test' treatment to standard-of-care therapy. [edit] 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. giving them the placebo). or Japan has been standardized to follow Good Clinical Practice guidance[12] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). [edit] Design features [edit] Informed consent An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent. The protocol also gives the study administrators (often a contract research organization) as well as the site team of physicians. They may be "sponsored" by single physicians or a small group of physicians. and the trial sponsor is a private company. and are designed to test simple questions. Some journals.e. encourage trialists to publish their protocols in the journal. Other clinical trials require large numbers of participants (who may be followed over long periods of time). biotechnology or medical device companies in the United States. Details of the trial are also provided in other documents referenced in the protocol such as an Investigator's Brochure. 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."[14] 21 . many clinical trials are small. e. European Union.[13] Regulatory authorities in Canada and Australia also follow ICH guidelines. Trials. design.a treatment exists that is clearly better than doing nothing for the subject (i. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. and organization of the planned trial. objective(s). even if conducted in various countries.The protocol describes the scientific rationale. not only to assure safety and health of the trial subjects. the alternate treatment would be a standard-of-care therapy. or an academic research body such as a university. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Although the term "clinical trials" is most commonly associated with the large. The format and content of clinical trial protocols sponsored by pharmaceutical. The protocol contains a precise study plan for executing the clinical trial. a government health agency. randomized studies typical of Phase III. nurses and clinic administrators a common reference document for site responsibilities during the trial.g.

risks. a sponsor must decide on the target number of patients who will participate. unique value. Since researchers can behave differently to subjects given treatments or placebos. By example. [edit] Statistical power In designing a clinical trial. 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. Subjects in the treatment and placebo groups are assigned randomly and blinded as to which group they belong.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. this consideration must be balanced with the fact that more patients make for a more expensive trial. The larger the sample size or number of participants in the trial. The sponsor's goal usually is to obtain a statistically significant result showing a significant difference in outcome (e.70 to detect a difference of 5 mg/dL.. in designing a clinical trial. [edit] Placebo groups Merely giving a treatment can have nonspecific effects. Foreign language translation is provided if the participant's native language is not the same as the study protocol. Informed consent is not an immutable contract. However. The power of a trial is not a single. potential benefits and key contacts.90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more. This is described as the "power" of the trial. such as its purpose. The participant then decides whether or not to sign the document in agreement. and these are controlled for by the inclusion of a placebo group. a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of . To fully describe participation to a candidate subject. 22 . required procedures. For example. duration. the doctors and nurses involved in the trial explain the details of the study. 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. but only have a power of .g. The number of patients required to give a statistically significant result depends on the question the trial wants to answer. trials are also doubledblinded so that the researchers do not know to which group a subject is assigned. The research team provides an informed consent document that includes trial details. the greater the statistical power. number of deaths after 28 days in the study) between the groups of patients who receive the study treatments. as the participant can withdraw at any time. to show the effectiveness of a new drug in a non-curable disease as metastatic kidney cancer requires many fewer patients than in a highly curable disease as seminoma if the drug is compared to a placebo.

they conduct extensive pre-clinical studies. Each phase of the drug approval process is treated as a separate clinical trial. 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 pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body). it will usually be approved by the national regulatory authority for use in the general population. A Phase 0 study gives no data on safety or efficacy. The drug-development process will normally proceed through all four phases over many years. Before pharmaceutical companies start clinical trials on a drug.[15] 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. 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. II. and III.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. [edit] Phases Clinical trials involving new drugs are commonly classified into four phases. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug. toxicity and pharmacokinetic information. [edit] Phase 0 Phase 0 is a recent designation for exploratory. Phase IV are 'postapproval' studies. If the drug successfully passes through Phases I. [edit] Pre-clinical studies Pre-clinical studies involve in vitro (test tube) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy. 23 . 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. being by definition a dose too low to cause any therapeutic effect. The Declaration of Helsinki provides guidelines on this issue.

Food effect A short trial designed to investigate any differences in absorption of the drug by the body. tolerability. also called dose escalation. where the subject can be observed by full-time staff. such as patients who have end-stage disease and lack other treatment options. caused by eating before the drug is given. If they do not exhibit any adverse side effects. to a larger amount of up to approx $6000 depending on length of participation. There are different kinds of Phase I trials: 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. pharmacokinetics. or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD). These trials are often conducted in an inpatient clinic. the dose is escalated. ethically acceptable. Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. These studies are usually run as a crossover study. Phase I trials also normally include doseranging. This phase includes trials designed to assess the safety (pharmacovigilance). a group of patients receives multiple low doses of the drug. and a new group of subjects is then given a higher dose. whilst samples (of blood.[16] [edit] Phase I Phase I trials are the first stage of testing in human subjects. Normally. However. there are some circumstances when real patients are used. and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. a small (20-50) group of healthy volunteers will be selected. The subject who receives the drug is usually observed until several half-lives of the drug have passed. feasible. In these studies. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing. and whether there is room for improvement. This exception to the rule most often occurs in oncology (cancer) and HIV drug trials. studies so that the appropriate dose for therapeutic use can be found. Phase I trials most often include healthy volunteers. This is continued until precalculated pharmacokinetic safety levels are reached. with volunteers being given two identical doses of the drug on different occasions. one while fasted. speed up the drug development process or save money. The dose is subsequently escalated for further groups. and pharmacodynamics of a drug. MAD Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. and one after being fed.Questions have been raised by experts about whether Phase 0 trials are useful. and the pharmacokinetic data is roughly in line with predicted safe values. Pay ranges from a small amount of money for a short period of residence. up to a predetermined level. 24 .

[edit] Phase III Phase III studies are randomized controlled multicenter trials on large patient groups (300±3. in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration. it is typically expected that there be at least two successful Phase III trials. demonstrating a drug's safety and efficacy. Phase III trials are the most expensive. 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). Some trials combine Phase I and Phase II."[17][18] While not required in all cases. as well as to continue Phase I safety assessments in a larger group of volunteers and patients. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Phase II studies are sometimes divided into Phase IIA and Phase IIB. demonstrating a drug's safety and activity in a selected group of patients. or to have toxic effects. Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)). or to support marketing claims for the drug. [edit] Trial design Some Phase II trials are designed as case series. Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works. When the development process for a new drug fails. and test both efficacy and toxicity. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. Other Phase II trials are designed as randomized clinical trials.000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is. Studies in this phase are by some companies categorised as "Phase IIIB studies. y y Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). in order to obtain 25 . where some patients receive the drug/device and others receive placebo/standard treatment.[edit] Phase II Once the initial safety of the study drug has been confirmed in Phase I trials. time-consuming and difficult trials to design and run. especially in therapies for chronic medical conditions. this usually occurs during Phase II trials when the drug is discovered not to work as planned. to obtain additional safety data. Randomized Phase II trials have far fewer patients than randomized Phase III trials.

first have to be discovered.[19] [edit] Phase IV Phase IV trial is also known as Post Marketing Surveillance Trial. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines. Drugs for other diseases have similar timelines. a new cancer drug has. on average. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[3] in different countries. Potential drugs. who are unlikely to subject themselves to trials). but in case of any adverse effects being reported anywhere. and shelf life. They will review the submission. it is hoped. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold. On average. it is not abnormal to see many drugs undergoing Phase III clinical trials in the market. Once a drug has proved satisfactory after Phase III trials. or on certain population groups such as pregnant women. the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies. 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. the drug may not have been tested for interactions with other drugs. characterized. purified. In all. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. give the sponsor approval to market the drug. troglitazone (Rezulin) and rofecoxib (Vioxx). For example. Some reasons a clinical trial might last several years: 26 . about 1. for example.approval from the appropriate regulatory agencies such as FDA (USA). and tested in labs (in cell and animal studies) before ever undergoing clinical trials. for example. at least 6 years of research behind it before it even makes it to clinical trials. formulation details. 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. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. or restricted to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay). TGA (Australia) or EMEA (European Union). the drugs need to be recalled immediately from the market. manufacturing procedures. 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. While most pharmaceutical companies refrain from this practice. and. [edit] Length Clinical trials are only a small part of the research that goes into developing a new treatment.

It is a challenge to find the appropriate patients and obtain their consent. Researchers who treat these particular patients must participate in the trial. Small-scale device studies may be administered by the sponsoring company. especially when they may receive no direct benefit (because they are not paid. if not years. At a participating site. In the case of cancer patients. administering study treatment(s). (Exceptions are epidemiological studies like the Nurses' Health Study. sets up meetings. maintaining data files. 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. monitors the sites for compliance with the clinical protocol. Some drug trials require patients to have unusual combinations of disease characteristics. obtaining consent from them or their families. (The sponsor provides the drug and medical oversight. and ensures that the sponsor receives 'clean' data from every site.) federally funded clinical trials are almost always administered by the researcher who designed the study and applied for the grant. provides them with supplies. 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. collecting data. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial.. Recently. the study drug is not yet proven to work. 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. identifying eligible patients. coordinates study administration and data collection. meaning not everyone can participate. getting statistical power) can take several years.) A CRO is a company that is contracted to perform all the administrative work on a clinical trial. 27 . to see if a cancer treatment has an effect on a patient. or the patient may receive a placebo). about 400 cancer medicines were being tested in clinical trials in 2005. but those that are may be delayed in getting approved because the number of participants is so low. According to the Pharmaceutical Research and Manufacturers of America (PhRMA). Not all of these will prove to be useful. Only certain people who have the target disease condition are eligible to take part in each clinical trial.y y y For chronic conditions like cancer. Phase III and Phase IV clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. trains them.[20] Clinical trials that do not involve a new drug usually have a much shorter duration. one or more research assistants (often nurses) do most of the work in conducting the clinical trial. fewer than 5% of adults with cancer will participate in drug trials. All drug and many device trials target a subset of the population. assisting with study start-up. and communicating with the IRB.S. it takes months.) [edit] Administration Clinical trials designed by a local investigator and (in the U. It recruits participating researchers. The biggest barrier to completing studies is the shortage of people who take part. as well as the sponsor (if any) and CRO (if any).

locations. and (in some cases.) If the patient is unable to consent for him/herself. They must understand the federal patient privacy (HIPAA) law and good clinical practice. as for instance for questions of when to stop sequential treatments (see Odds algorithm). 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. Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. The notion of informed consent of participating human subjects exists in many countries all over the world. [edit] Safety Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor. researchers can seek consent from the patient's legally authorized representative. However. but its precise definition may still vary.In some U. but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. safety and well being of trial subjects are protected". this body is called the Institutional Review Board (IRB). researchers must obtain the full and informed consent of participating human subjects. the various IRBs that supervise the study.S. the local IRB must certify researchers and their staff before they can conduct clinical trials. [edit] Sponsor y For safety reasons. it may be hard to turn this objective into a well-defined quantified objective function. the state has prioritized the individuals who can serve as the legally authorized representative. In some cases this can be done. if the study involves a marketable drug or device) the regulatory agency for the country where the drug or device will be sold. In California.[edit] Ethical conduct Clinical trials are closely supervised by appropriate regulatory authorities. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the U. many clinical trials of drugs are designed to exclude women of childbearing age. (One of the IRB's main functions is ensuring that potential patients are adequately informed about the clinical trial. pregnant women. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. International Conference of Harmonisation Guidelines for Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials.. and/or women who become pregnant during 28 . however. To be ethical. and then quantified methods may play an important role. The guidelines aim to ensure that the "rights. Most IRBs are located at the local investigator's hospital or institution.S. the local site investigators (if different from the sponsor).

FDA regulations and ICH guidelines both require that ³the information that is given to the subject or the representative shall be in language understandable to the subject or the representative. and can act unethically in order to obtain and maintain their participation. 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. and supervising the study staff throughout the duration of the study. [21] [edit] Local site investigators y y y A physician's first duty is to his/her patients. In larger clinical trials. 29 . or seems to be causing unexpected and study-related serious adverse events. while at the same time presenting the material as briefly as possible and in ordinary language. in other words. the investigator can stop participating at any time. known in the U. The sponsor is responsible for collecting adverse event reports from all site investigators in the study. On the other hand. for example if the study treatment is causing more deaths than the standard treatment. device or other medical treatments to be tested. as the trial proceeds. 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 DMC has the power to recommend termination of the study based on their review. and of any potential interactions of the study treatment(s) with already approved medical treatments." If the participant's native language is not English. This is an independent group of clinicians and statisticians.S. The DMC meets periodically to review the unblinded data that the sponsor has received so far. In some cases the male partners of these women are also excluded or required to take birth control measures. 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. investigators often have a financial interest in recruiting subjects. The sponsor is responsible for monitoring the results of the study as they come in from the various sites. Throughout the clinical trial. This allows the local investigators to make an informed judgment on whether to participate in the study or not. as a Data Safety Monitoring Board). the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug. This is an area where sponsors can slant their judgment to favor the study treatment. a sponsor will use the services of a Data Monitoring Committee (DMC.y y y y the study. that they (or their legally authorized representatives) give truly informed consent. 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. the sponsor must translate the informed consent into the language of the participant.

It may require changes in study procedures or in the explanations given to the patient. In the U. each local site investigator submits the study protocol. the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. regarding the relationship of the adverse event to the study treatments). the regulatory agency may make the wrong decision.S. there may not be formal adverse event reports. 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. Other researchers (such as in walk-in clinics) use independent IRBs. However. and promptly informing the local IRB of all serious and study-treatmentrelated adverse events. and supporting documentation to the local IRB. to see if they were correctly following study procedures. or misrepresents data it has acquired from clinical trials. [edit] Regulatory agencies y y If a clinical trial concerns a new regulated drug or medical device (or an existing drug for a new purpose). and the sponsor. is necessary before all but the most informal medical research can begin. the data collection forms. but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. or ethics board. and where there is no independent sponsor. When a local investigator is the sponsor. if the sponsor withholds negative data. Universities and most hospitals have in-house IRBs. This audit may be random. or for cause (because the investigator is 30 . However. the study protocol and procedures have been tailored to fit generic IRB submission requirements. [edit] IRBs Approval by an IRB. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study. before it allows the researcher to begin the study. In this case.y y y The local investigators are responsible for reviewing all adverse event reports sent by the sponsor. The local investigators are responsible for making an independent judgment of these reports. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred. or to be marketed. the consent(s). y y In commercial clinical trials. 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.. the FDA can audit the files of local site investigators after they have finished participating in a study. The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study.

³There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations´. In these cases.[24] National health agencies such as the U. and coordinates data collection from any other sites. there is a 50% tax credit for sponsors of certain clinical trials. Different countries have different regulatory requirements and enforcement abilities.[25] 31 . 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. depending on the amount of the grant and the amount of effort expected from them. especially the number of sites that are conducting the study. central and south America. Jacob Sijtsma of the Netherlands-based WEMOS. In the U. These other sites may or may not be paid for participating in the study. 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. "An estimated 40 percent of all clinical trials now take place in Asia. The costs to a pharmaceutical company of administering a Phase III or IV clinical trial may include. and whether the study treatment is already approved for medical use. Using internet resources can.S.suspected of fraudulent data). Clinical trials follow a standardized process.S. in some cases. an advocacy health organisation tracking clinical trials in developing countries."[1] edit] Economics [edit] Sponsor The cost of a study depends on many factors. says Dr. Eastern Europe. National Institutes of Health offer grants to investigators who design clinical trials that attempt to answer research questions that interest the agency. Clinical trials are traditionally expensive and difficult to undertake. the investigator who writes the grant and administers the study acts as the sponsor. 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. Avoiding an audit is an incentive for investigators to follow study procedures. the number of patients required. IRB fees and postage. among others: y y y y y y y y y manufacturing the drug(s)/device(s) tested staff salaries for the designers and administrators of the trial payments to the contract research organization. reduce the economic burden.

Other resources are available for individuals who want to participate in a clinical trial: y y y A patient may ask their physician about available clinical trials of treatments for their disease or medical condition. However. However.[edit] Participating in a clinical trial Newspaper advertisements seeking patients and healthy volunteers to participate in clinical trials.IFPMA Clinical Trials Portal and commercial organizations allow people to search for clinical trials. sponsors of clinical trials use various recruitment strategies. The US National Institutes of Health. in order to ensure that their motivation for participating is the hope of getting better or contributing to medical knowledge. flyers. including patient databases. investigators are almost always paid to participate. World Health Organization. when the sponsor is a private company or a national health agency. These amounts can be small. Depending on the kind of participants required. patients are not paid. or be substantial and include 'overhead' that allows the investigator to pay the research staff during times in between clinical trials. newspaper and radio advertisements.[edit] Investigators Many clinical trials do not involve any money. just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies). Most other clinical trials seek patients who have a specific disease or medical condition. and personal recruitment of patients by investigators. without the expectation of any benefit. posters in places the patients might go (such as doctor's offices). Phase 0 and Phase I drug trials seek healthy volunteers. [edit] Patients In Phase I drug trials. [edit] Criticism 32 . The nonprofit Center for Information and Study on Clinical Research Participation (CISCRP)[2] works with both the medical community and the public to bring together a general understanding of clinical trial research. participants are paid because they give up their time (sometimes away from their homes) and are exposed to unknown risks. however. 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. without their judgment being skewed by financial considerations. In most other trials.

She is scathing on the topic of how clinical trials are conducted in America: Many drugs that are assumed to be effective are probably little better than placebos. CIOMS serves the scientific interests of the international biomedical community in general and has been active in promulgating guidelines for the ethical conduct of research. or to rely on the judgment of trusted physicians or authoritative medical guidelines.Marcia Angell has been a stern critic of U.. and more. Clinical trials are also biased through designs for research that are chosen to yield favorable results for sponsors.. It is simply no longer possible to believe much of the clinical research that is published.... In short. Or a drug that is likely to be used by older people will be tested in young people... [edit] Guidelines for human subjects The International Ethical Guidelines for Biomedical Research Involving Human Subjects. A common form of bias stems from the standard practice of comparing a new drug with a placebo. The Guidelines are general instructions and principles of ethical biomedical research.[27] Seeding trials are particularly controversial. the public and the medical profession believed these drugs were potent. including control by the companies over the design.[26].. Angell believes that members of medical school faculties who conduct clinical trials should not accept any payments from drug companies except research support. and that that support should have no strings attached.. For example. which is why it's so important that investigators be truly disinterested in the outcome of their work. it is often possible to make clinical trials come out pretty much any way you want. and publication of research results. Because favorable results were published and unfavorable results buried . so that side effects are less likely to emerge. among other activities.. interpretation.. I take no pleasure in this conclusion. is a set of ethical 33 . recruitment of participants. standards for external review. These 15 guidelines address issues including informed consent. but there is no way to know because negative results are hidden. the sponsor's drug may be compared with another drug administered at a dose so low that the sponsor's drug looks more powerful.S. which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.[ Council for International Organizations of Medical Sciences The Council for International Organizations of Medical Sciences (CIOMS) is an international. She has speculated that "perhaps most" of the clinical trials are viewed by critics as "excuses to pay doctors to put patients on a company's already-approved drug". CIOMS promulgated guidelines in 1993 entitled International Ethical Guidelines for Biomedical Research Involving Human Subjects. when the relevant question is how it compares with an existing drug. sometimes informally referred to as CIOMS Guidelines. health care in general and the pharmaceutical industry in particular. nongovernmental. not-for-profit organization established jointly by WHO and UNESCO in 1949.

principles regarding human experimentation created in 1993 by CIOMS and updated in 2002. Some investigating doctors. In Europe. Unfortunately. great care is needed in the development of a CTR program. The Guidelines are general instructions and principles of ethical biomedical research. [edit] Guidelines for animal testing The Council has also issued International Guiding Principles for Biomedical Research Involving Animals. there are also objections raised from within the industry. as well as treatments of other people and large amounts of capital for those performing the trial. practical experience has shown that this is an over-estimation of the number of patients that physicians will be able to recruit and it is estimated that only about 10% of a physician¶s patients will actually wish to enroll in a clinical trial. [edit] Recruitment Over the last ten years. and more. Since such trials require the use of human test subjects and can severely impact the well-being of the subjects. there is no simple code of established practice. These 21 guidelines (15 in the original report) address issues including Informed consent. no unified regulatory body and no recourse to appeal. every day saved in the progression to marketing authorization can equate to millions of pounds made in patent-protected sales revenue. they claim. this aspect has yet to be effectively addressed. For example. However. question the need for extra activities as. These usually centre on a highly cautious approach to the ethics and legitimacy of patient-facing initiatives. there are sufficient numbers of suitable patients among those already attending their clinics. the proper management of clinical trials is crucial. recruitment of participants. Perhaps more importantly. in 2002 the European Commission issued guidelines for consultation which require patient advertising and details of recruitment initiatives to be submitted to appropriate ethics committees. clinical trial recruitment (CTR) initiatives can be highly successful. Clinical trial management A clinical trial is the application of the scientific method to human health. Considerable ethical scrutiny is applied to all patient recruitment materials and initiatives. Some nervousness is understandable given the strict controls that govern DTC marketing but for clinical research there is a critical need for increased 34 . Enhancing CTR is obviously an area in which great caution is required. for example. If an ethics committee doesn't like what a CRO has planned. getting patients and doctors into clinical trials has become the most delay-ridden aspect of the drug discovery and development process. Time lines can be dramatically reduced and recruitment targets can be met ahead of schedule. standards for external review. However. the CRO can't use it. When implemented effectively.

the credibility of the public bodies involved enhances the effectiveness of the scheme. not testing new methods for the current application. A strenuous effort to maintain this focus throughout clinical development will ultimately allow pharma companies to reap considerable rewards. This is. advocacy groups. A quick look at Cancer. which the contributing pharma companies and National Cancer Institute will use to accelerate patient recruitment for Phase I and II cancer studies. The American public sees a vast amount of government-sponsored education. both run by the National Institutes for Health. [edit] Study designs and methods A common pitfall is insufficiently rigorous evaluation of study designs and methods. but the investment.gov and ClinicalTrials. demonstrates how support for industry research can be broadened. If not approached ethically. designed to improve trial recruitment. The initiative created a $6 million fund. A recently announced US public-private partnership. more creative ideas to be considered and.com.patient understanding and education. This provides a collaborative environment and ensures that there is always an independent counterpoint when the integrity of industry-sponsored studies is attacked. Naturally. A review of recent press coverage also highlights a deep skepticism of industry involvement in clinical research. in a recent angina study. The reasons appear to cover the full range. The signs are that the caution of the industry is slowly giving way to a new openness and confidence. where clinical research receives more and more active support of government bodies. approach and partnerships in the US are demystifying clinical trials and generating considerable goodwill toward industry-driven research. from reliance on well-established designs without allowing newer. a firm¶s CTR campaign can leave them wide open to aggressive media criticism and adverse advocacy relationships. charities and patient groups. The key point to remember is that the objective of all this work is ultimately to improve care for the patient. A "straw poll" during a clinical project management training course revealed that virtually all clinical protocols have at least one amendment during the study. For example. of course. Over the past several years these problems have been addressed in the US. treadmill exercise testing was used as the primary efficacy criterion. This in turn is supported by private efforts such as Centerwatch. extremely well- 35 . at the other extreme. [edit] Public-private partnership The nature of American healthcare provision no doubt motivates patients to seek free or subsidized medication. which is currently offers a 300-page book on informed consent for patients. illustrates just how much work is being done.gov. designed to maximize understanding of clinical trials.

The basic risks that are associated with clinical Trial are: y y y Enrollment of the subject at the sites within the projected time line Failure of the molecule eg efficacy . Clinical Trial Management System A Clinical Trial Management System. performance. and safety problems are always to be considered. the great expansion of activity dictated by phase III studies introduces even more complexity and a new set of risks. first administration to humans is something of a leap into the unknown. Often. also known as CTMS. less than half the patients recruited showed sufficient electrocardiogram (ECG) changes to qualify for randomization. in this case. However. to the required standard. The problem was that with such a mild exercise protocol. and thus. recruitment can be predicted with some confidence. preparation. What is possibly less obvious is the risk of any early-phase design errors to later phases and to the whole drug project. is at least as critical as in phases I-II. thus. Once phase III is imminent. A quick pilot study would have alerted the sponsors before committing to major cost. It maintains and manages the planning. so the exercise protocol was substantially modified to reduce the physical demand. 36 . therefore. the patients were elderly. mainly because subjects are healthy and not potentially complicated patients. perhaps there is a degree of confidence emerging. but. Some of the risks are typically encountered in the main stages of a typical clinical trial. [edit] Risk distribution Delivering the results on time. as much more is known about the drug. may have a lower risk in phase I than in later phases. The application of the drug to a more realistic clinical setting means that we will not necessarily by studying "clean" patients. and reporting of clinical trials. [edit] Risk management All research and development must involve some risk. Patients will often have other diseases on top of that under study and will only be under observation for a small proportion of the time.validated methodology. 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. is a customizeable software system used by the biotechnology and pharmaceutical industries to manage the large amounts of data involved with the operation of a clinical trial. which acts as a digital dashboard for trial managers. In fact. a clinical trial management system provides data to a business intelligence system. Safety of the subjects eg number of SAEs reported to the enrolled subjects(Since DSMB analyse the trial data different time intervals during the study and if they find any risk associated to the patients safety at any time the trial may be terminated. may be seen as accumulating data to enable a product license application. The requirement for phase III. Attention to clinical protocol design.

compliance with FDA regulations. a common notation. including: project management. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS.In the early phases of clinical trials. Some popular requirements include: budgeting. These errors are raised for review to determine if there is an error in the data or clarification from the investigator is required. Despite differences. Popular adverse event dictionaries are MedDRA and WHOART and popular Medication dictionaries are COSTART and WHO-DRUG. most managers use an in-house or home-grown program to handle their data. the systems employ different means to verify the entry. To reduce the possibility of errors due to human entry. The system can check the data in the CDMS and compare it to the dictionaries. compliance with government regulations. The most popular method being double data entry. Currently. ASA could be mapped to Aspirin. The data items containing the adverse event terms or medication names can be linked to one of these dictionaries. As an example. Electronic data capture 37 . With the variance on the number of references that can be made for adverse event Terms or medication names. the data can be validated to check for logical errors. At the end of the clinical trial the dataset in the CDMS is analyzed and sent to the regulatory authorities for approval. Some systems allow for the storage of synonyms to allow the system to match common abbreviations and map them to the correct term. when the number of patients and tests are small. An example is a check of the subject's age to ensure that they are within the inclusion criteria for the study. EC/IRB approvals. feature-rich software provided by specialized vendors. adverse event terms and medication names. investigator management. As the amount of data grows. organizations increasingly look to replace their systems with more stable. standard dictionaries of these terms can be loaded into the CDMS. Once the data has been screened for typographical errors. patient management. the coding is generally centered around two areas. though. and compatibility with other data management systems. it would be impossible to create a complete list of CTMS requirements. Another function that the CDMS can perform is the coding of data. patient management. Each sponsor has different requirements that their CTMS must satisfy. budgeting and financials. and compatibility with other systems such as data management systems. and adverse event reporting systems. electronic data capture. Clinical data management system A clinical data management system or CDMS is used in clinical research to manage the data of a clinical trial. Each manager has different requirements that a system must satisfy. Items that do not match can be flagged for further checking. several requirements are pervasive.

An Electronic Data Capture (EDC) system is a computerized system designed for the collection of clinical data in electronic format for use mainly in human clinical trials. Typically, EDC systems provide:
y y y

a graphical user interface component for data entry a validation component to check user data a reporting tool for analysis of the collected data

EDC systems are used by life sciences organizations, broadly defined as the pharmaceutical, medical device and biotechnology industries in all aspects of clinical research,[1] but are particularly beneficial for late-phase (phase III-IV) studies and pharmacovigilance and post-market safety surveillance. EDC can increase the data accuracy and decrease the time to collect data for studies of drugs and medical devices. edit] History EDC is often cited as having its origins in another class of software ² Remote Data Entry (RDE) that surfaced in the life sciences market in the late 1980s and early 1990s. However its origins actually begin in the mid 1970s with a contract research organization known then as Institute for Biological Research and Development (IBRD). Dr. Richard Nichol and Joe Bollert contracted with Abbott Pharmaceuticals for the IBRD 'network' of Clinical Investigators to each have a computer and 'directly' enter clinical study data to the IBRD mainframe. IBRD then cleaned the data and provided reports to Abbott. Clinical research data²patient data collected during the investigation of a new drug or medical device is collected by physicians, nurses, and research study coordinators in medical settings (offices, hospitals, universities) throughout the world. Historically, this information was collected on paper forms which were then sent to the research sponsor (e.g., a pharmaceutical company) for data entry into a database and subsequent statistical analysis environment. However, this process had a number of shortcomings:
y y y

data are copied multiple times, which produces errors errors that are generated are not caught until weeks later visibility into the medical status of patients by sponsors is delayed

To address these and other concerns, RDE systems were invented so that physicians, nurses, and study coordinators could enter the data directly at the medical setting. By moving data entry out of the sponsor site and into the clinic or other facility, a number of benefits could be derived:
y y

data checks could be implemented during data entry, preventing some errors altogether and immediately prompting for resolution of other errors data could be transmitted nightly to sponsors, thereby improving the sponsor's ability to monitor the progress and status of the research study and its patients

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These early RDE systems used "thick-client" software²software installed locally on a laptop computer's hardware²to collect the patient data. The system could then use a modem connection over an analog phone line to periodically transmit the data back to the sponsor, and to collect questions from the sponsor that the medical staff would need to answer. Though effective, RDE brought with it several shortcomings as well. The most significant shortcoming was that hardware (e.g., a laptop computer) needed to be deployed, installed, and supported at every investigational (medical) site. In addition to being expensive for sponsors and complicated for medical staff, this model resulted in a proliferation of laptop computers at many investigational sites that participated in more than one research study simultaneously. Usability and space constraints led to a lot of dissatisfaction among medical practitioners. With the rise of the Internet in the mid 1990s, the obvious solution to some of these issues was the adoption of web-based software that could be accessed using existing computers at the investigational sites. EDC represents this new class of software. [edit] Current landscape The EDC landscape has continued to evolve from its evolution from RDE in the late 1990s, and today the market consists of a variety of new and established software providers.In addition to pure software companies; pharmaceutical, biotech and contract research organizations have developed their own EDC systems. [edit] The future of EDC As EDC software continues to mature, vendors are including capabilities that would have previously been developed and sold as separate software solutions: clinical data management systems (CDMS), clinical trial management systems (CTMS), business intelligence and reporting, and others. This convergence is expected to continue until electronic patient medical records become more pervasive within the broader healthcare ecosystem -- at which point the ideal solution would be to extract patient data directly from the electronic medical records as opposed to collecting the data in a separate data collection instrument. Standards such as CDISC and HL7 are already enabling this type of interoperability to be explored. Case report form A Case Report Form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site. All data on each patient participating in a clinical trial are held and/or documented in the CRF, including adverse events. 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. The size of a CRF can

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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. (It can also include required check-up visits months after the patient's treatment has stopped.)The sponsor is responsible for designing a CRF that accurately represents the protocol of the clinical trial, as well as managing its production, monitoring the data collection and auditing the content of the filled-in CRFs. Case report forms contain data obtained during the patient's participation in the clinical trial. Before being sent to the sponsor, this data is usually de-identified (not traceable to the patient) by removing the patient's name, medical record number, etc., and giving the patient a unique study number. The supervising Institutional Review Board (IRB) oversees the release of any personally identifiable data to the sponsor.From the sponsor's point of view, the main logistic goal of a clinical trial is to obtain accurate CRFs. However, because of human and machine error, the data entered in CRFs is rarely completely accurate or entirely readable. When the study administrators or automated mechanisms process the CRFs that were sent to the sponsor by local researchers, they make a note of queries. Queries are non-sensible or questionable data that must be explained. Examples of data that would lead to a query: a male patient being on female birth control medication or having had an abortion, or a 15-year old participant having had hip replacement surgery. Each query has to be resolved by the individual attention of a member of each local research team, as well as an individual in the study administration. To ensure quality control, these queries are usually addressed and resolved before the CRF data is included by the sponsor in the final clinical study report. Depending on variables relating to the nature of the study, (e.g., the health of the study population), the effectiveness of the study administrators in resolving these queries can significantly impact the cost of studies Patient-reported outcome A patient-reported outcome or PRO is a questionnaire used in a clinical trial or a clinical setting, where the responses are collected directly from the patient. [edit] Overview PRO 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. PRO data may be collected via self-administered questionnaires completed by the patient themselves or via interviewer-administered questionnaires. The latter will only qualify as a PRO where the interviewer is gaining the patient¶s views, not where the interviewer uses patient responses to make a professional assessment or judgment of the impact of the patient¶s condition. Thus, PROs are a means of gathering patient rather than clinical or other views on the content covered by the questionnaire. [edit] Characteristics

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by Rasch analysis) . The most widely used model of QoL is the needs-based model.A well-designed PRO questionnaire should assess either a single underlying characteristic or. that is. psychometric and scaling standards if it is to provide useful information. where it addresses multiple characteristics. QoL goes beyond impairment and disability by asking about the patient¶s ability to fulfil their needs and also about their emotional response to their restrictions. These measurement ³characteristics´ are termed constructs and the questionnaires used to collect them. The most commonly used PRO questionnaires assess one of the following constructs: y y y y Symptoms (impairments) Functioning (disability) Health related quality of life (HRRQL) Quality of life (QoL). measures. [edit] Validation and quality assessment It is essential that a PRO questionnaire meets certain development. 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). This must be demonstrated mathematically (for example. Measures of symptoms may focus on a range of impairments or on a specific impairment such as depression or pain. questionnaires should have a sound theoretical basis and should be relevant and well targeted to the patient group with which they are to be used. it cannot be assumed that a questionnaire is unidimensional simply because the author intended it to be. should be a number of scales that each address a single characteristic. Items (questions) in a unidimensional questionnaire can be added to provide a single scale score. each scale is scored and reported separately. Measures of functioning assess activities such as personal care. They should also be reliable. Specifically. valid and responsive and the structure of the scale (whether it possesses a single or multiple domains) should 41 . HRRQL instruments are generally multi-dimensional questionnaires assessing a combination of aspects of impairments and/or disability and reflect a patient¶s health status. termed instruments. activities of daily living and locomotor activities. Each scale within a multidimensional questionnaire should have been shown by the authors to be unidimensional. A questionnaire that measures multiple constructs is termed multi-dimensional. A multi-dimensional questionnaire is used to provide a profile of scores. It is not appropriate to produce an overall single summary score for a multi-dimensional questionnaire (akin to adding apples and pears together). However. In contrast. A questionnaire that measures a single construct is described as unidimensional. scales or tools.

methodology. The plan is designed to safeguard the health of the participants (while limiting their financial liability) as well as answer specific research questions. be of concern to the patient. depending on the purpose for which they were designed. and organization of a clinical trial. The latter implies that questionnaire covers issues of specific concern to the patient. SF-12 Health Survey (SF-12 Health Survey). the SF-36 Health Survey (SF-36 Health Survey). or may not. Condition specific tools may capture any of the constructs listed above. the Sickness Impact Profile and the Nottingham Health Profile. biotechnology or medical device companies in the United States.have been thoroughly tested using appropriate methodology in order to justify the use of scale or summary scores. The format and content of clinical trial protocols sponsored by pharmaceutical. Clinical trial protocols for other clinical trials do not necessarily follow the standard format. This information may. medications. [edit] Terminology The term PRO should not be confused with patient-based outcomes. The protocol usually also gives the background and reason the trial is being conducted. statistical considerations. Clinical trial protocol A Clinical Trial Protocol is a document that describes the objective(s). The protocol contains a study plan on which the clinical trial is based. However. and the length of the study. among other things. what types of people may participate in the trial. procedures. European Union. patientreported implies only that the patient provides the information. and dosages. Regulatory authorities in Canada and Australia also follow the ICH guidance. the schedule of tests. or Japan has been standardized: they are written to follow the Good clinical practice guidance issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 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. For example. to name a few. design. Examples include the Adult Asthma Quality of Life Questionnaire (AQLQ). While in a clinical trial. [edit] Examples Many of the common generic PRO tools assess HRQL. the Ankylosing Spondylititis Quality of Life questionnaire (ASQoL) and the Seattle Angina Questionnaire (SAQ). The protocol describes. but these could be provided in other documents referenced in the protocol (such as an Investigator's Brochure). Migraine Specific Quality of Life (MSQOL). 42 .

see Data Collection Forms for Clinical Trials by Spilker 2 . interactive voice response systems. so that their data can be combined as though they were all working together. development and quality assurance of the CRF such that the data collected will meet the highest standards. but are not limited to. No matter what CRF is utilized. 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 Clinical data acquisition Acquisition or collection of clinical trial data can be achieved through various methods that may include.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. if the correct data points were not collected. 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. 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. The following recommendations are meant to assist in the design. 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. It follows. local electronic data capture systems. that the design. The quality of the data collected relies first and foremost on the quality of that instrument. The ICH guidelines on Good clinical practice (GCP) use the term µCase report form¶ or µCRF¶ to refer to these systems 1 . Minimum Standards 43 . The DCF is part of the data validation process in a clinical trial. No matter how much time and effort go into conducting the clinical trial. the quality and integrity of the data is of primary importance. Some journals. which specifies the conduct of that clinical trial. The following is meant to highlight some of the most important points to consider during the design process. or central web based systems. purposefully publich trial protocols Data clarification form A Data Clarification Form (DCF) or Data Query Form (DQF) is a questionnaire specifically used in clinical research. development and quality assurance of such an instrument must be given the utmost attention. any of the following: paper or electronic medical records. such as Trials. therefore. a meaningful analysis may not be possible. In clinical trials. For an extensive discussion regarding creation of CRFs and examples of actual data collection forms. paper forms completed at a site.

44 . y y [edit] Best Practices y Design the CRF along with protocol to assure collection of only the se data the protocol specifies. CRF completion instructions and data submittal procedures prior to enrollment of a subject. development. Use NCR (no carbon required) paper or other means to assure exact replicas of paper collection tools y y y y y y y Clinical Document Architecture The HL7 Clinical Document Architecture (CDA) is an XML-based markup standard intended to specify the encoding. CDA is part of the HL7 version 3 standard. taking into account the flow of study procedures and typical organization of data in a medical record. If redundant data collection is used to assess data validity. structure and semantics of clinical documents for exchange. Document the process for CRF design. CDA documents are persistent in nature.y y Design the CRF to collect the data specified by the protocol. Design the CRF with the primary safety and efficacy endpoints in mind as the main goal of data collection. Make the CRF available for review at the clinical site prior to approval. Akin to other parts of the HL7 version 3 standard it was developed using the HL7 development Framework (HDF) and it is based on the HL7 Reference Information Model (RIM) and the HL7 Version 3 Data Types. Establish and maintain a library of standard forms. Avoid referential and redundant data points within the CRF whenever possible. approval and version control. Document training of clinical site personnel on the protocol. Make the CRF available at the clinical site prior to enrollment of a subject. Design the CRF to follow the data flow from the perspective of the person completing it. Keep questions. prompts and instructions clear and concise. the measurements should be obtained through independent means.

Analysis Data Model ([ADaM]) 45 . predefined collection of submission metadata "Domains" containing extensive variable collections. such as DICOM. y y Study Data Tabulation Model SDTM Implementation Guide ([SDTM-IG]) gives a standardized. Healthcare Information Technology Standards Panel has selected the CCD as one of its standards. Their main project. non-profit organization Dec 2001 . The data standards are defined as a series of Models. CDA documents can be transported using HL7 version 2 messages. bears the same name. which can be expressed using an underlying electronic format. [edit] Country specific notes In the U. MIME attachments to email. platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare".S. http or ftp. The U.The CDA specifies that the content of the document consists of a mandatory textual part (which ensures human interpretation of the document contents) and optional structured parts (for software processing). The structured part relies on coding systems (such as from SNOMED and LOINC) to represent concepts. Clinical Data Interchange Standards Consortium Clinical Data Interchange Standards Consortium (CDISC) is a non-profit organization.Invited to form DIA SIAC Feb 2000 .formed an Independent.Started as a Volunteer group Summer 1998 . using the Operational Data Model (ODM) as a base XML Schema. based on the data model as specified by ASTMs Continuity of Care Record. HL7 version 3 messages.Global participation [edit] CDISC standards y Study Data Tabulation Model (SDTM) Highlights: recommended for FDA regulatory submissions since 2004.S. as well as by other mechanisms. the CDA standard is probably best known as the basis for the Continuity of Care Document (CCD) specification. [edit] CDISC History y y y y Late 1997 . The perfered electronic format is XML. whose mission is "to develop and support global. [edit] Transport The CDA standard doesn't specify how the documents should be transported. the described data standard.

Designed to complement the SDTM submission by detailing the statistical analysis performed on the clinical trial results. y Clinical Data Acquisition Standards Harmonization ([CDASH]) Defines a minimal data collection set for sixteen safety SDTM Domains. a US non-profit medical research organization. storing of ODM is independent from hard. definitions and metadata.and software y y Laboratory Data Model (LAB) Case Report Tabulation Data Definition Specification (CRT-DDS) Also referred to as "define. but also: nursing diagnosis.. utilizes XML technology.and human. The purpose is to assist in the electronic exchange and gathering of clinical results (such as laboratory tests. LOINC applies universal code names and identifiers to medical terminology related to the Electronic health record. nursing interventions. a machine readable version of the regulatory submission "define. all information are independent from databases. y Operational Data Model (ODM) The highlights of ODM: includes audit trail.The objective is to establish a standardized data collection basline across all submissions. It was developed and is maintained by the Regenstrief Institute. harmonizing element names. It is endorsed by the American Clinical Laboratory Association and the College of American Pathologist. the database has expanded to include not just medical and laboratory code names. LOINC Logical Observation Identifiers Names and Codes (LOINC) is a database and universal standard for identifying medical laboratory observations. outcomes management and research). in 1994. Since its inception.pdf". LOINC was created in response to the demand for an electronic database for clinical care and management and is publicly available at no cost. y Standard for Exchange of Non-clinical Data (SEND) The animal trial equivalent of SDTM.xml". machine. provides extensible lists of controlled terms designed to harmonize data collected across submissions. clinical observations. 46 .readable. outcomes classification. and patient care data set. y CDISC Terminology Defines controlled terminology for SDTM and CDASH. Inc.

molar mass.what is measured. Other database fields include status and mapping information for database change management.000 observation terms that can be accessed and understood universally. distinct. substance information (e. Managed care providers. or measurement: 1.context or specimen type within which the observation was made 5. the automatic transfer to public health authorities of case reports for reportable diseases (e.the scale of measure. laboratory testing devices.LOINC is one of the standards for use in U. This has obvious disadvantages to the healthcare network that may need to adopt different codes to access and manage information coming from multiple sources. Time aspect. System. for disease control or detection of epidemics). improved transfer of payment information for services rendered and a significant improvement in the overall quality of health care by reducing errors in the system. ordinal. related terms. time stamp and so on 3. evaluated. improved community wide electronic health records. Component. However. translations. Type of scale.HL7 is now the preferred standard to electronically transfer results from different reporting systems to the appropriate healthcare networks[citation needed]. synonyms.g.procedure used to make the measurement or observation A unique code (format: nnnnn-n) is assigned to each entry upon registration. Kind of property. Type of method. CAS registry number).S. nominal or narrative 6. choices of answers for nominal scales. volume. and public health authorities. and unique 6-part name is given to each term for test or observation identity.characteristics of what is measured. Mapping each entity-specific code to its corresponding universal code can represent a significant investment of both human and financial capital. In 1999. for example. observation.g. Some of the advantages resulting from adopting LOINC may include improved communication in integrated healthcare delivery networks. the health information enclosed is identified by a multiplicity of code values that may vary according to the entity producing those results. laboratories. The scale may be quantitative. A universal code system will enable facilities and departments across the world to receive and send results from their areas for comparison and consultation and contribute toward a larger public health initiative of improving clinical outcomes and quality of care. such as length.interval of time over which the observation or measurement was made 4. mass. it was identified by the HL7 Standards Development Organization as a preferred code set for laboratory test names in transactions between health care facilities.[citation needed] A formal. 47 . Federal Government systems for the electronic exchange of clinical health information. or observed 2. often have negotiated contracts that reimburse episodes of care and unique coding to trigger automated claim payment. The database currently has over 41. Each database record includes six fields for the unique specification of each identified single test.

the software RELMA(Regenstrief LOINC Mapping Assistant) is available in separate downloads that contain an additional word index in Spanish or Simplified Chinese that allows searching in these languages in addition to English[1]. DICOM has been widely adopted by hospitals and is making inroads in smaller applications like dentists' and doctors' offices. printers.46 MiB) PS 3.07 MiB) PS 3. The different devices come with DICOM conformance statements which clearly state the DICOM classes they support. German.3: Information Object DefinitionsPDF (4.48 MiB) PS 3. [edit] Parts of the DICOM Standard The DICOM standard is divided into related but independent parts:[4] The links below are to the 2007 version published in December 2006 y y y y y y y y y PS 3. whose members[2] are also partly members of NEMA. Currently(as of January. and integration of standards within the broader health care system. A number of efforts have been undertaken to translate the LOINC documents and terms into various languages. and network hardware from multiple manufacturers into a picture archiving and communication system (PACS). and transmitting information in medical imaging.2: ConformancePDF (6. 2009). The communication protocol is an application protocol that uses TCP/IP to communicate between systems. printing.97 MiB) PS 3. International interest in LOINC continues to grow. financing.8: Network Communication Support for Message ExchangePDF (901 KiB) PS 3.9: Retired (formerly Point-to-Point Communication Support for Message Exchange) 48 . workstations.43 MiB) PS 3. enforcement. Spanish. The National Electrical Manufacturers Association (NEMA) holds the copyright to this standard.5: Data Structure and EncodingPDF (1.1: Introduction and OverviewPDF (241 KiB) PS 3. It includes a file format definition and a network communications protocol.[3] DICOM enables the integration of scanners.32 MiB) PS 3.The fact that universal standards are being promoted (if not adopted by national organizations and agencies) is an indication that the dialogue will continue regarding the development.[1] It was developed by the DICOM Standards Committee. For more information on LOINC International. structure. monitoring.7: Message ExchangePDF (1. Digital Imaging and Communications in Medicine Digital Imaging and Communications in Medicine (DICOM) is a standard for handling. such as Simplified Chinese. servers. DICOM files can be exchanged between two entities that are capable of receiving image and patient data in DICOM format.6: Data DictionaryPDF (7.4: Service Class SpecificationsPDF (1. storing. see LOINC International.

May 21-23. the latest version of the standard is still 3. like Papyrus (developed by the University Hospital of Geneva. DeJarnette Research Systems. was released in 1985. This version gained more acceptance among vendors. it has been constantly updated and extended since 1993. Vortech (acquired by Kodak that same year) and 3M. network support added and the Conformance Statement was introduced. The text was vague and had internal contradictions. The Veterans Administration and the Navy also purchased systems off this contract. however. The first large scale deployment of ACR/NEMA technology was made in 1992 by the US Army and Air Force as part of the MDIS (Medical Diagnostic Imaging Support) program run out of Ft.0 interconnectivity technology was held at Georgetown University. ACR/NEMA 300. Commercial equipment supporting ACR/NEMA 2. Maryland.0 was presented at the annual meeting of the Radiological Society of North America (RSNA) in 1990 by these same vendors. it became clear that improvements were needed. Many soon realized that the second version also needed improvement. DICOM is a standard directed at addressing technical interoperability issues in medical imaging. Detrick. The image transmission was specified as over a dedicated 25 differential (EIA485) pair cable.0. Switzerland) and SPI. In the beginning of the 1980s it was almost impossible for anyone other than manufacturers of computed tomography or magnetic resonance imaging devices to decode the images that the machines generated. Several extensions to ACR/NEMA 2. like "the 2007 version of DICOM".DICOM is the third version of a standard developed by American College of Radiology (ACR) and National Electrical Manufacturers Association (NEMA). Siemens Medical Systems. New service classes were defined. DeJarnette Research Systems and Merge Technologies provided the modality gateway interfaces from third party imaging modalities to the Siemens SPI network. The first demonstration of ACR/NEMA V2. the standard has its limitations. Instead of using the version number the standard is often version-numbered using the release year. In 1988 the second version was released.0 were created. Their first standard. Very soon after its release. Its name was then changed to DICOM so as to improve the possibility of international acceptance as a standard. General Electric Medical Systems. Officially. In 1993 the third version of the standard was released. It is not a framework or architecture for achieving a useful clinical 49 . Six companies participated in this event. While the DICOM standard has achieved a near universal level of acceptance amongst medical imaging equipment vendors and healthcare IT organizations. driven by Siemens Medical Systems and Philips Medical Systems). (Standard Product Interconnect. Radiologists wanted to use the images for dose-planning for radiation therapy. 1990. Merge Technologies. ACR and NEMA joined forces and formed a standard committee in 1983. Loral Aerospace and Siemens Medical Systems led a consortium of companies in deploying the first US military PACS (Picture Archiving and Communications System) at all major Army and Air Force medical treatment facilities and teleradiology nodes at a large number of US military clinics.

Another example is NM data. the format for each Data Element is: GROUP (2 bytes) ELEMENT (2 bytes) VR (2 bytes) LengthInByte (2 bytes) Data (variable length).1 of Part 5 of the DICOM Standard. see section 7. ID. including items such as name. JPEG 2000. and also one special attribute containing the image pixel data (i. but when written to a file. etc.5: Data Structure and EncodingPDF (1. DICOM Value Representations y PS 3. That means that a file of a chest X-Ray image. For many modalities. or UN. A single DICOM object can only contain one attribute containing pixel data. for VRs that are not OB. where an NM image by definition is a multi-dimensional multiframe image. this corresponds to a single image. The same basic format is used for all applications. DICOM differs from other data formats in that it groups information into data sets. and Run-length encoding (RLE). usually a true "header" (containing copies of a few key attributes and details of the application which wrote it) is added. the main object has no "header" as such .43 MiB) Description Application Entity Age String Attribute Tag Code String Value Representation AE AS AT CS 50 . OF. so that the image can never be separated from this information by mistake. for example. LZW (zip) compression can be used for the whole data set (not just the pixel data) but this is rarely implemented.workflow. But note that the attribute may contain multiple "frames". including the pixel data). DICOM uses three different Data Element encoding schemes. UT. logically. A DICOM data object consists of a number of attributes.merely a list of attributes. JPEG Lossless. RSNA's Integrating the Healthcare Enterprise (IHE) initiative layered on top of DICOM (and HL-7) provides this final piece of the medical imaging interoperability puzzle. including JPEG. Pixel data can be compressed using a variety of standards.or four-dimensional data can be encapsulated in a single DICOM object.e. including network and file usage. allowing storage of cine loops or other multi-frame data. OW. SQ. actually contains the patient ID within the file. For the other Explicit Data Elements or Implicit Data Elements.. In these cases three. With Explicit Value Representation (VR) Data Elements.

most of which involve transmission of data over a network.DA DS DT FL FD IS LO LT OB OF OW PN SH SL SQ SS ST TM UI UL UN US UT DICOM Services Date Decimal String Date/Time Floating Point Single (4 bytes) Floating Point Double (8 bytes) Integer String Long String Long Text Other Byte Other Float Other Word Person Name Short String Signed Long Sequence of Items Signed Short Short Text Time Unique Identifier Unsigned Long Unknown Unsigned Short Unlimited Text DICOM consists of many different services. and the file format below is a later and relatively minor addition to the standard. [edit] Store 51 .

an image and demography.g. an archive station for instance. It describes how to store medical imaging information on removable media. dose delivered. This is a historical 52 . [edit] Storage Commitment The DICOM storage commitment service is used to confirm that an image has been permanently stored by a device (either on redundant disks or on backup media. this service allows a modality to better coordinate with image storage servers by giving the server a list of objects to send before or while actually sending such objects. but this is not legal).similar to a server). [edit] Off-line Media (DICOM Files) The off-line media files correspond to Part 10 of the DICOM standard. etc. burnt to a CD). It helps give the radiology department a more precise handle on resource (acquisition station) use. for example. end time. beginning time.similar to a client). Also known as MPPS. e. it's also mandatory to include the File Meta Information. Except for the data set containing. avoiding the need to type such information multiple times (and the mistakes caused by retyping).DICOM restricts the filenames on DICOM media to 8 characters (many people wrongly use 8.2. uses the confirmation from the Service Class Provider (SCP . normally to print an "X-Ray" film.) to a PACS or workstation. and duration of a study. to make sure that it is safe to delete the images locally.2). [edit] Modality Worklist This enables a piece of imaging equipment (a modality) to obtain details of patients and scheduled examinations electronically. [edit] Modality Performed Procedure Step A complementary service to Modality Worklist. etc. The Service Class User (SCU .3.. There is a standard calibration (defined in DICOM Part 14) to help ensure consistency between various display devices. etc.3. [edit] Printing The DICOM Printing service is used to send images to a DICOM Printer. this enables the modality to send a report about a performed examination including data about the images acquired. No information must be extracted from these names (PS10:6. [edit] Query/Retrieve This enables a workstation to find lists of images or other such objects and then retrieve them from a PACS.The DICOM Store service is used to send images or other persistent objects (structured reports. This is a common source of problems with media created by developers who did not read the specifications carefully. a modality or workstation. including hard copy printout.

The Docle system is used in Health Communication Network's electronic medical record and patient management software package. y Docle design principle No.The MIME type for DICOM files is defined by RFC 3240 as application/dicom. 3 Clinical codes grow with evolving order with both speciation and large scale structures in a linnean manner. It also mandates the presence of a media directory. [edit] Design According to Dr Y Kuang Oon. DICOM files typically have a . 2 Clinical codes are derived from ubiquitous health language in this manner: if the health concept is one word then the first four characters of the word else if it is two words then the first four characters of the first word plus the first character of the second word else the first characters of each word for the case of three or more words. DOCLE DOCLE (Doctor Command Language). is a non-numeric health coding and medical classification system. developer behind Docle. Medical Director.There is also an ongoing media exchange test and "connectathon" process for CD media and network operation that is organized by the IHE organization. Docle can be explained simply by the following design principles: y Docle design principle No. which provides index and summary information for all the DICOM files on the media. DOCLE has been modelled on the linnean biological classification system since 1995. 4 53 . Medical Director is the most widely used electronic medical record system by Australian primary health care providers.requirement to maintain compatibility with older existing systems. 1 Clinical codes are wordful meanings and are intention revealing. so there is less need for meaningful file names. y Docle design principle No. the DICOMDIR file. y Docle design principle No. Docle generates clinical codes from ubiquitous health language using an algorithm. The DICOMDIR information provides substantially greater information about each file than any filename could.dcm file extension. hence it is a human readable clinical coding system.

In the United States. Electronic data capture An Electronic Data Capture (EDC) system is a computerized system designed for the collection of clinical data in electronic format for use mainly in human clinical trials. Analogous to the clinical concept codes being the neurons and the joiner codes being the glia Clinical research associate A clinical research associate (CRA) is a profession defined by Good clinical practice guidelines (ICH GCP). medical device and biotechnology industries in all aspects of clinical research. A clinical research associate ensures compliance with the clinical trial protocol. Typically. IBRD then cleaned the data and provided reports to Abbott. the rules are codified in Title 21 of the Code of Federal Regulations. checks clinical site activities. EDC systems provide: y y y a graphical user interface component for data entry a validation component to check user data a reporting tool for analysis of the collected data EDC systems are used by life sciences organizations. However its origins actually begin in the mid 1970s with a contract research organization known then as Institute for Biological Research and Development (IBRD). makes on-site visits. Dr. as an independent freelancer or for a Contract Research Organization (CRO). [edit] History EDC is often cited as having its origins in another class of software ² Remote Data Entry (RDE) that surfaced in the life sciences market in the late 1980s and early 1990s. reviews Case Report Forms (CRFs) and communicates with clinical research investigators.[1] but are particularly beneficial for late-phase (phase III-IV) studies and pharmacovigilance and post-market safety surveillance. 54 . He or she may work directly with the sponsor company of a clinical trial. The main function of a clinical research associate is to monitor clinical trials.Clinical codes are designed to be snapped on together to form clinical statements (docle closures) using joiner codes. broadly defined as the pharmaceutical. EDC can increase the data accuracy and decrease the time to collect data for studies of drugs and medical devices. In the European Union these guidelines are part of EudraLex. A clinical research associate is usually required to possess an academic degree in Life Sciences and needs to have a good knowledge of Good clinical practice and local regulations. Richard Nichol and Joe Bollert contracted with Abbott Pharmaceuticals for the IBRD 'network' of Clinical Investigators to each have a computer and 'directly' enter clinical study data to the IBRD mainframe.

a laptop computer) needed to be deployed. this process had a number of shortcomings: y y y data are copied multiple times. a number of benefits could be derived: y y data checks could be implemented during data entry. RDE brought with it several shortcomings as well. [edit] Current landscape The EDC landscape has continued to evolve from its evolution from RDE in the late 1990s. preventing some errors altogether and immediately prompting for resolution of other errors data could be transmitted nightly to sponsors. and study coordinators could enter the data directly at the medical setting. this model resulted in a proliferation of laptop computers at many investigational sites that participated in more than one research study simultaneously. and research study coordinators in medical settings (offices. hospitals. Though effective. and supported at every investigational (medical) site.g. nurses. [edit] The future of EDC 55 . biotech and contract research organizations have developed their own EDC systems.g. universities) throughout the world.In addition to pure software companies. Historically. RDE systems were invented so that physicians. which produces errors errors that are generated are not caught until weeks later visibility into the medical status of patients by sponsors is delayed To address these and other concerns. and to collect questions from the sponsor that the medical staff would need to answer. By moving data entry out of the sponsor site and into the clinic or other facility. The system could then use a modem connection over an analog phone line to periodically transmit the data back to the sponsor.. this information was collected on paper forms which were then sent to the research sponsor (e. The most significant shortcoming was that hardware (e.. Usability and space constraints led to a lot of dissatisfaction among medical practitioners. installed. thereby improving the sponsor's ability to monitor the progress and status of the research study and its patients These early RDE systems used "thick-client" software²software installed locally on a laptop computer's hardware²to collect the patient data. In addition to being expensive for sponsors and complicated for medical staff. pharmaceutical. nurses. a pharmaceutical company) for data entry into a database and subsequent statistical analysis environment. EDC represents this new class of software. the obvious solution to some of these issues was the adoption of web-based software that could be accessed using existing computers at the investigational sites. With the rise of the Internet in the mid 1990s.Clinical research data²patient data collected during the investigation of a new drug or medical device is collected by physicians. However. and today the market consists of a variety of new and established software providers.

Patient diary A Patient Diary is a tool used during a clinical trial or a disease treatment to measure treatment compliance. y It was developed by the International Conference on Harmonisation (ICH) 56 . An Electronic Patient Diary registers the diary in a storage device and allows for monitoring the time the medication was taken. Patient diaries are way to find out if a patient takes the medication according to the treatment schedule. clinical trial management systems (CTMS). vendors are including capabilities that would have previously been developed and sold as separate software solutions: clinical data management systems (CDMS). business intelligence and reporting. This convergence is expected to continue until electronic patient medical records become more pervasive within the broader healthcare ecosystem -.As EDC software continues to mature. and symptoms or Quality of Life data were recorded. It has largely been replaced by a newer generation of software called Electronic Data Capture.to late-1980s as software installed locally on portable computers with modems.research of new drugs and/or medical devices. which is an important problem during clinical trials and the treatment of degenerative diseases with relatively few symptoms Remote Data Entry A Remote Data Entry (RDE) system is a computerized system designed for the collection of data in electronic format. RDE systems provide: y y y a graphical user interface component for data entry a validation component to check user data a reporting tool for analysis of the collected data RDE software was started in the mid. Electronic Common Technical Document The electronic Common Technical Document (eCTD) is an interface for the pharmaceutical industry to agency transfer of regulatory information. or EDC. that provides the same type of functionality over the Internet using web pages. The term is most commonly applied to a class of software used in the life sciences industry for collecting patient data from participants in clinical research studies -.at which point the ideal solution would be to extract patient data directly from the electronic medical records as opposed to collecting the data in a separate data collection instrument. and others. Standards such as CDISC and HL7 are already enabling this type of interoperability to be explored. Typically. The content is based on the Common Technical Document (CTD) format.

To date.S. While a single sequence may be viewed with web browser and the ICH stylesheet provided. also called a Clinical Research Organization. country) Common modules: 2-5 (common to all the regions) The CTD only defines the content of the common modules.. [edit] eCTD (data structure) The eCTD is a message specification for the transfer of files and metadata from a submitter to a receiver. The contents of the Regional Module 1 are defined by each of the ICH regions (USA. A cumulative eCTD consists of one or more sequences. over 30. a legal person.Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). viewing a cumulative eCTD requires specialized eCTD viewers Contract research organization A Contract Research Organization.e. The primary technical components are: y y y y 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 eCTD has five modules y y y y y 1 Administrative Information and Prescribing Information 2 Common Technical Document Summaries 3 Quality 4 Nonclinical Study Reports 5 Clinical Study Reports There are two categories of modules: y y Regional module: 1 (different for each region. i.000 eCTD sequences have been submitted to the FDA alone[1] . which may be a corporation] that 57 . CROs offer clients a wide range of "outsourced" pharmaceutical research services to aid in the drug and medical device research & development process.e. Europe and Japan). (CRO) is a service organization that provides support to the pharmaceutical/biotech industry.[1] In the Code of Federal Regulations (CFR). Each submission message constitutes one "sequence". Food and Drug Administration regulations state that a CRO is "a person [i. the U.

toxicology. Particularly over the last few years. and many other complementary services. As industry margins come under increasing pressure. CROs will become more and more important strategic partners for pharmaceutical companies. data management. At bottom. evaluation of reports. clinical.g. biostatistics and medical writing services for preparation of an FDA New Drug Application (NDA). Abbreviated New Drug Application (ANDA). regulatory affairs support. in the latter¶s interest to consider probable developments in the CRO market and its major players. niche specialty groups and can offer their clients the experience of moving a new drug or device from its conception to FDA marketing approval without the drug sponsor having to maintain a staff for these services. medical and safety monitoring. design of a protocol. Given that such pressures are likely to increase in the future. CROs range from large. [edit] Reasons for outsourcing to CROs Outsourcing offers a number of advantages to drug companies." [21 CFR 312. this forced the pharmaceutical industry to utilize µdownsizing¶ strategies more to concentrate resources on core skills. preclinical. computer integrated manufacturing and marketing medicines directly to consumers. External cost pressures have acted as a major driver for the pharmaceutical outsourcing market. and clinical laboratory services for processing trial samples. or Biologics License Application (BLA).[2] [edit] Outsourcing in clinical research The CRO industry developed mostly in the late 1990s when pharmaceutical R&D efforts became more complex and competition in rapidly-growing therapeutic areas increased. Outsourcing has been particularly influential in the pharmaceutical industry as the success of a large pharmaceutical company depends on competence in fields as diverse as combinatorial chemistry.. selection or monitoring of investigations. manufacturing or marketing processes so as to concentrate on their core specialties. therefore. e. formulation and manufacturing. These include:[3] 58 . companies could begin outsourcing aspects of their development. It is.3(b)] Services offered by CROs include: product development.assumes. as an independent contractor with the sponsor. clinical trial management (preclinical through phase IV). international full service organizations to small. one or more of the obligations of a sponsor. the outsourcing market has developed in response to the downward and upward cost pressures exerted on pharmaceutical manufacturers¶ profit margins. and preparation of materials to be submitted to the Food and Drug Administration.

[5] [edit] CRO market size and growth Industry analysers IMS Health and BCC Research estimate that the global pharmaceutical market will grow at about a 5% rate in 2009 to over $820 billion[6] and be worth over $1 trillion by 2013[7].y y y y y y y y y Sponsor can convert the fixed costs of maintaining the personnel. which equates to roughly 18% of their sales and is a 5% increase from the previous year.[9] This figure is expected to grow at 15% over the next seven years and should increase further with the broadening of the spectrum of services outsourced to cover the entire value chain. it is important to understand the CRO selection process. namely the oncology class. the total contracts value may go up to $20 billion by 2010. expertise and facilities like data management necessary for clinical trial management into variable costs Non-availability of services in-house Knowledge of regulatory affairs in a particular country of interest Increased complexity of clinical trials Necessity for medical and clinical knowledge in specific therapeutic areas or indications Increased amount of data required from clinical trials Multinational and multi-center nature of current clinical trials Large requirement of patient populations Regionalized diseases To effectively evaluate the potential impact of outsourcing. Further. and overwhelming number of drugs currently in development (667 for cancer vs. expected to see continued growth of upwards of 21% over the next few years [10] due to the large target market. Pharmaceutical and biotechnology companies in the US spent approximately $59 billion on R&D in 2007. certain therapeutic areas within pharmaceutical development are slated for an even greater growth curve. strong unmet medical need. As outsourced services in developing countries such as China and India move up the value chain to cover phase 1/2 trials. and 186 for infections). 252 for CNS disorders. 206 for cadiovascular disorders.[11] Study design A number of different study designs are indicated below.[8] A significant portion of R&D budgets are used for the outsourcing services offered by the CRO industry. [edit] Treatment studies y Randomized controlled trial o Double-blind randomized trial o Single-blind randomized trial o Non-blind trial 59 . approximately $15 billion in 2007.[4] and the key factors in CRO selection.

recall bias is likely to occur in cross-sectional or case-control studies where subjects are asked to recall exposure to risk factors. For example. Non-inferiority trials are designed to demonstrate that a treatment is at least not appreciably worse than another.g. hormone replacement therapy) than subjects who don't have the condition. A longitudinal study research subjects over two or more points in time. Superiority trials are designed to demonstrate that one treatment is more effective than another. [edit] Other terms y y y y y y The term retrospective study is sometimes used as another term for a case-control study. many factors must be taken into account. When using "parallel groups". in a "crossover study". 60 . breast cancer) may be more likely to recall the relevant exposures that they had undergone (e. Different types of studies are subject to different types of bias.considered a type of quasi-experiment [edit] Observational studies y y y Cohort study o Prospective cohort o Retrospective cohort o Time series study Case-control study o Nested case-control study Cross-sectional study o Community survey (a type of cross-sectional study) [edit] Important considerations When choosing a study design. by contrast. The nature of this type of analysis tends to overestimate the degree of association between variables. each patient receives several treatments.g. Subjects with the relevant condition (e. while a cross-sectional study assesses research subjects at one point in time. The ecological fallacy may occur when conclusions about individuals are drawn from analyses conducted on grouped data.y Nonrandomized trial (quasi-experiment) o Interrupted time series design (measures on a sample or a series of samples from the same population are obtained several times before and after a manipulated event or a naturally occurring event) . Equivalence trials are designed to demonstrate that one treatment is as effective as another. each patient receives one treatment.

a blocking factor is a source of variability that is not of primary interest to the experimenter. [edit] Blocking to "remove" the effect of nuisance factors For randomized block designs. during the experiment. but are not of primary interest. it is possible to assess the effect of different levels of the factor of interest without having to worry about variations due to changes of the block factors. since they can eliminate or minimize unintended influences such as researcher bias. An example of a blocking factor might be the sex of a patient. All experiments have nuisance factors. this source of variability is controlled for. Within blocks. there is one factor or variable that is of primary interest. there are also several other nuisance factors. by blocking on sex. which are accounted for in the analysis. an important technique known as blocking can be used to reduce or eliminate the contribution to experimental error contributed by nuisance factors. In a controlled experiment one set of samples have been (or is believed to be) modified and the other set of samples are either expected to show no change (negative control) or expected to show a definite change (positive control). However. nuisance factors might be the specific operator who prepared the treatment. [1][2] [edit] Examples of controls 61 . blocking is the arranging of experimental units in groups (blocks) that are similar to one another. For example. The basic concept is to create homogeneous blocks in which the nuisance factors are held constant and the factor of interest is allowed to vary. [edit] Definition of blocking factors A nuisance factor is used as a blocking factor if every level of the primary factor occurs the same number of times with each level of the nuisance factor. The analysis of the experiment will focus on the effect of varying levels of the primary factor within each block of the experiment. and the room temperature. the time of day the experiment was run. thus leading to greater precision. The experimenter will typically need to spend some time deciding which nuisance factors are important enough to keep track of or control. Nuisance factors are those that may affect the measured result. Typically. environmental changes and biological variation. in applying a treatment.In the statistical theory of the design of experiments. Controlled experiments are used to investigate the effect of a variable on a particular system. if possible. [edit] Blocking used for nuisance factors that can be controlled When we can control nuisance factors. Scientific control Scientific controls are a vital part of the scientific method.

suppose a researcher feeds an experimental artificial sweetener to sixty laboratory rats and observes that ten of them subsequently die. or be used as the "100%" value against which the test sample results are weighed. The two groups are kept in otherwise identical conditions. the researcher can use an experimental control. The positive control should give a large amount of enzyme activity. it is important to carefully verify that the supposed effects of the drug are produced only by the drug itself.g. Neither the patients nor the doctor know which group receives the real drug. or any other number of variables that may interfere with the experimental design many of which may not be readily obvious. Perhaps the rats were simply not supplied with enough food or water. while the negative control should give very low to no activity. The positive control confirms that the basic conditions of the experiment were able to produce a positive result. a positive control would be an assay where you add some of the purified enzyme. or the water was contaminated and undrinkable. [edit] Necessity of controls Controls are needed to eliminate alternate explanations of experimental results. [edit] Positive and negative control The simplest forms of controls are positive and negative controls. separating the rats into two groups: one group that receives the sweetener and one that does not. Negative controls confirm that the procedure is not observing an unrelated effect (therefore minimizing false positives). which serves both to curb bias and to isolate the effects of the drug. Eliminating each of these possible explanations individually would be time-consuming and difficult.In testing a drug. but which is known from previous experience to give a positive result. in an enzyme assay to measure the amount of an enzyme in a set of extracts. In experiments where crop yield is affected (e. Physicians achieve this with a double-blind study in a clinical trial: two (statistically) identical groups of patients are compared. soil fertility). and both groups are 62 . or the rats were under some psychological or physiological stress. Instead. A positive control is a procedure that is very similar to the actual experimental test. For example. The underlying cause of death could be the sweetener itself or something unrelated. one of which receives the drug and one of which receives a placebo. the experiment can be controlled by assigning the treatments to randomly selected plots of land. often the value of the negative control is treated as a "background" value to be subtracted from the test sample results.[3] Positive controls confirm that the procedure is effective in observing the effect (therefore minimizing false negatives). even if none of the actual experimental samples produce a positive result. A negative control is known to give a negative result. For example. and a negative control would be where you do not add any extract. This mitigates the effect of different soil composition on the yield. The negative control demonstrates the base-line result obtained when a test does not produce a measurable positive result.

greater effects of other variables. an experimental control is used to prevent the effects of one variable from being drowned out by the known. Epidemiological methods Texts and literature in epidemiology often make use of jargon related to epidemiological methods without reference to their actual definition. In other cases. although only linear relations may be taken into account. In scientific parlance. This is broadly equivalent to conditioning on the variables in the second set. Incidence rate.observed in the same ways. For example. Now. Such analyses may be described as "controlling for variable X". Incidence measures 1. or "controlling for the variations in X". In this case. and the extent of parents' education. the researchers can either use a control group or use statistical techniques to control for the other variables. the researchers understand that many other factors probably have a much greater effect on standardized test scores than the free books: household income. for example. A control is something that does not change in the experiment. Controlling tends to reduce the experimental error. Controlling for a variable Controlling for a variable is the act of deliberately varying the experimental conditions in order to take a single variable into account in the prediction of the outcome variable. However. Hazard rate 3. Prevalence measures 63 . Cumulative incidence 2. where cases included are defined using a case definition 2. [edit] Measures [edit] Measures of occurrence 1. these are called confounding variables. Controlling for a variable is also a term used in statistical data analysis when inferences may need to be made for the relationships within one set of variables given that some of the inter-relations may derive from relations to variables in another set. any difference in morbidity between the two groups can be ascribed to the sweetener itself--and no other factor--with much greater confidence. suppose a program that gives out free books to children in subway stations wants to measure the effect of the program on standardized test scores.

2. For example. to forensics. used to prevent research outcomes from being influenced by either the placebo effect or the observer bias. in open taste tests comparing different product brands. double-blind. Absolute measures 1. from medicine. consumers may favor a different brand.1. also frequently occurs in its literal sense of blindness. There can be varying degrees of blinding (eg. subject. where the same word. Virulence and Infectivity Mortality rate and Morbidity Case fatality Sensitivity (tests) and Specificity (tests) Blind experiment The blind method is a part of the scientific method. Odds ratio 4. 'blind'. Attributable risk 1. The terms 'blind' (adj) or 'to blind' (vt) when used in this sense are figurative extensions of the literal idea of blindfolding someone. Blinding is a basic tool to prevent conscious as well as subconscious bias in research. Levin¶s attributable risk [edit] Other measures 1. funder. or annoyance to the reader. Point prevalence 2. Period prevalence [edit] Measures of association 1. Rate ratio 3. To blind a person involved in research (whether a researcher. Occasionally researchers prefer to use the terms masked (adj) or to mask (vt) instead of 'blind/blinded/to blind'. This preference is operative especially in ophthalmology. as explained more below. Attributable risk in exposed 2. In these contexts it is simply more convenient to avoid any ambiguity. Risk ratio 2. 64 . to psychology and the social sciences. triple-blind). Percent attributable risk 3. where the brand identities are concealed. or other person) is to prevent them from knowing certain information about the process. single-blind. in blind taste tests. consumers usually choose their regular brand. Blinded research is an important tool in many fields of research. Hazard ratio 2. The opposite of a blind trial is an open trial. Relative measures 1. 4. 3. However. Absolute risk reduction 2.

the others have Coca-Cola. etc. In most cases. Nevertheless. but the experimenter will be in full possession of the facts. there is a risk that subjects are influenced by interaction with the researchers ² known as the experimenter's bias. usually on human subjects. Volunteer subjects are encouraged to try the two cups of soda and polled for which ones they prefer. In addition it's possible the marketing person could prepare the separate sodas differently (more ice in one cup. The marketing person knows which soda is in which cup but is not supposed to reveal that information to the subjects. In a double-blind experiment.from the same word being used in two senses in close proximity. A classic example of a single-blind test is the "Pepsi challenge. 65 . However. In a single-blind experiment. If the marketing person is employeed by the company which is producing the challenge there's always the possibility of a conflict of interests where the marketing person is aware that future income will be based on the results of the test. in an attempt to eliminate subjective bias on the part of both experimental subjects and the experimenters." A marketing person prepares several cups of cola labeled "A" and "B". One set of cups has Pepsi. [edit] Double-blind trials Double-blind describes an especially stringent way of conducting an experiment. or where the experimenters will not introduce further bias and so the experimenters need not be blind. where the experimenter has an expectation of what the outcome should be. and may consciously or subconsciously influence the behavior of the subject. push one cup in front of the volunteer. Only after all the data have been recorded (and in some cases. Single-blind experimental design is used where the experimenters either must know the full facts (for example. The problem with a single-blind test like this is the marketing person can give (unintentional or not) subconscious cues which bias the volunteer. Performing an experiment in double-blind fashion is a way to lessen the influence of the prejudices and unintentional physical cues on the results (the placebo effect. the individual subjects do not know whether they are socalled "test" subjects or members of an "experimental control" group. analyzed) do the researchers learn which individuals are which. when comparing sham to real surgery) and so the experimenters cannot themselves be blind.) which can cause a bias. [edit] Single-blind trials Single-blind describes experiments where information that could introduce bias or otherwise skew the result is withheld from the participants. there is no expectation that 'blind/blinded' will be obsessively avoided via replacement with 'mask/masked'. Single-blind trials are especially risky in psychology and social science research. double-blind experiments are held to achieve a higher standard of scientific rigour. neither the individuals nor the researchers know who belongs to the control group and the experimental group. in most research contexts.

until the study is over and the random code is broken. [edit] Medical applications Double-blinding is relatively easy to achieve in drug studies. while the part of the software that defines the key is the third party. since software should not cause any bias. only a meta analysis of several well designed RCTs is considered more reliable. where the human subject has to identify an unknown stimulus X as being either A or B.) The use of the term triple-blind experiments is disputed. involving a simple incision. where that is a possible experimental design. Sometimes triple-blind is used to mean that multiple investigators are all blinded to the protocol (such as the clinician giving the treatment and a radiologist or pathologist who interprets the results. taste. Neither the patients nor the researchers monitoring the outcome know which patient is receiving which treatment. It is also difficult to use the double blind method to compare surgical and non-surgical interventions (although sham surgery.[citation needed] 66 . by formulating the investigational drug and the control (either a placebo or an established drug) to have identical appearance (color. and experimenter's bias). and the general population). studies have been suspended in cases where the tested drug combinations were so effective that it was deemed unethical to continue withholding the findings from the control group.observer bias. Evidence-based medicine practitioners prefer blinded randomised controlled trials (RCTs). might be ethically permitted). These are high on the hierarchy of evidence. An example is the ABX test. In analogy to the above. A good clinical protocol will foresee these potential problems to ensure blinding is as effective as possible.[1][2] or where the treatment is very distinctive in taste or has unusual side-effects that allow the researcher and/or the subject to guess which group they were assigned to. etc. Random assignment of the subject to the experimental or control group is a critical part of double-blind research design. Patients are randomly assigned to the control or experimental group and given random numbers by a study coordinator. the part of the software that provides interaction with the human is the blinded researcher. The key that identifies the subjects and which group they belonged to is kept by a third party and not given to the researchers until the study is over. [edit] "Triple-blind" trials Triple-blind trials are double-blind trials in which the statistician interpreting the results also does not know which intervention has been given. who also encodes the drugs with matching random numbers. Effective blinding can be difficult to achieve where the treatment is notably effective (indeed. Computer-controlled experiments are sometimes also referred to as double-blind experiments.).Double-blind methods can be applied to any experimental situation where there is the possibility that the results will be affected by conscious or unconscious bias on the part of the experimenter.

since exposure and disease status are measured at the same point in time. 67 . The fundamental difference between cross-sectional and longitudinal studies is that cross-sectional studies take place at a single point in time and that a longitudinal study involves a series of measurements taken over a period of time. Both are a type of observational study. such as IQ and memory. In a cross-sectional survey. a specific group is looked at to see if a substance or activity. An open-label trial may be unavoidable under some circumstances. Crosssectional research takes a 'slice' of its target group and bases its overall finding on the views or behaviours of those targeted.[1] [2] This contrasts with single blind and double blind experimental designs. such as comparing the effectiveness of a medication to intensive physical therapy sessions. it may not always be possible to distinguish whether the exposure preceded or followed the disease. is related to the health effect being investigated--for example. Open-label trials may also be uncontrolled. where participants are not aware of what treatment they are receiving (researchers are also unaware in a double blind trial). "freezes" a specific moment in time-aims at finding the same kind of relationships that might be shown by the "moving picture" of the cohort study. in the social sciences and in other fields as well. lung cancer. this would support the hypothesis that lung cancer is correlated with smoking.Open-label trial An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered. groups can be compared at different ages with respect of independent variables. but at far less cost. [edit] Cross-sectional studies in medicine Cross-sectional studies can be thought of as providing a "snapshot" of the frequency and characteristics of a disease in a population at a particular point in time. If a significantly greater number of smokers already have lung cancer than those who don't smoke. This type of data can be used to assess the prevalence of acute or chronic conditions in a population. with all participants receiving the same treatment. The cross-sectional survey--which. say smoking. like a snapshot. assuming them to be typical of the whole group. Cross-sectional study Cross-sectional studies (also known as Cross-sectional analysis) form a class of research methods that involve observation of some subset of a population of items all at the same time. Open-label trials may be appropriate for comparing two very similar treatments to determine which is most effective. in which. However. An open-label trial may still be randomized. Cross-sectional studies are used in most branches of science.

Because of this benefit. and studying them at intervals through time. the relationship between income. Longitudinal studies are often used in psychology to study developmental trends across the life span. The reason for this is that unlike cross-sectional studies. A retrospective study is a longitudinal study that looks back in time. Cohort studies sample a cohort. Because longitudinal studies are observational. It is not possible to conclude which of these possibilities is the case using one-off cross-sectional studies. this may mean that 10% of the population are always poor. and therefore the differences observed in those people are less likely to be the result of cultural differences across generations. For instance. it has been argued that they may have less power to detect causal relationships than do experiments. and personal expenditure. in the sense that they observe the state of the world without manipulating it. In medicine. cross-sectional analysis relates to how variables affect each other at the same time and period. It is a type of observational study. For instance a researcher may look up the medical records of previous years to look for a trend Cohort study A cohort study or panel study is a form of longitudinal study used in medicine and social science. In advertising. by virtue of being able to exclude time-invariant unobserved individual differences. It is one type of study design and should be compared with a crosssectional study. defined as a group experiencing some event (typically birth) in a selected time period. Panel studies sample a cross-section. and in sociology to study life events throughout lifetimes or generations. 68 . longitudinal studies track the same people. Longitudinal studies allow social scientists to distinguish short from long-term phenomena. locality. the design is used to uncover predictors of certain diseases. and by virtue of observing the temporal order of events. the design is used to identify the changes that advertising has produced in the attitudes and behaviors of those within the target audience who have seen the advertising campaign. such as poverty.Cross-sectional analysis studies the relationship between different variables at a point in time. they have more power than cross-sectional observational studies. longitudinal studies make observing changes more accurate and they are applied in various other fields. But because of the repeated observation at the individual level. Unlike time series. the Communicus System. If the poverty rate is 10% at a point in time. and survey it at (usually regular) intervals. Types of longitudinal studies include cohort studies and panel studies. En navorsing is 'n groot bol nonsens Longitudinal study A longitudinal study is a correlational research study that involves repeated observations of the same items over long periods of time ² often many decades. or that the whole population experiences poverty for 10% of the time.

smoking) correlate with outcome Y (say. The value of a cohort study depends on the researchers' capacity to stay in touch with all members of the cohort. are exposed to a drug or a vaccine. lung cancer).A cohort is a group of people who share a common characteristic or experience within a defined period (e. or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation. say 1948. Nevertheless. so defined. and record a wide range of information (exposures) about them. Moreover. The study groups. Some of these studies have continued for decades. are observed over a period of time to determine the frequency of new incidence of the studied disease among them. cohort studies are informative for efficiently studying a wide-range of exposure-disease associations. [edit] Examples An example of an epidemiologic question that can be answered by the use of a cohort study is: does exposure to X (say. Prospective (longitudinal) cohort studies between exposure and disease strongly aide in studying causal associations. The groups are matched in terms of many other variables such as economic status and other health status so that the variable being assessed. smoking) can be isolated as the cause of the dependent variable (in this case. lung cancer)? Such a study would recruit a group of smokers and a group of non-smokers (the unexposed group) and follow them for a set period of time and note differences in the incidence of lung cancer between the groups at the end of this time. leave school. The comparison group may be the general population from which the cohort is drawn. Thus a group of people who were born on a day or in a particular period. are sensitive to attrition and take a long follow-up time to generate useful data. The cohort cannot therefore be defined as a group of people who already have the disease. the cohort is identified before the appearance of the disease under investigation. [edit] Application In medicine. Some cohort studies track groups of children from their birth. the results that are obtained from long-term cohort studies are of substantially superior quality to retrospective/cross-sectional studies. but otherwise similar. failure to refute a hypothesis strengthens confidence in it. Crucially. and cohort studies are considered the gold standard in observational epidemiology. and the collection of data at regular intervals.g. subgroups within the cohort may be compared with each other. are born. The advantage of prospective cohort study data is the longitudinal observation of the individual through time. Alternatively. form a birth cohort. lose their job. 69 . a cohort study is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and effect.. cohort studies are expensive to conduct. the independent variable (in this case. so recall error is reduced. though distinguishing true causality usually requires further corroboration from further experimental trials.). However. etc.

In this example, a statistically significant increase in the incidence of lung cancer in the smoking group as compared to the non-smoking group is evidence in favor of the hypothesis. However, rare outcomes, such as lung cancer, are generally not studied with the use of a cohort study, but are rather studied with the use of a case-control study. Shorter term studies are commonly used in medical research as a form of clinical trial, or means to test a particular hypothesis of clinical importance. Such studies typically follow two groups of patients for a period of time and compare an endpoint or outcome measure between the two groups. Randomized controlled trials, or RCTs are a superior methodology in the hierarchy of evidence, because they limit the potential for bias by randomly assigning one patient pool to an intervention and another patient pool to nonintervention (or placebo). This minimises the chance that the incidence of confounding variables will differ between the two groups. Nevertheless, it is sometimes not practical or ethical to perform RCTs to answer a clinical question. To take our example, if we already had reasonable evidence that smoking causes lung cancer then persuading a pool of non-smokers to take up smoking in order to test this hypothesis would generally be considered quite unethical. An example of a cohort study that has been going on for more than 50 years is the Framingham Heart Study.The largest cohort study in women is the Nurses' Health Study. Started in 1976, it is tracking over 120,000 nurses and has been analyzed for many different conditions and outcomes. The largest cohort study in Africa is the Birth to Twenty Study which began in 1990 and tracks a cohort of over 3,000 children born in the weeks following Nelson Mandela's release from prison. [edit] Variations

[edit] Retrospective cohort
A "prospective cohort" defines the groups before the study is done, while a "retrospective cohort" does the grouping after the data is collected. Whereas prospective cohorts should be summarized with the relative risk, retrospective cohorts should be summarized with the odds ratio. An example of a retrospective cohort is Long-Term Mortality after Gastric Bypass Surgery.[1]

[edit] Nested case-control study
An example of a nested case-control study is Inflammatory markers and the risk of coronary heart disease in men and women, which was a case control analyses extracted from the Framingham Heart Study cohort.[2]

[edit] Household panel survey

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Household panel surveys are an important sub-type of cohort study. These draw representative samples of households and survey them, following all individuals through time on a usually annual basis. Examples include the US Panel Study on Income Dynamics (since 1968), the German Socio-Economic Panel (since 1984), the British Household Panel Survey (since 1991), the Household, Income and Labour Dynamics in Australia Survey (since 2001) and the European Community Household Panel (19942001). Prospective cohort study A prospective cohort study is a research effort that follows over time groups of individuals who are similar in some respects (e.g., all are working adults) but differ on certain other characteristics (e.g., some smoke and others do not) and compares them for a particular outcome (e.g., lung cancer).[1] It should be emphasized that prospective studies begin with a sample whose members are free of the disease or disorder under study (e.g., free of lung cancer or free of major depression). Given the individual differences that exist in a sample (e.g, some people smoke, others do not), all the individuals in the sample are followed over time. The incidence rates for the disease under study are ascertained in key subgroups. For example, in a sample that was free of lung cancer at the outset of the study, after 20 years, one may anticipate that the nonsmokers have the lowest 20-year incidence rate of the disease, moderate smokers, the next highest rate, and the heavy smokers, the highest rate. The prospective study is important for research on the etiology of diseases and disorders in humans because for ethical reasons people cannot be deliberately exposed to suspected risk factors in controlled experiments. It can be more expensive than a case±control study.[2] Case-control study Case-control is a type of epidemiological study design. Case-control studies are used to identify factors that may contribute to a medical condition by comparing subjects who have that condition (the 'cases') with patients who do not have the condition but are otherwise similar (the 'controls').[1] Case-control studies are a relatively inexpensive and frequently-used type of epidemiological study that can be carried out by small teams or individual researchers in single facilities in a way that more structured experimental studies often cannot be. They have pointed the way to a number of important discoveries and advances, but their retrospective, non-randomized nature limits the conclusions that can be drawn from them. The great triumph of the case-control study was the demonstration of the link between tobacco smoking and lung cancer, by Sir Richard Doll and others after him. Doll was able to show a statistically significant association between the two in a large case control study.[2] Opponents, usually backed by the tobacco industry, argued (correctly) for many years that this type of study cannot prove causation, but the eventual results of cohort studies confirmed the causal link which the case-control studies suggested, and it is now

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accepted that tobacco smoking is the cause of about 87% of all lung cancer mortality in the US. [edit] Case-control studies For establishing cause-and-effect relationships, e.g., between types of sexual behavior developing cervical cancer, no study design is more highly regarded than the randomized experiment. For medical interventions, the 'gold standard' is the double blind randomized controlled trial, a specific type of experiment. While such trials may be ideal for testing the efficacy of (what are hoped to be) beneficial interventions, such as surgeries or drug treatments, there are many instances in which trials would be impossible, impractical, and/or unethical. For example, it would generally be seen as unethical to randomly assign research subjects to be exposed to toxic substances in order to evaluate the substances' effects. Studying infrequent events such as death from cancer using randomized clinical trials or other controlled prospective studies requires that large populations be tracked for lengthy periods to observe disease development. In the case of lung cancer this could involve 20 to 40 years, potentially longer than the careers of many epidemiologists. In addition, these studies, which generally rely on government funding, are unlikely to be supported because of the low likelihood that the population will develop the disease. Case-control studies use patients who already have a disease or other condition and look back to see if there are characteristics of these patients that differ from those who don¶t have the disease. The case-control study provides a cheaper and quicker study of risk factors; if the evidence found is convincing enough, then resources can be allocated to more "credible" and comprehensive studies. One major disadvantage of case-control studies is that they do not give any indication of the absolute risk of the factor in question. For instance, a case-control study may tell you that a certain behavior may be associated with a tenfold increased risk of death as compared with the control group. Although this sounds alarming, it would not tell you that the actual risk of death would change from one in ten million to one in one million, which is quite a bit less alarming. For that information, data from outside the casecontrol study must be consulted.

[edit] Study methodology [edit] Comparison with cross-sectional studies
Cross-sectional studies involve data collected at a single point in time, often using survey research methods. In epidemiology, cross-sectional studies often involve secondary analysis of data collected for another purpose. Major sources of such data are often large institutions like the Census Bureau or the Centers for Disease Control in the United

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in national health surveys). Others.in the UK individual census data is released only after a century. This provides a more specific analysis of the possible associations. Such studies can cover study groups as large as the entire population of the United States. and high income individuals in each city. Recent census data is not provided on individuals . then aggregated. the drinking or the depression? An important secondary difficulty is that cross-sectional studies often fail to 'control for' confounding factors. Another complication facing epidemiologists conducting secondary analysis of crosssectional data is that often data are only available on an aggregate or "ecological" basis. they do not exhibit the problems associated with aggregated cross-sectional data. so that what matters is not only the individual-level relationship between income and infant mortality. Instead data are aggregated at the group level. they cannot provide confirmation that the first variable is a cause and the second variable is its effect. and then other studies. Inferences about individuals cannot reliably be made from ecological data.In the case-control study. however. but others are small and geographically limited. cohort studies or even sometimes randomized trials can be implemented to study this relationship. while still being true that there is a strong relationship between infant mortality and family income at the individual level. the association is determined for each individual case-control pair. or even by states/provinces or country. such as case-control. although cross-sectional studies confirm that people who consume large amounts of alcohol also show high rates of many other diseases. All aggregate statistics are subject to compositional effects. For example. For example. Cross-sectional studies can contain individual-level data (one record per individual. One benefit of cross-sectional studies is that they are considered to be "hypothesis generating". middle. it might be true that there is no correlation between infant mortality and family income at the city level. statistics on infant mortality and low birth weight might not be available on a level below the city or county. For example. no individual records are available to the researcher. and potentially determines more accurately which possible causes are directly related to the effect being studied. and which are merely related by a common cause. Nested case-control study 73 .States. Because case-control studies are based on individual-level data. by zip code. For example. but also the proportions of low. third variables that affect or even determine the relationship between the putative cause and effect. for example. such that clues to exposure/disease relationships can often be seen in these studies. The primary difficulty is that most cross-sectional data have nothing to say about temporal order: which came first. might only convey group-level information. that is. urban zone. such inferences run afoul of the ecological fallacy.

NIH might be encouraged to maintain a registry of new and existing cohorts. with relatively minor loss in statistical efficiency. on page 58 in the 4th edition of Human Development: A Life-Span View cite that in fact the process is contained in a Petri dish. to foster the development of specimen banks. Exposure is defined prior to disease development based on data collected at baseline or on assays conducted in biological samples collected at baseline. this may lead to results that do not correspond to the situation that arises in a living organism. It tends to focus on organs. and to serve as a clearinghouse for information about optimal storage conditions for various types of specimens. Compared with case-control studies. and/or biomolecules. such experimental results are often annotated with in vitro. due to death or failure to follow-up cases. in contradistinction with in vivo. the nested case-control design potentially offers impressive reductions in costs and efforts of data collection and analysis compared with the full cohort approach. and compared with cohort studies can reduce cost and save time. Some may argue that in vitro refers to a process that is created in a "test tube". All cases who developed the outcome of interest during the follow-up are selected and compared with a subgroup of the non-cases. The drawback of nested case-control studies is non-diseased persons from whom the controls are selected may not be fully representative of the original cohort. [edit] In vitro research This type of research aims at describing the effects of an experimental variable on a subset of an organism's constituent parts. cells. however. a specified number of matched controls is selected from among those in the cohort who have not developed the disease by the time of disease occurrence in the case. cases of a disease that occur in a defined cohort are identified and. tissues. because the test conditions may not correspond to the conditions inside of the organism. nested case-control studies can reduce 'recall bias' and temporal ambiguity. Robert Kail and John Cavanaugh. for each. cellular components. with an inventory of data collected for each. Consequently. In vitro In vitro (Latin for within the glass) refers to the technique of performing a given procedure in a controlled environment outside of a living organism.In the nested case-control study. it is better suited for deducing the 74 . Many experiments in cellular biology are conducted outside of organisms or cells. For many research questions. proteins. To advance its prevention research agenda. [edit] Similar terms y Panel study A case-control study in which cases and controls are drawn from within a prospective study. The nested case-control design is particularly advantageous for studies of biologic precursors of disease.

and may give misleading results.[2] The research is conducted inside universities. breeding. others may be caught in the wild or supplied by dealers who obtain them from auctions and pounds. and commercial facilities that provide animaltesting services to industry. It should be pointed out that the term is historical. as currently most lab ware is disposable and made out of polypropylene (sterilizable by autoclaving. pharmaceutical companies. conditions are less clustered and not aided. behavioural studies.[1] Although much larger numbers of invertebrates are used and the use of flies and worms as model organisms is very important. medical schools. xenotransplantation. drug testing and toxicology tests. ex: microcentrifuge tubes) or clear polystyrene (ex: serological pipettes) rather than glass to ease labwork. hence for historical reasons several enzymes in the Krebs cycle may appear to have incorrect nomeclature. defense establishments. non-physiological stoichiometric concentration may result in enzymatic active in a reverse direction. 75 . results are generally more discernible. the controlled conditions present in the in vitro system differ significantly from those in vivo. and minimize the possibility of cuts from broken glass. Therefore in vitro studies are usually followed by in vivo studies. experiments on invertebrates are largely unregulated and not included in statistics. in vitro research is vital and highly productive. However. The massive adoption of low-cost in vitro molecular biology techniques has caused a shift away from in vivo research which is more idiosyncratic and expensive in comparison to its molecular counterpart. as well as applied research such as biomedical research. while in vitro. developmental biology. Protein folding may differ as in a cell there is a high density of other protein and there are systems to aid in the folding. while most animals are purposebred.mechanisms of action (See in vivo for its description and respective merits). such as A-DNA. ensure sterility. Sources of laboratory animals vary between countries and species. Examples include: y y y In biochemistry. Animals are also used for education. and defense research. Most animals are euthanized after being used in an experiment. Currently. Animal testing Animal testing / animal experimentation is the use of non-human animals in scientific experimentation. farms. It is estimated that 50 to 100 million vertebrate animals worldwide ² from zebrafish to non-human primates ² are used annually. DNA may adopt other configurations.[3] It includes pure research such as genetics. including cosmetics testing. With fewer variables and perceptually amplified reactions to subtle causes.

became the first of 76 .[4] with the Institute for Laboratory Animal Research of the U. and vivisection have similar denotations but different connotations. in vivo testing. review committees serve as gatekeepers for determining whether the use of animals proposed is warranted. dissected pigs and goats.[6] The practice of animal testing is regulated to various extents in different countries. animal experimentation. tissues.[10] The word "vivisection" is preferred by those opposed to this research. "vivisection" means the "cutting up" of a living animal. Aristotle ( Erasistratus (304-258 BCE) were among the first to perform experiments on living animals. The term is now used to refer to any experiment using living animals.[17] On November 3. for example. the Encyclopaedia Britannica defines "vivisection" as: "Operation on a living animal for experimental rather than healing purposes.[15] In the 1890s. National Academy of Sciences arguing that even sophisticated computers are unable to model interactions between molecules.[5] Some non-governmental organizations like PETA and BUAV question the necessity of it. argue that virtually every medical achievement in the 20th century relied on the use of animals in some way. Laika. that the costs outweigh the benefits. and death. Literally.[13] Galen. poorly regulated.S. whereas scientists typically use the term "animal experimentation. implying torture. cells. and historically referred only to experiments that involved the dissection of live animals. In the 1880s. all experimentation on live animals. 1957. organs. Louis Pasteur convincingly demonstrated the germ theory of medicine by inducing anthrax in sheep. cannot reliably predict effects in humans. a Russian dog.[16] Insulin was first isolated from dogs in 1922. In 1984 the WHO's Council for International Organizations of Medical Sciences (CIOMS) issued International Guiding Principles for Biomedical Research Involving Animals. animal research.[8] [edit] Definitions The terms animal testing."[14] Animals have been used throughout the history of scientific research.Supporters of the practice. and developed countries have developed regulatory frameworks that are more extensive. making animal research necessary in some areas. In the United States and in many other countries. or that animals have an intrinsic right not to be used for experimentation.[7] The trend in developed nations to offshore trials in biomedical research has also affected preclinical testing on animals. and revolutionized the treatment of diabetes. more broadly. These opponents make a range of arguments: that it is cruel. organisms."[9] For others. and aim to minimize suffering. and is known as the "father of vivisection. Ivan Pavlov famously used dogs to describe classical conditioning. suffering. poor scientific practice. although to a lesser extent than clinical trials on humans. the word has a pejorative connotation. They examine protocols to see if these can be improved by reducing or replacing animal use. and the environment. such as the British Royal Society."[11][12] The earliest references to animal testing are found in the writings of the Greeks in the ) (384-322 BCE) and second and fourth centuries BCE. a physician in second-century Rome.

Claude Bernard. founded the first anti-vivisection society in France in 1883[28] ² famously wrote in 1865 that "the science of life is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen". in 1996. There were also objections on an ethical basis.and anti. Walter B.[30] In 1896.[21] Claude Bernard. save for differences in degree."[26][27] O'Meara and others argued that animal physiology could be affected by pain during vivisection.".[27] On the other side of the debate.[24] In the 1960s.¶ ´[31] These divisions between pro. but conscience without common sense may lead to folly. In 1655. congress passed laws that required safety testing of drugs on animals before they could be marketed.S. in reaction to the Thalidomide tragedy. Dolly the sheep was born... However.[27] Early objections to animal testing also came from another angle ² many people believed that animals were inferior to humans and so different that results from animals could not be applied to humans. further laws were passed requiring safety testing on pregnant animals before a drug can be sold. which is the handmaiden of crime.[23] Toxicology testing became important in the 20th century. when hundreds of medical 77 . the physiologist and physician Dr. Cannon said ³The antivivisectionists are the second of the two types Theodore Roosevelt described when he said. in the U. the advocate of Galenic physiology Edmund O'Meara said that "the miserable torture of vivisection places the body in an unnatural state. are entirely conclusive for the toxicology and hygiene of man. the U. antibiotic treatments and vaccines for leprosy were developed using armadillos.animal testing groups first came to public attention during the brown dog affair in the early 1900s. contending that the benefit to humans did not justify the harm to animals.[20] This genetic research progressed rapidly and. by integrating DNA from the SV40 virus into the genome of mice."[23] Bernard established animal experimentation as part of the standard scientific method. µCommon sense without conscience may lead to crime. laws regulating drugs were more relaxed. known as the "prince of vivisectors"[22] and the father of physiology ² whose wife. in response to a tragedy in 1937 where a drug labeled ³Elixir of Sulfanilamide´ killed more than 100 people.[29] Arguing that "experiments on animals .S. Other countries enacted similar legislation..many animals to orbit the earth. In the 1970s. the government could only ban a drug after a company had been prosecuted for selling products that harmed customers. For example.[18] then given to humans.the effects of these substances are the same on man as on animals. In the 19th century. rendering results unreliable. argued that experiments on animals are "entirely conclusive for the toxicology and hygiene of man.[19] The ability of humans to change the genetics of animals took a large step forwards in 1974 when Rudolf Jaenisch was able to produce the first transgenic mammal. regarded as the "prince of vivisectors"[22] and one of the greatest men of science.[25] The controversy surrounding animal testing dates back to the 17th century. those in favor of animal testing held that experiments on animals were necessary to advance medical and biological knowledge. the first mammal to be cloned from an adult cell.. Marie Françoise Martin..

under the provisions of the Animal Welfare Act and the National Institutes of Health's (NIH) Guide for the Care and Use of Laboratory Animals (the Guide). Institutional Animal Care and Use Committee. with America's first specifically anti-vivisection organization being the American AntiVivisection Society (AAVS).[36] The IACUC must ensure that alternatives.. who wrote to Ray Lankester in March 1871: "You ask about my opinion on vivisection. in the USA the antivivisectionists' efforts were defeated in every legislature. a laboratory animal veterinarian. but not for mere damnable and detestable curiosity. I quite agree that it is justifiable for real investigations on physiology. Although the provisions of the Animal Welfare Act do not include purposebred rodents and birds. when Henry Bergh founded the American Society for the Prevention of Cruelty to Animals (ASPCA). the first law specifically aimed at regulating animal testing. including non-animal alternatives. Overall. 78 . though the use of non-human primates always raises what he calls a "red flag of special concern.[38][39] Animal Welfare Act regulations are enforced by the USDA. Antivivisectionists of the era generally believed the spread of mercy was the great cause of civilization."[37] The IACUCs regulate all vertebrates in testing at institutions receiving federal funds in the USA.S. which every research facility is obliged to maintain. this movement had little legislative success until the passing of the Laboratory Animal Welfare Act. whereas Public Health Service regulations are enforced by OLAW and in many cases by AAALAC. overwhelmed by the superior organization and influence of the medical community. in his experience.students clashed with anti-vivisectionists and police over a memorial to a vivisected dog. so I will not say another word about it. The legislation was promoted by Charles Darwin. and that pain relief is given unless it would interfere with the study. and vivisection was cruel. in 1966. researchers are required to consult with the institution's veterinarian and its Institutional Animal Care and Use Committee (IACUC). any procedure can be performed on an animal if it can be successfully argued that it is scientifically justified. writes that. else I shall not sleep to-night. In the U. the first animal protection law was enacted in the British parliament. It is a subject which makes me sick with horror. followed by the Cruelty to Animals Act (1876). these species are equally regulated under Public Health Service policies that govern the IACUCs. IACUCs take their work very seriously regardless of the species involved. In general. founded in 1883.[35] [edit] Care and use of animals See also: Animal testing regulations."[33][34] Opposition to the use of animals in medical research first arose in the United States during the 1860s. have been considered. and Animals (Scientific Procedures) Act 1986 [edit] Regulations The regulations that apply to animals in laboratories vary across species. that the experiments are not unnecessarily duplicative.[32] In 1822. Larry Carbone. However.

the lack of an adaptive immune system and their simple organs prevent worms from being used in medical research such as vaccine development.2 million.[42][49] A "procedure" refers to an experiment that might last minutes. Congress Office of Technology Assessment reported that estimates of the animals used in the U.[53] Similarly.[41] The Nuffield Council on Bioethics reports that global annual estimates range from 50 to 100 million animals. The most used invertebrate species are Drosophila melanogaster.1 million animals were used.[42] Animals bred for research then killed as surplus. which make up about 90% of research animals. a reduction from a high of 50 million used in 1970. Fruit flies are commonly used. [edit] Species Although many more invertebrates than vertebrates are used. range from 10 million to upwards of 100 million each year. In the case of C.S.[40] Accurate global figures for animal testing are difficult to obtain. flies are not widely used in 79 . Home Office figures show that nearly three million procedures were carried out in 2004 on just under the same number of animals. a fruit fly. include invertebrates.[48] In the UK. and Caenorhabditis elegans. the total number of animals used in that country in 2005 was almost 1. According to the U.[50] Most animals are used in only one procedure: animals either die because of the experiment or are euthanized afterwards. researchers at Tufts University Center for Animals and Public Policy estimated that 14-21 million animals were used in American laboratories in 1992. and animals not yet weaned (which most laboratories do not count)[43] are also not included in the figures. None of the figures.[edit] Numbers Types of vertebrates used in animal testing in Europe in 2005: a total of 12.S. The British Union for the Abolition of Vivisection (BUAV) estimates that 100 million vertebrates are experimented on around the world every year. Department of Agriculture (USDA). the U.[47] In 1986. several months. these experiments are largely unregulated by law.[51] while studies in the fly D. with thousands of flies or nematodes fitting into a single room. and that their own best estimate was at least 17 million to 22 million.[44] but this does not include rats and mice.[52] These animals offer great advantages over vertebrates. a nematode worm. the worm's body is completely transparent and the precise lineage of all the organism's cells is known. or years. animals used for breeding purposes. melanogaster can use an amazing array of genetic tools.S. However. including their short life cycle and the ease with which large numbers may be studied. 10±11 million of them in the European Union.[45][46] In 1995. such as shrimp and fruit flies. including those given in this article.[49] It is the third consecutive annual rise and the highest figure since 1992. elegans.

squirrel monkeys. some of the dogs are purpose-bred. cynomolgus monkeys.[40][44] Most of the NHPs used are macaques.[58] The main species used is the zebrafish.500 cats were used in the U. genetics. and bone and joint studies. most primates are domestically purpose-bred.[44] In the U.[65] The 80 . The water is within 1 cm of the small flower pot bottom platform where the rat sits. because they are gentle and easy to handle. research that tends to be highly invasive.[54] and diseases in insects can be very different from diseases in more complex animals. studies of neurology.S.000 fish and 20.S. fish.S. newspaper ads. in 2000. which are translucent during their embryonic stage. y Non-human primates Non-human primates (NHPs) are used in toxicology tests.[60] The U. Over 25.S.[58] Albino rabbits are used in eye irritancy tests because rabbits have less tear flow than other animals. around 70.000 to 15.S. and owl monkeys are imported. and education ² particularly beagles. while most are supplied by so-called Class B dealers licensed by the USDA to buy animals from auctions.S. studies of AIDS and hepatitis. according to the American Anti-Vivisection Society.applied medical research.000 amphibians were used in the UK in 2004.000 primates are used each year in the U. Over 20. testing. or its nose would become submerged into the water shocking it back to an awakened state.[59] Dogs are widely used in biomedical research. and rabbits Main articles: Animal testing on rodents and Animal testing on rabbits This rat is being deprived of restful REM sleep by a researcher using a single platform ("flower pot") technique. and the lack of eye pigment in albinos make the effects easier to visualize.S. in 2006 there were 1133 chimpanzees in U. reproduction.[64] but marmosets.[62] Rhesus monkeys. and squirrel monkeys are also used.000 monkeys are imported into the U. had the potential to cause "pain and/or distress". They are commonly used as models for human diseases in cardiology. and Europe.000 NHPs are used each year in the United States and European Union. Xenopus laevis. as their immune system differs greatly from that of humans. shelters.[58] Rabbits are also frequently used for the production of polyclonal antibodies. spider monkeys. endocrinology. and xenotransplantation.[61] Around 65.S.000 rabbits were used for animal testing in the UK in 2004. the rat would either fall into the water only to clamber back to its pot to avoid drowning. Department of Agriculture's Animal Welfare Report for 2005 shows that 66.[55] y Rodents. according to the Humane Society of the United States. and baboons and chimpanzees are used in the U. Nearly 200. annually. primate centers. At the onset of REM sleep. around 12.[63] In total. and the African clawed frog.. and China. and who are sometimes accused of stealing pets. Danio rerio. behavior and cognition. In the U. Cats are most commonly used in neurological research. around half of whom were used in experiments which. They are caught in the wild or purpose-bred.000 dogs were used in USDA-registered facilities in that year. whereas in Europe the majority are imported purpose-bred.

animal sources are governed by Council Directive 86/609/EEC. and dealers who supply animals sourced from pounds. 1. sources include breeders who supply purpose-bred animals.[4][64][68] In 2008 a proposal to ban all primates experiments in the EU has sparked a vigorous debate. or by Covance.S.S. and their current heaviest non-toxicological use occurs in the monkey AIDS model. using strains and mutants supplied from a few main stock centers. Fourteen states explicitly prohibit the practice. which requires lab animals to be specially bred.S. Department of Agriculture (USDA) to sell animals for research purposes. a practice known as bunching. and newspaper ads. auctions.[66] This transgenic technology is now being applied in the search for a treatment for the genetic disorder Huntington's disease.S. the National Institutes of Health Knockout Mouse Project. businesses that trade in wild animals. but wild-caught primates may be used if exceptional and specific justification can be established. while Class B dealers are licensed to buy animals from "random sources" such as auctions.[67] Notable studies on non-human primates have been part of the polio vaccine development. pound seizure.[74] The USDA recovered at least a dozen stolen pets during a raid on a Class B dealer in Arkansas in 2003. with the development of a method that could introduce new genes into a rhesus macaque.first transgenic primate was produced in 2001. the Mayo Institute.S. which is the single largest importer of primates into the U. Sources differ for vertebrate and invertebrate animals.[71] Large centers also exist to distribute strains of genetically-modified animals.[72] In the U. and Harvard and Yale Medical Schools. most animals used in experiments are bred for the purpose under the 1988 Animal Protection Act.[73] It was in part out of public concern over the sale of pets to research facilities that the 1966 Laboratory Animal Welfare Act was ushered in ² the Senate Committee on Commerce reported in 1966 that stolen pets had been retrieved from Veterans Administration facilities. and Iowa ² require their shelters to provide animals to research facilities. while the remainder either allow it or have no relevant legislation. unless the animal has been lawfully imported and is not a wild animal or a stray.[80] 81 . and development of Deep Brain Stimulation. Some Class B dealers have been accused of kidnapping pets and illegally trapping strays. Animal shelters also supply the laboratories directly.[77] In the UK. for example.. Stanford University.[75] Four states in the U. Class A breeders are licensed by the U. Utah. The latter requirement may also be exempted by special arrangement. SIV. the University of Pennsylvania. Inc.[69] [edit] Sources Animals used by laboratories are largely supplied by specialist dealers. aims to provide knockout mice for every gene in the mouse genome.[70] For vertebrates. Over half the primates imported between 1995 and 2000 were handled by Charles River Laboratories.. Oklahoma. between 1995 and 1999. and newspaper ads.[78][79] The United States also allows the use of wild-caught primates.[76] In the European Union.580 wild baboons were imported into the U. ² Minnesota. Most laboratories breed and raise flies and worms themselves.

Department of Agriculture. 39 percent (1.[edit] Pain and suffering The extent to which animal testing causes pain and suffering. argue that the lives of laboratory animals have intrinsic value. infection that is unresponsive to treatment.S.[93] Regulations focus on whether particular methods cause pain and suffering. is the subject of much debate. 55 percent (1. and their potential treatment with analgesia and anesthesia.[82] There have. however.[83] The Guide states that the ability to recognize the symptoms of pain in different species is vital in efficiently applying pain relief and that it is essential for the people caring for and using animals to be entirely familiar with these symptoms. research projects are classified as mild.296) of project licenses in force were classified as mild. a fourth category of "unclassified" means the animal was anesthetized and killed without recovering consciousness. such as depression. moderate. while policy makers consider suffering to be the central issue and see animal euthanasia as a way to reduce suffering. The animal can be made to inhale a gas.[94] The animals are euthanized at the end of studies for sample collection or post-mortem examination. two percent (63) as substantial.[97] The methods that are preferred are those published by councils of veterinarians. and the capacity of animals to experience and comprehend them. such as carbon 82 . are required regulatory issues in receiving animal protocol approval. not whether their death is undesirable in itself. all issues of animal pain and distress.[81] According to the U. others. [edit] Euthanasia There is general agreement that animal life should not be taken wantonly. been suggestions of systemic underestimation of procedure severity.000 animals (not including rats. On the subject of analgesics used to relieve pain.[44] In the UK. during studies if their pain or suffering falls into certain categories regarded as unacceptable. such as the RSPCA. in 2006 about 670. and regulations require that scientists use as few animals as possible. according to the researchers. mice. birds. Accordingly.000 were used in procedures in which pain or distress was relieved by anesthesia. while 84. or invertebrates) were used in procedures that did not include more than momentary pain or distress. and substantial in terms of the suffering the researchers conducting the study say they may cause. the Guide states "The selection of the most appropriate analgesic or anesthetic should reflect professional judgment as to which best meets clinical and humane requirements without compromising the scientific aspects of the research protocol".811) as moderate.000 were used in studies that would cause pain or distress that would not be relieved.[95] or when they are unsuitable for breeding or unwanted for some other reason.[92] However. In December 2001. or the failure of large animals to eat for five days. About 420.[96] Methods of euthanizing laboratory animals are chosen to induce rapid unconsciousness and death without pain or distress. and 4 percent (139) as unclassified.

These studies are particularly powerful since the basic controls of development. though small numbers of other species are used. foxes. Sedatives or anesthetics such as barbiturates can be given intravenously. or inducing air embolism are acceptable only with prior anesthesia to induce unconsciousness. or specific genes are deleted by gene targeting. Slow or rapid freezing. ranging from sea slugs through to armadillos. with or without sedation or anesthesia depending on the method. Those opposed to animal testing object that pure research may have little or no practical purpose. Fruit flies. It causes death by a concussion to the brain. scientists aim to understand both how organisms normally develop. such as the homeobox genes. with or without prior sedation or anesthesia. horses. Compared to pure research. have similar functions in organisms as diverse as fruit flies and man.[99] Pure research uses larger numbers and a greater variety of animals than applied research. Mutants are created by adding transposons into their genomes. Some physical methods are only acceptable after the animal is unconscious. Gunshot may be used. Electrocution may be used for cattle. and function.[98] edit] Pure research Basic or pure research investigates how organisms behave. nematode worms. develop. Physical methods are also used. Captive bolts may be used. and what can go wrong in this process. sheep. pigs and rabbits. often by a prior electrical stun. but researchers argue that it may produce unforeseen benefits. and mink after the animals are unconscious. mice and rats together account for the vast majority. Recommended methods include decapitation (beheading) for small rodents or rabbits. or by use of a face mask. mice. applied research is usually carried out in 83 . but only in cases where a penetrating captive bolt may not be used. which is largely academic in origin. ruminants. but this is currently only used on rodents.monoxide and carbon dioxide.[100] Examples of the types of animals and experiments used in basic research include: y Studies on embryogenesis and developmental biology. rendering the distinction between pure and applied research ² research that has a specific practical aim ² unclear.[103][104] [edit] Applied research Applied research aims to solve specific and practical problems. Amphibians and fish may be immersed in water containing an anesthetic such as tricaine. and immature rats and rabbits. swine. by being placed in a chamber. or inhalant anesthetics may be used. Pithing (inserting a tool into the base of the brain) is usable on animals already unconscious. High-intensity microwave irradiation of the brain can preserve brain tissue and induce death in less than 1 second. Cervical dislocation (breaking the neck or spine) may be used for birds. typically on dogs. Maceration (grinding into small pieces) is used on 1 day old chicks.[101][102] By studying the changes in development these changes produce.

such applied studies may be an early stage in the drug discovery process. pigs. and it is argued that they are not always comparable to human diseases. scientists assessing the usefulness of animal models of Parkinson's disease.[116] The vast majority of these transgenic models of human disease are lines of mice. or organs from one species to another. as well as providing ways to develop and test new treatments. birds. including rats. new drug treatments such as levodopa. to mimic specific conditions such as single gene disorders. as the bacteria responsible for this disease cannot yet be grown in culture. modified or removed. without the same time course or cellular pathology. sheep.the pharmaceutical industry. In turn. Here.[121] In contrast. the British anti-vivisection interest group BUAV argues that these models only superficially resemble the disease symptoms. such as Huntington's disease.[68][119][122] y y [edit] Xenotransplantation Xenotransplantation research involves transplanting tissues. Certain domestic and wild animals have a natural propensity or predisposition for certain conditions that are also found in humans. as a way to overcome the shortage of human organs for use in organ transplants. as well as the medical research charity The Parkinson's Appeal.[114] or even transgenic mice that carry the same mutations that occur during the development of cancer. and later deep brain stimulation. Examples include: y Genetic modification of animals to study disease. multifactorial diseases with genetic components.[119] Such studies can be difficult to interpret. armadillos are the primary source of bacilli used in leprosy vaccines. Examples include restricting blood flow to the brain to induce stroke. Transgenic animals have specific genes inserted.[79] Studies on models of naturally occurring disease and condition.[120] For example. although such models are now widely used to study Parkinson's disease. Cats are used as a model to develop immunodeficiency virus vaccines and to study leukemia because their natural predisposition to FIV and Feline leukemia virus.[117] Certain breeds of dog suffer from narcolepsy making them the major model used to study the human condition. or giving neurotoxins that cause damage similar to that seen in Parkinson's disease. the mammalian species in which genetic modification is most efficient.[118] Studies on induced animal models of human diseases.[115] These models allow investigations on how and why the disease develops.[123] Current research involves 84 .[56] Smaller numbers of other animals are also used. such as diabetes. and amphibians. fish. or by universities in commercial partnerships. which are often discovered or generated by pure research programmes.[113] Other models mimic complex. Armadillos and humans are among only a few animal species that naturally suffer from leprosy. state that these models were invaluable and that they led to improved surgical treatments such as pallidotomy. These may involve the use of animal models of diseases or conditions. an animal is treated so that it develops pathology and symptoms that resemble a human disease.

diarrhea. and chests. wild baboons were imported to the UK from Africa to be used in experiments that involved grafting pigs' hearts and kidneys onto the primates' necks. Documents leaked from Huntingdon Life Sciences to The Observer in 2003 showed.[83] The newspaper also wrote that researchers were deliberately underestimating the suffering in order to obtain licences.000 animals are used for each chemical being tested. around one million animals are used every year in Europe in toxicology tests. or by placing them in an inhalation chamber. and may interfere with the results.000 needed to test pesticides. The experiments were conducted by Imutran Ltd. The Observer reports that some baboons died after suffering strokes.[128] According to 2005 EU figures. such as Huntingdon Life Sciences. or subcutaneously. inhaled either by placing a mask over the animals and restraining them. also known as safety testing. through a tube into the stomach. but according to BUAV. abdomens. Most tests involve testing ingredients rather than finished products. or by contract animal testing facilities. packing materials. food additives.[128] The substances are applied to the skin or dripped into the eyes. A report from Imutran said: "The Home Office will attempt to get the kidney transplants classified as 'moderate. injected intravenously. with 12. Doses may be given once.' ensuring that it is easier for Imutran to receive a licence and ignoring the 'severe' nature of these programmes. while others died en route to the UK. Novartis told the newspaper that developing new cures for humans invariably means experimenting on live animals.[124] Although transplant rejection remains a problem.[40] According to Nature. which are about 10% of all procedures. or simply in the animal's food. or administered orally. between 1994 and 2000. The LD50 ("Lethal Dose 50%") test is used to evaluate the toxicity of a substance by determining the dose required to kill 85 .[130][131] Toxicology tests are used to examine finished products such as pesticides. or their chemical ingredients. on behalf of a wide variety of customers. and air freshener. a subsidiary of Novartis Pharma AG in conjunction with Cambridge University and Huntingdon Life Sciences. is conducted by pharmaceutical companies testing drugs."[83][127] [edit] Toxicology testing Toxicology testing. and paralysis. There are several different types of acute toxicity tests.[125][126] The British Home Office released figures in 1999 showing that 270 monkeys had been used in xenotransplantation research in Britain during the previous four years. they therefore repeat the tests using their finished products to obtain a less toxic label. intramuscularly. 5. medications. or for the lifespan of the animal. vomiting. manufacturers believe these tests overestimate the toxic effects of substances.[129] The tests are conducted without anesthesia. repeated regularly for many months.using primates as the recipients of organs from pigs that have been genetically-modified to reduce the primates' immune response against the pig tissue.[124] recent clinical trials that involved implanting pig insulinsecreting cells into diabetics did reduce these people's need for insulin. because interactions between drugs can affect how animals detoxify chemicals.

or underestimate risk. L'Oreal. one to three months (subchronic). Belgium. teratogenicity.S. For these. subjective. as of 2005. the European Union (EU) agreed to phase in a near-total ban on the sale of animal-tested cosmetics throughout the EU from 2009. France.[137] The most stringent tests are reserved for drugs and foodstuffs. phototoxicity (toxicity triggered by ultraviolet light) and mutagenicity. ulceration. mutagenicity. after 13 years of discussion. France. The cost of the full complement of tests is several million dollars per substance and it may take three or four years to complete.. Such tests. "the LD50 acute toxicity test . and to ban all cosmetics-related animal testing. hemorrhaging. has protested the proposed ban by lodging a case at the European Court of Justice in Luxembourg. where a test substance is applied to an animal's eyes or skin.[138] However. eye and skin irritancy. and the UK. and more than three months (chronic) to test general toxicity (damage to organs).[140] Cosmetics testing on animals is particularly controversial.[129] This variability stems from using the effects of high doses of chemicals in small numbers of laboratory animals to try to predict the effects of low doses in large numbers of humans.50% of the test animal population. asking that the ban be quashed.[142] The ban is also opposed by the European Federation for Cosmetics Ingredients..[134] The Humane Society of the United States writes that the procedure can cause redness. lasting less than a month (acute). a modified form of the Draize test called the low volume eye test may reduce suffering and provide more realistic results.[139] Although relationships do exist. the recommended protocol involves observing the effects of the substance at intervals and grading any damage or irritation.. as Nature reported. carcinogenicity. but that the test should be halted and the animal killed if it shows "continuing signs of severe pain or distress". which are still conducted in the U.[135] This test has also been criticized by scientists for being cruel and inaccurate."[129] Irritancy is usually measured using the Draize test. over-sensitive. "critical information for assessing hazard and risk potential".[136] Although no accepted in vitro alternatives exist.[142] 86 . and in 2002. a number of tests are performed. and failing to reflect human exposures in the real world. most animal tests either over. which use fewer animals and cause less suffering. but it has not yet replaced the original test. involve general toxicity.[132][133] Nature writes that. eye and skin irritancy. which represents 70 companies in Switzerland. These toxicity tests provide. This test was removed from OECD international guidelines in 2002. and reproductive problems. For Draize eye testing. opinion is divided on how to use data on one species to predict the exact level of risk in [edit] Cosmetics testing another. replaced by methods such as the fixed dose procedure. which is home to the world's largest cosmetics company. Belgium.[141] Cosmetics testing is banned in the Netherlands. usually an albino rabbit. or even blindness. or do not reflect toxicity in humans particularly well. cloudiness. in the words of a 2006 United States National Academy of Sciences report. still accounts for one-third of all animal [toxicity] tests worldwide. Germany and Italy.

[149] The British government has additionally required that the cost to animals in an experiment be weighed against the gain in knowledge. which test whether experimental drugs work by inducing the appropriate illness in animals. toxicology tests. Specific tests on reproductive function. and argues that to save human lives it is permissible to kill animals. Acute toxicity is studied by using a rising dose until signs of toxicity become apparent. or carcinogenic potential can all be required by law. who argues that animals are beings with beliefs.[edit] Drug testing in a British facility. and viewpoints have shifted significantly over the 20th century.[148] There remain strong disagreements about which animal testing procedures are useful for which purposes. sub-acute. The dominant ethical position. which allows researchers to determine the effect of the drug and the dose-response curve. intraperitoneally. is required to involve two species of mammals. 87 . provided that animal suffering and use is minimized. The view that animals have moral rights (animal rights) is a philosophical position proposed by Tom Regan. in the European Union. in order to discover if any toxic drug metabolites build up over time. metabolized and excreted by the body when introduced orally.how drugs are absorbed. desires and self-consciousness. is that achievement of scientific and medical goals using animal testing is desirable. investigating pharmacokinetics . laws regulating drugs were lax. Testing for chronic toxicity can last up to two years and. and to which species of animals. Regan still sees clear ethical differences between killing animals and killing humans. which gauge acute. embryonic toxicity. Beagles used for safety testing of pharmaceuticals Before the early 20th century. and chronic toxicity. Current European legislation demands that "acute toxicity tests must be carried out in two or more mammalian species" covering "at least two different routes of administration". intravenously.[150] A wide range of minority viewpoints exist as well. intramuscularly.[144] efficacy studies. one of which must be non-rodent. Tests on pharmaceutical products involve: y metabolic tests. The drug is then administered in a double-blind controlled trial. y y y Ethics The ethical questions raised by performing experiments on animals are subject to much debate. or transdermally. worldwide. as well as disagreements over which ethical principles apply. depending on the result of other studies and the type of drug being tested.[143] Sub-acute toxicity is where the drug is given to the animals for four to six weeks in doses below the level at which it causes rapid poisoning. Nowadays all new pharmaceuticals undergo rigorous animal testing before being licensed for human use.[151] Such beings are seen as having inherent value and thus possessing rights.

and enhance animal welfare for the animals still used. living for six years and giving birth to several lambs.However.[157] In February 1997 a team at the Roslin Institute in Scotland announced the birth of Dolly the sheep. since it showed that not only could cloned animals be produced for use in farming. People for the Ethical Treatment of Animals (PETA) filmed staff inside Huntingdon Life Sciences (HLS) in the UK. an international campaign to close HLS.[152] Another prominent position is articulated by Peter Singer. Europe's largest animal-testing facility. shouting at them.[179] 88 . but was euthanized in 2003 after contracting a progressive lung disease. suffering or distress. hitting puppies. and that human beings have no moral right to use an individual animal in ways that do not benefit that individual. a ewe that had been cloned from tissue taken from another adult sheep. and that animal tests should only be performed where necessary. some such as Bernard Rollin have taken his position further and argue that any benefits to human beings cannot outweigh animal suffering.[158] Dolly appeared to be a normal sheep. and simulating sex acts while taking blood samples.[153] Although these arguments have not been widely accepted. particularly the great apes.[21] Dolly was produced through nuclear transfer to an unfertilised oocyte.[154][155] [edit] Prominent cases In 1997. The "three Rs"[92] are guiding principles for the use of animals in research in most countries: y y y Reduction refers to methods that enable researchers to obtain comparable levels of information from fewer animals. in response to these concerns some governments such as the Netherlands and New Zealand have outlawed invasive experiments on certain classes of non-human primates. which has been criticized for its sometimes violent tactics.[159] Although the production of Dolly was a scientific breakthrough.[161] [edit] Alternatives to animal testing Scientists and governments state that animal testing should cause as little suffering to animals as possible.[156] The employees were dismissed and prosecuted. and HLS's licence to perform animal experiments was revoked for six months. who sees no convincing reason to include a being's species in considerations of whether their suffering is important in utilitarian moral considerations. and was the only lamb that survived from 277 attempts at this technique. Refinement refers to methods that alleviate or minimize potential pain. Replacement refers to the preferred use of non-animal methods over animal methods whenever it is possible to achieve the same scientific aim. it was controversial. in principle.[160] but also that it would now be. possible to clone a human being. The broadcast of the undercover footage on British television in 1997 triggered the formation of Stop Huntingdon Animal Cruelty. or to obtain more information from the same number of animals.

drug discovery would be as reliable as drug manufacturing.[181] and of little practical effect in improving animal welfare. In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject. and pharmacological agents that can be tolerated by a live organism and perturb its systems are yet another.Although such principles have been welcomed as a step forwards by some animal welfare groups. and faster-breeding cousins. this is known as in vitro. cheaper. the nature and properties of a chemical tool cannot be considered independently of the system it is to be tested in. In this situation. However. If it were simple to ascertain the properties required to develop a lead discovered in vitro to one that is active in vivo. [edit] in vivo vs. In utero In utero is a Latin term literally meaning "in the uterus". Animal testing and clinical trials are two forms of in vivo research. or a in vitro controlled environment. Compounds that bind to isolated recombinant proteins are one thing. be removed by surgery.[182] In situ (pronounced / n si tu /) is a Latin phrase meaning in the place. [edit] Methods of use According to Christopher Lipinski and Andrew Hopkins."[1] In the past. the more specific term is ex vivo. In vivo In vivo (Latin for "within the living") refers to experimentation using a whole. This type of cancer can often. Once cells are disrupted and individual parts are tested or analyzed.[180] they have also been criticized as both outdated by current research. for example. It is used in many different contexts. cultured cells derived from biopsies. chemical tools that can perturb cell function another. "Whether the aim is to discover drugs or to gain knowledge of biological systems. depending on where it is located. the guinea pig was such a commonly used in vivo experimental subject that they became part of idiomatic English: to be a guinea pig. rats and mice. they have largely been replaced by their smaller. It is used in biology to describe the state of an embryo or fetus. In silico 89 . living organism as opposed to a partial or dead organism. Medicine Cancer in situ means cancer that is in one place. ex vivo research In molecular biology in vivo is often used to refer to experimentation done in live isolated cells rather than in a whole organism.

a mathematician from National Autonomous University of Mexico (UNAM) presented the report "DNA and RNA Physicochemical Constraints. the term may be applied to epidemiological studies that do not involve clinical subjects. silicium. In his talk. In papyro in papyro: referring to experiments or studies carried out only on paper. The phrase "in silico" originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences).[2] The first referenced book chapter where "in silico" appears was written by Hans B. respectively.In silico is an expression used to mean "performed on computer or via computer simulation. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute." which is correct Latin for "in silicon" (the Latin term for silicon. Pedro Miramontes. possibly through similarity to the words "vivo" and "vitro"[citation needed] "In silico" is now almost universal. Silex is also a correct latin word).[citation needed] But the phrase "in silice" means "in flint" in Latin. "silicon" would take the form "silico" in such a phrase. [edit] History The expression in silico was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos." The phrase is coined in analogy to the Latin phrases in vivo and in vitro which are commonly used in biology (see also systems biology) and refer to experiments done in living organisms and outside of living organisms. Contrary to widespread belief. was created at the beginning of the 19th century by Berzelius. The first referenced paper where "in silico" appears was written by a French team in 1991. "In silico" was perceived as catchier.bioinfo. Miramontes used the term "in silico" to characterize biological experiments carried out entirely in a computer.[1] In silico has been used in white papers written to support the creation of bacterial genome programs by the Commission of the European Community. The work was later presented by Miramontes as his PhD dissertation. the "-on" ending for certain elements is from Greek. such 90 . in silico does not mean anything in Latin.de/isb/). The proper Latin phrase would likely be in simulacra to describe experiments done on the likeness (simulacrum) or model of a phenomenon. For example. In Greek. Latin typically uses the correct Greek forms for Greek words when they are used in Latin. and did not refer to calculations done by computer generically. it even occurs in a journal title (In Silico Biology: http://www. "In silico" is reasonable from the viewpoint of (ancient) Greek case endings. Cellular Automata and Molecular Evolution".[3] [edit] In silico versus in silicio "In silico" was briefly challenged by "in silicio. New Mexico.

but is yet called in vitro.) However. from the [Latin] root meaning within the glass. that are commonly used in chemistry labs and biology labs. environmental. Louise Brown. normally only geographically dispersed trials can properly evaluate this. Today. efficacy will vary significantly between population groups with different genetic. and ethnic or cultural backgrounds ("demographic" factors). because early biological experiments involving cultivation of tissues outside the living organism from which they came. refers to the tube-shaped containers of glass or plastic resin. The fertilised egg (zygote) is then transferred to the patient's uterus with the intent to establish a successful pregnancy. different geographic locations. However. is used. A colloquial term for babies conceived as the result of IVF. test tube babies. are conducted at several clinical research centers. The benefits of multicenter trials include a larger number of participants. the possibility of inclusion of a wider range of population groups. In vitro fertilisation In vitro fertilisation (IVF) is a process by which egg cells are fertilized by sperm outside the womb. particularly Phase III trials. was born in 1978. (Petri-dishes may also be made of plastic resins. were carried out in glass containers such as beakers. to distinguish it from an in vivo procedure. The term in vitro.that is. called test tubes. a study carried out through computer/abstract simulations can also be considered in papyro. The process involves hormonally controlling the ovulatory process. test tubes. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed. or in silico. Most large clinical trials. The term is similar to phrases such as in vivo. Like the latter. but overlaps with in silico . all of which increase the generalizability of the study. in vitro. in vitro. This is used when parents are having infertility problems or they want to have multiple births. the term in vitro is used to refer to any biological procedure that is performed outside the organism it would normally be occurring in. in papyro (the correct latin is in paprus) has no actual Latin meaning and was constructed as an analogue to the more popular and longstanding biological sciences terms (vivo and vitro). [edit] Competitive enrollment 91 . or petri dishes. the IVF method of Autologous Endometrial Coculture is actually performed on organic material. The first "test tube baby". removing ova (eggs) from the woman's ovaries and letting sperm fertilise them in a fluid medium. In many cases. in vitro fertilisation is usually performed in the shallower containers called Petri dishes. In papyro is mutually exclusive from in vitro and in vivo. where the tissue remains inside the living organism within which it is normally found.as meta-analysis. Multicenter trial A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. and the ability to compare results among centers.

and these too contribute to the decision on whether to license it. In 1986. or a different vaccine which might be intended to protect against a different pathogen. [edit] Methodology A basic vaccine trial might involve forming two groups from a random sample of the target population. If the vaccine produces no statistically significant results. then it is rejected. This will be done to help ensure that subject enrollment is completed as planned. However. an adjuvant-containing cocktail. They are designed to be administered through primary care physicians. and a statistical test is performed on these two sets of data to determine whether or not there is any statistically significant difference between them. Vaccine trial A vaccine trial is a clinical trial that aims at establishing the safety and efficacy of a vaccine prior to it being licensed. planned allocation numbers should be transferred from the centre with low subject recruitment to a centre with high recruitment where subject inclusion is expected to be completed earlier than planned. community health centers and local outpatient facilities.[1] The trials give patients access to new medications and keep doctors involved with new developments in research.Enrollment should be competitive. Data on antibody production and immunity to the disease in question is collected from both groups some time after the administration of the vaccine or placebo. critics state that drug company payments to doctors for patients enrolled in such studies present a conflict of interest and potential for abuse. since a sufficient time period must elapse for the subjects to react to the vaccine and develop the required antibodies. If the subject recruitment rate is lower than expected at one centre and higher than expected at another.[2][3] Community-based trials are becoming prevalent in human-testing stage pharmaceutical research. One group receives the vaccine while the control group receives a placebo. Clinical site 92 . Community-based clinical trial Community-based clinical trials are clinical trials conducted directly through doctors and clinics rather than academic research facilities. [edit] Methodological issues and problems Vaccine trials may take months or years to complete. Side effects of the vaccine are also noted. the Community Consortium held the first such trials in the United States to determine the efficiacy of preventative treatments after the onset of Pneumocystis pneumonia.

A clinical site is a medical facility staffed with a clinical investigator (MD) and qualified for performing clinical research.e. clinical trial management (preclinical through phase IV). as an independent contractor with the sponsor. e. Food and Drug Administration regulations state that a CRO is "a person [i. and/or the regulatory authority(ies)..1. To be qualified as a clinical site. GCP and the applicable regulatory requirements. in the product information and in other information sources provided by the sponsor.S. selection or monitoring of investigations.. and inspection by the appropriate regulatory authority(ies). Per ICH GCP 4. in the current Investigator's Brochure. preclinical. Abbreviated New Drug Application (ANDA). the U. evaluation of reports. regulatory affairs support. and experience to assume responsibility for the proper conduct of the clinical trial. design of a protocol. or Biologics License Application (BLA).4 the investigator/institution should permit monitoring and auditing by the sponsor. data management. which set the guidelines for good clinical practice (GCP) at clinical sites. Per ICH GCP 4. CROs range from large. a legal person.5 the investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties. Per ICH GCP 4. as described in the clinical protocol. and preparation of materials to be submitted to the Food and Drug Administration.g.1. and many other complementary services. one or more of the obligations of a sponsor. toxicology. and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor. international full service organizations 93 .1 the investigator(s) should be qualified by education.3(b)] Services offered by CROs include: product development.3 the investigator should be aware of. and clinical laboratory services for processing trial samples." [21 CFR 312. Contract research organization A Contract Research Organization. biostatistics and medical writing services for preparation of an FDA New Drug Application (NDA).1.2 the investigator should be thoroughly familiar with the appropriate use of the investigational product(s). training. strict regulations are to be adhered to. the institutional review board/independent ethics committee (IRB/IEC). (CRO) is a service organization that provides support to the pharmaceutical/biotech industry. The foundations for these regulations are defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and regulatory authorities. and should comply with. CROs offer clients a wide range of "outsourced" pharmaceutical research services to aid in the drug and medical device research & development process. formulation and manufacturing.1. Per ICH GCP 4. clinical. Per ICH GCP 4. which may be a corporation] that assumes.1.[1] In the Code of Federal Regulations (CFR). should meet all the qualifications specified by the applicable regulatory requirement(s). medical and safety monitoring. also called a Clinical Research Organization.

Oversight and administrative efforts that monitor a participant's health during a clinical trial. and welfare of subjects under the investigator's care. In some cases. academic members participate in clinical trials as members of SMOs.to small. and for the control of drugs under investigation. niche specialty groups and can offer their clients the experience of moving a new drug or device from its conception to FDA marketing approval without the drug sponsor having to maintain a staff for these services. and universities. Pharmaceutical or biotech companies who view the development and commercialization of treatments as their business. researchers and institutions who view trials as a source of income and prestige. Regulators who wish to ensure treatments are safe and work effectively. These organizations include: y y y y Hospitals. A typical area of academic clinical trials is the advancement and optimization of already existing therapies. such as medical schools. Academic clinical trials are run at academic sites.[2] Academic clinical trials Academic clinical trials are a valuable component of the health care system. academic clinical trials may for instance test how a combination of registered drugs may improve treatment outcomes. Thus. There are many different organizations which have an interest in academic clinical trials and facilitate or take part in their conduct. universities. Site management organizations are for-profit organizations which enlist and manage the physician practice sites that actually recruit and follow patients enrolled in clinical trials. safety. The government and other clinical trial funding agencies 94 . Such research questions are not a primary focus of for-profit companies. they benefit patients and help determine the safety and efficacy of new drugs and devices. for protecting the rights. or they may apply registered treatments in additional. and applicable regulations. the investigational plan. Clinical investigator A clinical investigator involved in a clinical trial is responsible for ensuring that an investigation is conducted according to the signed investigator statement. less frequent indications. and thus these trials are typically initiated by individual investigators or academic research organizations. and non-academic sites which may be managed by so-called site management organizations (SMOs). academic hospitals. charitable and governmental funding. and receive private. Patients and patients' organizations and associations who want faster access to advanced treatments. Clinical monitoring Clinical monitoring .

the complexity of the protocol and the condition being studied. This will differ among programs and sites depending on available technology. In monitoring. There are a number of factors that must be considered in making this decision: y y y y Complexity of the protocol Disease being evaluated Experience of the investigator/staff Number of study subjects enrolled at the site 95 . Therefore. fax and regular mail communications into a monitoring strategy. an extremely simple. They want to be certain that safety measures are in place to protect participants. sponsor and site Standard Operating Procedures (SOPs) and personal preference. email. [edit] Functions of the clinical monitor . Establishing who will monitor requires consideration of the sponsor¶s SOPs. Almost all field monitoring requires regular visits to the site by the clinical research associate throughout the period of the study. many problems can be traced back to a lack of communication. and the training and experience of the CRA. the experience of the investigator and staff. low risk study might be monitored almost exclusively by telephone except for the startup and closeout visits. the CRA must determine how long he or she will need to be there and make appropriate arrangements. A good communication strategy should have a high priority in your monitoring plan. [edit] Frequency of monitoring visits Another key determination in a monitoring plan is the frequency with which the CRA will visit each site. inappropriate communication and/or unclear communication. the CRA may be required to be present during all or part of a subject¶s treatment. but the strategy for individual sites may change considerably during the course of the study depending on study conditions and site performance. [edit] The intensity of monitoring The intensity of monitoring will vary across studies and among sites. Must or should the CRA be present while the site is seeing study subjects? Will the CRA have any interaction with study subjects? In early phase I studies. The Clinical Research Associate¶s overall monitoring plan should remain fairly consistent.Clinical Research Associate How to monitor a study in the field requires considerable thought. On very rare occasions. A clinical research associate (CRA) must determine how to integrate telephone.require data and safety monitoring boards to oversee clinical trials. like any business. while other times the CRA will comonitor with other CRAs. Sometimes a CRA is the sole monitor for a site.

Catching and solving problems early will save a lot of extra work as the study progresses. the CRA must adjust the visit schedule to ensure compliance with the SOP. a CRA must visit each site often enough to stay on top of the activities that are required for good 96 . Not only that. and perhaps even quarterly as the study progresses. Initially. Some sites will do a better job complying with GCPs than others and may need less frequent monitoring.y y y y Rate of enrollment Site performance Sponsor monitoring SOPs CRA experience and effectiveness The protocol dictates the conduct of the study by establishing the procedures that subjects must undergo and a schedule of assessments. Site personnel often view frequent visits by the CRA as an indication of the importance of their study to the sponsor. ³all sites must be visited every six weeks or less´. In this case. especially at the beginning of the study. the more frequently the CRA will have to visit.All sites should be visited soon after the first subjects are enrolled just to be sure the site understands and is correctly following protocol procedures. The more activities that are required during a study visit. The CRA should visit a site regularly even though enrollment may be slow or nonexistent. Subject visits may spread out over the course of longterm studies and require less review. The faster a site enrolls and the more data generated. the more frequently the site will need monitoring. allowing for more time between monitoring visits. the course of the therapy will probably be complete for each subject in about ten days. In some instances. The disease being studied is also a factor.. sponsor SOPs dictate the frequency of monitoring visits. which will probably involve visits. the CRA may be able to space the monitoring visits further apart. Subject enrollment may complete or level off after a period of time. This requires a different frequency of visits than a cholesterol-lowering study with a treatment period of one or two years. Generally speaking. Once the site has demonstrated the ability to do the study well. it generally works. Call it encouragement or guilt. the SOP normally establishes a minimum schedule. The frequency of monitoring visits may change as the study progresses. In short. followed by monthly. In that case. Sometimes a few extra visits are all that is necessary to get a study back on track or to re-establish priorities at the site. A less experienced site may require more or longer monitoring visits. For instance.The frequency and duration of monitoring visits will also vary from site to site depending on the experience of the investigator and staff. The rate of enrolment will also affect monitoring frequency. the more subjects a site has. a bit of encouragement may help. but seeing the CRA walk through the door reminds the site of their commitment to enroll subjects and complete the study on time. If so.g. Slow subject enrollment may include a lack of enthusiasm on the part of the site personnel regarding the study. weekly visits may be required. the more monitoring will be required. if the CRA is monitoring an infectious disease study. e.

If the CRA is in a situation where it is not plausible to visit sites with the degree of frequency necessary for safe monitoring. This report is a standard document that a CRA will use for all field monitoring visits. The number will change depending on the complexity of the study.monitoring. The top five deficiency categories for site inspections as reported in the 2001 Report to the Nation are as follows: y y y y y Failure to follow the protocol Failure to keep adequate and accurate records Problems with the informed consent form Failure to report adverse events Failure to account for the disposition of study drugs 97 . With the complexity of protocols. it should be discussed with their superior. This list is published annually by the Center of Drug Evaluation and Research (CDER) and has remained essentially unchanged for over a decade. it is important to develop a sense for what you should monitor at each site and how much attention should be given to each activity. As a general rule. where the sites closest together are linked in your itinerary for a single trip. The CRA should schedule a minimum of four hours for a site visit. However. The more experience the CRA has. There is always the chance that the CRA simply cannot physically visit the sites as often as he or she would like to or need to because of travel time and the actual number and location of sites. Another factor that has an impact on CRA visits frequency is the number and location of sites for which he or she has monitoring responsibility. the CRA must not view this as the only list of activities that must be done. Creative scheduling of your travel itinerary is a must. the easier making this determination will be. To be successful as a CRA. It serves as both a checklist for the CRA and as documentation of the visit. It helps to be aware of where problems are most likely to arise during the conduct of a study. the CRA will have to spend some time integrating travel requirements with the experience and study complexity. a good CRA should be able to effectively monitor twelve to eighteen sites. It helps to use the ³loop method´ for travel. regulatory requirements and good monitoring practice. they will need to spend a day or more at most sites. Here again. Most sponsors have a site visit or monitoring report that the CRA completes during and after the visit. site and CRA experience and locations. A good indication of potential problems is the list of activities that received the most deficiencies during FDA audits. [edit] Monitoring activity The CRA should have a general plan for what will be monitored at each site visit.

each focused on a major area of regulatory responsibility: y y y y y y y y y The Office of the Commissioner (OC) The Center for Drug Evaluation and Research (CDER) The Center for Biologics Evaluation and Research (CBER) The Center for Food Safety and Applied Nutrition (CFSAN) The Center for Devices and Radiological Health (CDRH) The Center for Veterinary Medicine (CVM) The National Center for Toxicological Research (NCTR) The Office of Regulatory Affairs (ORA) The Office of Criminal Investigations (OCI) 98 . The FDA is headquartered in Rockville. dietary supplements. the U. MD with 223 field offices[3] supported by 13 laboratories located throughout the United States. should receive specific attention during monitoring visits.These areas. Food and Drug Administration (United States) The Food and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods. The agency is organized into the following major subdivisions. the site was renamed from the White Oak Naval Surface Warfare Center to the White Oak Federal Research Center. The FDA also enforces section 361 of the Public Health Service Act and the associated regulations. medical devices. The first building. Independent CRAs and those employed by Contract research organizations need to spend enough time with sponsors¶ representatives to clearly understand those expectations. biological medical products. blood products. vaccines. When FDA arrived. and cosmetics. radiation-emitting devices. Virgin Islands. veterinary products. In recent years the agency began undertaking a large-scale effort to consolidate its DC-metro area operations from its main headquarters in Rockville and several fragmented office buildings in the vicinity to the former site of the Naval Ordnance Laboratory in the White Oak area of Silver Spring. and Puerto Rico. in addition to the things the sponsor wants emphasized. including sanitation requirements on interstate travel as well as specific rules for control of disease on products ranging from pet turtles to semen donations for assisted reproductive medicine techniques. was dedicated and opened with 104 employees on the campus in December 2003. a Life Sciences Laboratory. Sponsor expectations for studies are important. drugs. The project is slated to be completed by 2013. [edit] Organization The FDA is an agency within the United States Department of Health and Human Services responsible for protecting and promoting the nation's public health.S. MD.

illnesses. and review documentation in the case of medical devices. are the individuals who inspect production and warehousing facilities..´ and vigilare (Latin). ³to keep awake or alert."[2] 99 . or ADRs. ORA and OCI are primarily field offices.While most of the Centers are located around the Washington. Pharmacovigilance Pharmacovigilance (PV) is the pharmacological science relating to the detection. or placing limits on the types of issues that can be discussed. biological products. and other items where Clinical trials publication Clinical trials publication is having research published in a peer reviewed journal following clinical trials. particularly long term and short term side effects of medicines. which are officially described as: "A response to a drug which is noxious and unintended. assessing and evaluating information from healthcare providers and patients on the adverse effects of medications. or outbreaks. Consumer Safety Officers. assessment.[1] Generally speaking. drugs. Most agreements for a clinical trial between sponsor and investigator grants that the sponsor may control publication of results by requesting publication delays. biological products. and which occurs at doses normally used« for the prophylaxis. monitoring. and to coordinate the disclosure of results when a clinical trial is being conducted at multiple sites. These controls serve to prevent disclosure of information that would compromise the sponsor's ability to patent inventions. to keep watch. to prevent disclosure of confidential information shared with investigator. understanding and prevention of adverse effects. ³drug. These are legitimate business concerns. with their workforce spread across the country.C. or for the modification of physiological function. more commonly called Investigators. Most investigators will want to have such a publication but the nature of clinical trials may create special considerations and obstacles. researching. diagnosis or therapy of disease. area as part of the Headquarters divisions. investigate complaints. deleting portions of a manuscript.´ Pharmacovigilance is particularly concerned with adverse drug reactions. D. conducting the vast majority of the field work the Agency. ORA is considered the "eyes and ears" of the agency. pharmacovigilance is the science of collecting. herbalism and traditional medicines with a view to: y y identifying new information about hazards associated with medicines preventing harm to patients. but may not restrict the investigator from freely publishing research results in the end of the study and approval process. The etymological roots are: pharmakon (Greek).

in clinical trials) Drug design Drug design also sometimes referred to as rational drug design is the inventive process of finding new medications based on the knowledge of the biological target. Even very severe ADRs. usually expressed as a percent or ratio of the treated population..[1] The drug is most commonly a organic small molecule which activates or inhibits the function of a biomolecule such as a protein which in turn results in a therapeutic benefit to the patient.. etc. [edit] Terms commonly used in drug safety y y y y y Benefits are commonly expressed as the proven therapeutic good of a product. are often undetected because study populations are small. Efficacy is used to express the extent to which a drug works under ideal circumstances (i. drug design involves design of small molecules that are complementary in shape and charge to the biomolecular target to which they interact and therefore will bind to it.[2] This type of modeling often referred to as computer-aided drug design. In the most basic sense. Modeling techniques for prediction of binding affinity are reasonably successful. The phrase '"drug design" is to some extent a misnomer.[citation needed] Because clinical trials involve several thousand patients at most. but should also include the patient¶s subjective assessment of its effects Risk is the probability of harm being caused. less common side effects and ADRs are often unknown at the time a drug enters the market. such as liver damage. What is really meant by drug design is ligand design. or to the infectivity or 100 . [edit] Background Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology. that first must be optimized before a ligand can becomes a safe and efficacious drug. the probability of an occurrence Harm is the nature and extent of the actual damage that could be caused.Pharmacovigilance is gaining importance for doctors and scientists as the number of stories in the mass media of drug recalls increases. However there are many other properties such as bioavailability. clinical practice (not clinical trials). It should not be confused with risk Effectiveness is used to express the extent to which a drug works under real world circumstances. lack of side effects. Drug design frequently but not necessarily relies on computer modeling techniques. i. These other characteristics are often difficult to optimize using rational drug design techniques.e.e. metabolic half life. Postmarketing pharmacovigilance uses tools such as data mining and investigation of case reports to identify the relationships between drugs and ADRs.

survival of a microbial pathogen. these drugs should also be designed in such a way as not to affect any other important "offtarget" molecules that may be similar in appearance to the target molecule since drug interactions with off-target molecules may lead to undesirable side effects. [edit] Ligand based 101 . [edit] Types Flow charts of two strategies of structure-based drug design There are two major types of drug design. Most commonly. In addition mRNA based gene silencing technologies may have therapeutic applications. The first is referred to as ligand-based drug design and the second. Sequence homology is often used to identify such risks. Drugs may be designed that bind to the active region and inhibit this key molecule. In addition. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. drugs are organic small molecules but protein based drugs (also known as biologics) are becoming increasing more common. structure-based drug design. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning.

In this case. which is usually referred as database searching. These pieces can be either atoms or fragments. a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. These other molecules may be used to derive a pharmacophore which defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. two essential pieces of information are required. Another category of structure-based drug design methods is about ³building´ ligands. disease linkage studies that show an association between mutations in the biological target and certain disease states. as well as the structural dynamic and electronic information about the ligands. The key advantage of such a method is that novel structures. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. In order for a biomolecule to be selected as a drug target. Alternatively various automated computational procedures may be used to suggest new drug candidates. not contained in any database. This method is usually referred as ligand-based drug design. a model of the biological target may be built based on the knowledge of what binds to it and this model in turn may be used to design new molecular entities that interact with the target. This knowledge may come from. for example. which is usually referred as receptorbased drug design. rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. As the experimental methods as X-ray crystallography and NMR develop. In this case. ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. 102 .[4] Using the structure of the biological target. The second is that the target is "drugable".Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. Current methods for structure-based drug design can be divided roughly into two categories. This encourages the rapid development of the structure-based drug design. can be suggested. The first is evidence that modulation of the target will have therapeutic value. and matching the apparent effects to treatments.[5][6][7] [edit] Rational drug discovery In contrast to traditional methods of drug discovery which rely on trial-and-error testing of chemical substances on cultured cells or animals. The first category is about ³finding´ ligands for a given receptor. the amount of information concerning 3D structures of biomolecular targets has increased dramatically. candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. [edit] Structure based Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. These techniques are raising much excitement to the drug design community.[3] In other words.

The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Several methods for predicting drug metabolism have been proposed in the scientific literature. machine learning. neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target. Those challenges are caused by the large chemical space describing potential new drugs without side-effects. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. In addition. the threedimensional structure of the target may be determined. and minimal toxic effects. that is they should possess properties that are predicted to lead to oral bioavailability. and testing before an optimal molecule is discovered. One way of estimating druglikeness is Lipinski's Rule of Five. These methods use linear regression. polarizability. computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule. ab initio quantum chemistry methods. the target is normally cloned and expressed. enhance. Alternatively knowledge based scoring function may be used to provide binding affinity estimates. adequate chemical and metabolic stability. etc. Therefore in practice it still takes several iterations of design. a virtual screen may be performed of candidate drugs.) of the drug candidate which will influence binding affinity.[13] Due to the complexity of the drug design process. and a recent example is SPORCalc. The reality however is that present computational methods provide at best only qualitative accurate estimates of affinity. Once a suitable target has been identified. Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. The expressed target is then used to establish a screening assay. This may be done by using the screening assay (a "wet screen"). or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential. [edit] Computer-assisted drug design Computer-assisted drug design uses computational chemistry to discover. or study drugs and related biologically active molecules. On the other hand. Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. 103 . In addition. The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. synthesis. if the structure of the target is available. Semi-empirical. Ideally the candidate drug compounds should be "druglike". two terms of interest are still serendipity and bounded rationality.

Products may include new or iterated or like-kind medical devices. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to GLP testing for safety of the device and its components. hind limb and heart. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Studies include: bioavailability studies. as well as decrease the need for expensive and timeconsuming clinical studies. assessment of transport. drugs. distribution and elimination of compounds. analysis of drugs and metabolites in biological matrices. Systems used include: in vivo animal models. and during which important feasibility. Pre-clinical studies include a wide range of studies in a variety of systems to characterize biopharmaceutic and pharmacokinetic properties.Drug design with the help of computers may be used at any of the following stages of drug discovery: 1. gene therapy solutions. lead optimization optimization of other pharmaceutical properties while maintaining affinity Nonclinical studies Nonclinical or Pre-Clinical studies are research studies that are conducted. they can facilitate transition of discovery to development. Each class of product may undergo different types of preclinical research. Pre-clinical studies serve a vital role in the drug discovery and development processes. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all 104 . QSAR. isolated perfused liver. etc. These studies can be used to identify lead compounds likely to possess favorable biopharmaceutic and pharmacokinetic properties in humans. in silico modeling.or ligand-based design) 2. etc. iterative testing and safety (also known as Good Laboratory Practice or "GLP") data is collected. intestine. Pre-clinical development Pre-clinical development is a stage of research that begins before clinical trials (testing in humans) can begin. synthetic chemistry. Caco-2 cell monolayer absorption model. drugs may undergo pharmacodynamics (PD). The main goals of pre-clinical studies (also named preclinical studies and nonclinical studies) are to determine a product's ultimate safety profile. In addition. metabolism studies in human liver microsomes. pharmacokinetics (PK).) 3. ADME. pharmacokinetic studies. validated models for cytochrome P450 enzymes. typically on animals. For instance. hit-to-lead optimization of affinity and selectivity (structure-based design. before a permit for a clinical trial on humans can be obtained. hit identification using virtual screening (structure. determination of mechanisms of intestinal absorption. prediction of oral absorption in humans.drug interactions. kidney. and toxicity testing through animal testing. animal and human liver microsomes. assessment of potential for metabolic drug .

Food and Drug Administration (FDA).2 Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development. Based on pre-clinical trials. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences). The information collected from these studies is vital so that safe human testing can begin. Studies of a drug's toxicity include which organs are targeted by that drug. Differences in the gut. goats for mammary implant studies.1 Depending on a drugs functional groups. For example. No Observable Effect Levels (NOEL) on drugs are established. In addition. which will effect both efficacy and toxicology. generic drugs are identical or bioequivalent to the brand name counterpart with respect to pharmacokinetic and pharmacodynamic properties.components are sustainable in a living model. and gastric emptying rates are increased. A generic must contain the same active ingredients as the original formulation. The most commonly used models are murine and canine. Typically. 105 . or noxious metabolites. site of activity. Typically. The generic drug may still have a patent on the formulation but not on the active ingredient. which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. in drug development studies animal testing involves two species.S. etc). therefore. as well as if there are any long-term carcinogenic effects or toxic effects on mammalian reproduction. Generic drug A generic drug (generic drugs. or other considerations make certain models more appropriate based on the dosage form. Medical device studies also use this basic premise. pigs and sheep which allow for testing in a similar sized model as that of a human. circulatory system. Also. although primate and porcine are also used. enzyme activity. generics are identical in dose. However. The choice of species is based on which will give the best correlation to human trials. dogs for gastric studies. By extension. Most pre-clinical studies must adhere to Good Laboratory Practices (GLP) in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States. Most studies are performed in larger species such as dogs. rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. some species are used for similarity in specific organs or organ system physiology (swine for dermatological and coronary stent studies. canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's. According to the U. short: generics) is a drug which is produced and distributed without patent protection. it may be metabolized in similar or different ways between species. both in vitro and in vivo tests will be performed.

explicit and judicious use of current best evidence in making decisions about the care of individual patients. According to the Centre for Evidence-Based Medicine. and randomized controlled trials (RCTs). however. route of administration. In the US. Ex cathedra statements by the "medical expert" are considered to be least valid form of evidence. Evidence-based medicine Evidence-based medicine (EBM) aims to apply evidence gained from the scientific method to certain parts of medical practice. EBM aims for the ideal that healthcare professionals should make "conscientious. and judicious use of current best evidence" in their everyday practice. and intended use[1]. the market competition often leads to substantially lower prices for both the original brand name product and the generic forms. It seeks to assess the quality of evidence[1] relevant to the risks and benefits of treatments (including lack of treatment).strength. over compound design and chemical synthesis to biological testing and ADME profiling. "Evidence-based medicine is the conscientious. safety. which are only partially subject to scientific methods.and value-of-life judgments. The goal is the rapid identification of novel drugs and drug targets embracing multiple early phase drug discovery technologies ranging from target identification and validation. so the effective life of a drug patent tends to be between seven and twelve years Chemogenomics Chemogenomics can be defined as the study of genomic responses to chemical compounds. such as meta-analysis of medical literature. When generic products become available. drug patents give twenty years of protection. risk-benefit analysis. engineering. edit] Process and progress Using techniques from science. All "experts" are now expected to reference their pronouncements to scientific studies. and statistics. seeks to clarify those parts of medical practice that are in principle subject to scientific methods and to apply these methods to ensure the best prediction of outcomes in medical treatment. In most cases. [edit] Classification [edit] Evidence-based guidelines 106 . EBM. even as debate about which outcomes are desirable continues. efficacy. The time it takes a generic drug to appear on the market varies."[2] EBM recognizes that many aspects of medical care depend on individual factors such as quality. explicit. but they are applied for before clinical trials begin. generic products are available once the patent protections afforded to the original developer have expired.

diagnosis. prognosis.[6] [edit] Qualification of evidence Evidence-based medicine categorizes different types of clinical evidence and ranks them according to the strength of their freedom from the various biases that beset medical research. This approach has also been called evidence based healthcare.Evidence-based guidelines (EBG) is the practice of evidence-based medicine at the organizational or institutional level. Level II-3: Evidence obtained from multiple time series with or without the intervention. patient testimonials. The above Levels are only appropriate for treatment or interventions. and more. and D. For example. placebo-controlled trials involving a homogeneous patient population and medical condition. In contrast. or reports of expert committees. The UK National Health Service uses a similar system with categories labeled A. and hence different "levels" are required. This includes the production of guidelines. based on clinical experience. Preventive Services Task Force for ranking evidence about the effectiveness of treatments or screening: y y y y y Level I: Evidence obtained from at least one properly designed randomized controlled trial. For example. Level III: Opinions of respected authorities. C. different types of research are required for assessing diagnostic accuracy or natural history and prognosis. Level II-1: Evidence obtained from well-designed controlled trials without randomization. and regulations.[7] [edit] Evidence-based individual decision making Evidence-based individual decision (EBID) making is evidence-based medicine as practiced by the individual health care provider. and even expert opinion have little value as proof because of the placebo effect. the strongest evidence for therapeutic interventions is provided by systematic review of randomized. Systems to stratify evidence by quality have been developed.S. Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies. policy. B. therapy. the Oxford Centre for Evidence-based Medicine suggests levels of evidence (LOE) according to the study designs and critical appraisal of prevention. preferably from more than one center or research group. and harm studies:[16] 107 . Dramatic results in uncontrolled trials might also be regarded as this type of evidence. double-blind. difficulties in ascertaining who is an expert. case reports. the biases inherent in observation and reporting of cases. such as this one by the U. There is concern that current evidencebased medicine focuses excessively on EBID. descriptive studies.

of poor quality. recommendation for a clinical service is classified by the balance of risk versus benefit of the service and the level of evidence on which this information is based. [edit] Categories of recommendations In guidelines and other publications. Clinicians should not routinely offer the service to asymptomatic patients. Level D: At least fair scientific evidence suggests that the risks of the clinical service outweighs potential benefits. or extrapolations from level A studies.[18] Despite the differences between systems. bench research or first principles. Thus. [edit] Statistical measures in evidence-based medicine 108 . all or none (see note below). cohort study. case-control study. Outcomes Research. Clinicians need not offer it unless there are individual considerations. A newer system is by the Grade Working Group and takes in account more dimensions that just the quality of medical evidence. Ecological Study. but none now die on it. or when some patients died before the Rx became available. or based on physiology. Exploratory Cohort. Level B: Consistent Retrospective Cohort. Level I: Scientific evidence is lacking.y y y y Level A: Consistent Randomised Controlled Clinical Trial. Preventive Services Task Force uses:[19] y y y y y Level A: Good scientific evidence suggests that the benefits of the clinical service substantially outweighs the potential risks. such that the risk versus benefit balance cannot be assessed. the individual studies still require careful critical appraisal. Note: The all or none principle is met when all patients died before the Rx became available. Clinicians should discuss the service with eligible patients. but some now survive on it. Clinicians should discuss the service with eligible patients. clinical decision rule validated in different populations. Level C: Case-series study or extrapolations from level B studies. Level B: At least fair scientific evidence suggests that the benefits of the clinical service outweighs the potential risks. Level D: Expert opinion without explicit critical appraisal. Level C: At least fair scientific evidence suggests that there are benefits provided by the clinical service. However. Clinicians should help patients understand the uncertainty surrounding the clinical service. the quality of evidence to support a clinical decision is a combination of the quality of research data and the clinical 'directness' of the data. The U.S. the purposes are the same: to guide users of clinical research information about which studies are likely to be most valid. but the balance between benefits and risks are too close for making general recommendations.[17] "Extrapolations" are where data is used in a situation which has potentially clinically important differences than the original study situation. or conflicting.

then the NNT is computed as 1/(pB-pA). The NNT for breast mammography is 1/285. NNT is always computed with respect to two treatments A and B. an NNT of 4 means if 4 patients are treated.. a phenomenon known as the placebo effect. only one would respond. If the probabilities pA and pB of this endpoint under treatments A and B. e. and then converted to.g.) This reflects Bayes' theorem. in comparing antibiotics with placebo in the eradication of Helicobacter pylori. The pretest odds of a particular diagnosis. but they do not affect AUC-ROC. and B is no treatment). by sham surgery. so 285 mammograms need to be performed to diagnose one breast cancer. a patient is given an inert "sugar pill" and told that the pill may improve his/her condition. Tools used by practitioners of evidence-based medicine include: y Likelihood ratios. are known. y y An NNT of 1 is the most effective and means each patient treated responds. A is a 5-year treatment with the hypothetical drug.Evidence-based medicine attempts to express clinical benefits of tests and treatments using mathematical methods. The fact that the pill is inert is withheld from the patient.[citation needed] As another example. with A typically a drug and B a placebo (in our example above. (Odds can be calculated from. In one common placebo treatment. this belief sometimes causes the patient's condition to change. determines the post-test odds. The differences in likelihood ratio between clinical tests can be used to prioritize clinical tests according to their usefulness in a given clinical situation. Cutoff values for positive and negative tests can influence specificity and sensitivity. multiplied by the likelihood ratio.[20] Placebo The placebo effect can be produced by inert tablets. The area under the receiver operating characteristic curve (AUC-ROC) reflects the relationship between sensitivity and specificity for a given test. 109 . In general. the [more familiar] probability. and by false information. A defined endpoint has to be specified (in our example: the appearance of colon cancer in the 5 year period). The intervention may cause the patient to believe that the treatment will change his/her condition. Number needed to treat or Number needed to harm are ways of expressing the effectiveness and safety of an intervention in a way that is clinically meaningful. An NNT of 20 to 40 can still be considered clinically effective. An NNT of 2 or 3 indicates that a treatment is quite effective (with one patient in 2 or 3 responding to the treatment). and high-quality publications about clinical tests will provide information about the AUC-ROC. such as when electrical stimulation is turned ³off´ in those with Parkinson¶s disease implanted brain electrodes[1] A placebo is a sham medical intervention intended to lead the recipient to believe that the intervention may improve his/her condition. High-quality tests will have an AUC-ROC approaching 1. respectively.

it can heal. the deceptive nature of the placebo creates tension between the Hippocratic Oath and the honesty of the doctor-patient relationship.[24] Their basic mechanism has been investigated since 1978. The phenomenon is related to the perception and expectation which the patient has.[26] Both conditioning and expectations play a role in placebo effect. but the reviewers examined studies which had both placebo and untreated groups in order to distinguish the placebo effect from the natural progression of the disease. and the placebo effect is a pervasive phenomenon.[28] and can effect earlier stages of information processing.[4] The placebo effect points to the importance of perception and the brain's role in physical health.[7] Most studies have attributed the difference from baseline till the end of the trial to a placebo effect.[5] This view was notably challenged in 2001 when a systematic review of clinical trials concluded that there was no evidence of clinically important effects except perhaps in the treatment of pain and continuous subjective outcomes. it is part of the response to any active medication. where a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. differences in size and color of placebo pills. the response to a placebo increased from 44% to 62% when the doctor gave them with "warmth. which is known as the nocebo effect.[6] but the authors later published a Cochrane review with similar conclusions.[32][33] [edit] Placebo effect and the brain 110 . it can cause negative effects. and confidence". Placebo effects are a scientific mystery.[29] A conditioned pain reduction can totally removed when its existence is explained.[31] Expectancy effects have been found to occur with a range of substances. Conditioning has a longer lasting effect.Placebos are widely used in medicine. suggesting that endogenous opioids are involved. attention. when it was found that the opioid antagonist naloxone could block placebo painkillers. Beecher published the "The Powerful Placebo".[5] [edit] Mechanism of the effect When an inert substance makes a patient better.[5] The article received a flurry of criticism. but if it is viewed as harmful.[3] However. In 1955 Henry K. In one study. if the substance is viewed as helpful.[30] The expectancy effect can be enhanced through factors such as the enthusiasm of the doctor. or the use of other inventions such as injections. as evidenced by a study of acunpuncture.[2] in fact.[27] and make different kinds of contribution.[25] [edit] Expectancy and conditioning Placebo exert an "expectancy" effect whereby an inert substance which is believed to be a drug has effects similar to the actual drug. that effect is called the placebo effect. and placebos have since been considered to have clinically important effects. Placebos can act similarly through classical conditioning. Those who think a treatment will work display a stronger placebo effect than those who do not.

[71] The rostral anterior cingulate cortex and its subcortical connectivity could be related to the expectation of potential pain stimuli[72][73] The higher brain works by regulating subcortical processes.Functional imaging upon placebo analgesia shows that it links to the activation.) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray[65] on spinal nociceptive reflexes. nucleus accumbens.[65] (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978[74]. amygdala. and conversely. for example.[64][65][66] and the spinal cord. the brainstem periaqueductal gray matter.[79] Glucose: the expectation of an intravenous injection of glucose increases the release of dopamine in the basal ganglia of men (but not women). the N2 peak of which is at about 230 ms. anti-analgesic nocebos responses were associated with deactivation in this part of the brain of dopamine and opioid release. and increased functional correlation between this activation. posterior parietal cortex and inferior parietal lobule).[76] Depression: Placebos reducing depression affect many of the same areas that are activated by antidepressants with the addition of the prefrontal cortex[77][78] Caffeine: placebo caffeinated coffee causes an increase in bilateral dopamine release in the thalamus. in the anterior cingulate.[75] The brain is also involved in less studied ways upon nonanalgesic placebo effects: y y y y y Parkinson¶s disease: placebo relief is associated with the release of dopamine in the brain.[69] They occur not only during placebo analgesia but after receiving the analgesic placebo (the areas are different here. The prefrontal involvement could be related to recalling the placebo and maintaining its cognitive presence in a ³selfreinforcing feedback loop´ (during pain an individual recalls having taken the placebo and reduced pain reinforces its status as an analgesic).[70] Different areas in the higher brain have different functions. prefrontal. with this effect being largest in those with no prior experience of the drug.[81] Present functional imaging upon placebo analgesia has been summarized as showing that the placebo response is ³mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. and the P2 one at about 380 ms. finds placebo effects upon the N2±P2. orbitofrontal and insular cortices. a biphasic negative±positive complex response.[80] Methylphenidate: the expectation of intravenous injection of this drug in inexperienced drug users increased the release of dopamine in the ventral cingulate gyrus and nucleus accumbens. while the expectations of anti-analgesic nocebos acts in the opposite way to block this.[67][68] These changes can act upon the brain¶s early stages of information processing: research using evoked brain potentials upon painful laser pulses. and involve the medial prefrontal cortex. Dopaminergic reward pathways 111 . High placebo responses link with enhanced dopamine and mu-opioid activity in the circuitry for reward responses and motivated behavior of the nucleus accumbens.

³somatic focus´.[117] 112 .[109] The analgesia for cutaneous heating of left hand skin was 56%. In a dental postoperative pain model. Beecher. the response rate is wide from 0% up to nearly everyone. A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice.[108] Research upon ischemic arm pain.[113] The desire for relief from pain.may underlie these expectancies´.[102] The accompanying editorial concluded."[103] Other researches have argued that open provision of placebos for treating ADHD in children can be effective in maintaining ADHD children on lower stimulant doses in the short term. "We cannot afford to dispense with any treatment that works.[114] Another factor increasing the effectiveness of placebos is the degree to which a person attends to their symptoms. neither does everyone respond to an active drug. The findings could not be replicated[112] and it now thought to have no effect.[83] [edit] Doctor-patient relationship A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year.[110] Though not everyone responds to a placebo. even if we are not certain how it does. there was considerable research to find whether there was a specific personality to those that responded to placebos. ³goal motivation´.[2] The most frequently prescribed placebos were antibiotics for viral infections.[82] And ³Diseases lacking major ³top-down´ or cortically based regulation may be less prone to placebo-related improvement´. the percentage of patients who reported relief following placebo (39%) is similar to the percentage following 4 mg (36%) and 6 mg (50%) of hidden morphine.[104] [edit] The individual [edit] Who is affected Placebos do not work upon everyone. placebo analgesia was found in 27%.[105][106] Henry K. analgesia occurred in 39%. Specialists and hospital-based physicians reported much lower rates of placebo use.[116] Those with Alzheimer¶s disease lose the capacity to be influenced by placebos.[115] Individual variation in response to analgesic placebos has been linked to regional neurochemical differences in the internal affective state of the individuals experiencing pain. in a paper in 1955[107] suggested placebo effects occurred to about 35% of people. and vitamins for fatigue. However. and how far pain is expected to be relieved increases placebo analgesia. and this is attributed to the loss of their prefrontal cortex dependent capacity to have expectations.[111] [edit] Individual differences In the 1950s. most commonly to "fend off" requests for unjustified medications or to calm a patient.

The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active. An adverse effect may be termed a "side-effect". a patient who disbelieves in a treatment may experience a worsening of symptoms. e.[119][120][121] The authors note "additional work is necessary to elucidate the generalizability of the findings". such as the patient's mentality towards his or her ability to get well. it violates the rights of that person to receive the best available treatment. and may result 113 . when judged to be secondary to a main or therapeutic effect. This effect. which is not caused by the substance. now called by analogy the "nocebo effect" (Latin nocebo = "I will harm") can be measured in the same way as the placebo effect.[185] Adverse effect In medicine.g. This is particularly likely given that new therapies seem to have greater placebo effects[citation needed]. Clinical trials control for this effect by including a group of subjects that receives a sham treatment. While placebo controlled trials might provide information about the effectiveness of a treatment. [edit] Placebo-controlled studies The placebo effect makes it more difficult to evaluate new treatments. which often leads to a nocebo effect.. The subjects in such trials are blinded as to whether they receive the treatment or a placebo. but due to other factors.[184] Knowingly giving a person a placebo when there is an effective treatment available is a bioethically complex issue. Apparent benefits of a new treatment (usually a drug but not necessarily so) may not derive from the treatment but from the placebo effect. This issue is covered by the Declaration of Helsinki. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed. when members of a control group receiving an inert substance report a worsening of symptoms. Often clinical trials are double blinded so that the researchers also do not know which subjects are receiving the active or placebo treatment. or even purely coincidental worsening of symptoms.[118] [edit] Genes In social anxiety disorder (SAD) an inherited variant of the gene for tryptophan hydroxylase 2 (enzyme that synthesizes the neurotransmitter serotonin) is linked to reduced amygdala activity and greater susceptibility to the placebo effect.Children seem to have greater response than adults to placebos. an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery. [edit] Nocebo In the opposite effect.

In clinical trials. effects from treatment that do not depend on the treatment itself. which could be due to medical error. It may also be indicated by symptoms reported by a patient. there is also a further "natural history" group that does not receive any treatment at all. 114 . The harmful outcome is usually indicated by some result such as morbidity. alteration in body weight. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. mortality. where subjects do not know whether they are receiving real or placebo treatment. a distinction is made between adverse events (AEs) and serious adverse events (SAEs). Using a drug or other medical intervention which is contraindicated may increase the risk of adverse effects. loss of function. that is. such as drug interactions. Such factors include knowing one is receiving a treatment. Placebos are most commonly used in blinded trials. They may also lead to non-compliance with a treatment regimen. foods. birth defects. including an increase or decrease in the susceptibility of the individual to other chemicals. it is not possible to know whether the treatment itself had any effect. or as a pathological change detected at the microscopic. that look like real treatments but in fact have no physical effect are used to create "blind" trials in which the participants do not know whether they are getting the active treatment or not. The purpose of the placebo group is to account for the placebo effect. Blind trials control all of these by making whatever expectations there are equal for all cases. increasing or discontinuing a treatment. permanent damage. [1] The results of these trials are often included in the labeling of the medication to provide information both for patients and the prescribing physicians. Generally. [edit] Methodology [edit] Blind trials Things like sugar pills. Adverse effects may cause a reversible or irreversible change. Adverse effects may cause medical complications of a disease or procedure and negatively affect its prognosis. Placebo-controlled studies A Placebo-controlled study is a way of testing a medical therapy in which. any event which causes death. a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Without a placebo group to compare against. attention from health care professionals. in addition to a group of subjects that receives the treatment to be evaluated. Some adverse effects only occur only when starting. or requires hospitalization is considered an SAE.from an unsuitable or incorrect dosage or procedure. so that physical effects can be measured independently of the participants' expectations. and the expectations of a treatment's effectiveness by those running the research study. levels of enzymes. macroscopic or physiological level. Often. or procedures.

[5]However. The efficacy of the entire treatment process alone: the difference between P and NH (i. It has been shown that "mock" surgery can have similar effects. the doctors are made unaware too. For example. The Placebo drug group (P): who receive a placebo drug that simulates the active drug. equally matched trial groups. The Natural history group (NH): who receive no treatment of any kind (and whose condition. is allowed to run its natural course).". 3. not only are the patients made unaware when they are receiving a placebo. and compared with each other. [edit] Natural history groups The practice of using an additional natural history group as the trial's so-called "third arm" has emerged.. is difficult. due to the difficulty involved). and thus what his or her patient believes.e.e. The efficacy of the active drug's active ingredient: the difference between A and P (i. 2. studies generally do not include an untreated group. 2. P-NH). A-NH).[citation needed] and so some surgical techniques must be studied with placebo controls (rarely double blind.. the light fittings are changed at night in the absence of the office workers (this is a real case). The efficacy of the active drug's treatment: the difference between A and NH (i. clinical trials are usually conducted in "doubleblind" manner: that is. 115 .e. it is necessary to remember the adjective µrandom¶ [in the term µrandom sample¶] should apply to the method of drawing the sample and not to the sample itself.Placebos are not the only possible technique for creating "blindness" (= unawareness of the treatment): to test the effectiveness of prayer by others. so determining the actual size of the placebo effect. A-P).. 1. The outcomes within each group are observed. David[6] wrote: ". The Active drug group (A): who receive the active test drug.. compared to totally untreated patients. the participants are not told who has and has not had prayers said for them. To test the effect of changing the frequency of fluorescent lights on headaches. allowing us to measure: 1. 3. therefore. and trials are conducted using three randomly selected. Khan published a meta-analysis of studies of investigational antidepressants and found a 30% reduction in suicide and attempted suicide in the placebo groups and a 40% reduction in the treated groups. [edit] Double-blind trials Because a doctor's belief in the value of a treatment can affect his or her behavior. Nearly all studies conducted find benefit in the placebo group..

with all other things being equal. This creates a problem in creating placebos that can be mistaken for active treatments. In 2005. in some particular way. a drug that produces physiological effects that encourage the belief in the control groups that they have received an active drug. there is controversy over what might or might not be an appropriate placebo for such therapeutic treatments. However. The magnitude of the placebo response: the difference between P and NH (i. A psychoactive placebo was used in the Marsh Chapel Experiment. devoted an issue to the issue of "The Placebo Concept in Psychotherapy" that contained a range of contributions to this question. a significant level of placebo response can also prove to be an index of how much the treatment has been directed at a wrong target. It therefore can be necessary to use a psychoactive placebo.4. which means that neither the experimenters nor the subjects know which subjects are in the "test group" and which are in the "control group". "Talking therapies" (such as hypnotherapy. and non-drug psychiatry) are now required to have scientific validation by clinical trial. counseling. a substance that produces noticeable physical effects intended to lead the control subjects to believe they had received the 116 . psychotherapy. a double-blind study in which the experimental group received the psychedelic substance psilocybin while the control group received a large dose of niacin. the placebo is not simulating the active drug in an appropriate way. the degree to which there is a considerably lower level of "placebo response" than one would expect is an index of the degree to which. P-NH). However. [edit] Indexing In certain clinical trials of particular drugs. It is a matter of interpretation whether the value of P-NH indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". In these cases. The results of these comparisons then determine whether or not a particular drug is considered efficacious.. it is reasonable to conclude that: y y the degree to which there is a considerably higher level of "placebo response" than one would expect is an index of the degree to which the drug's active ingredient is not efficacious. [edit] Placebo recognition Appropriate use of a placebo in a clinical trial often requires or at least benefits from a double-blind study design. the Journal of Clinical Psychology.e. in particular cases such as the use of Cimetidine to treat ulcers. it may happen that the level of the "placebo responses" manifested by the trial's subjects are either considerably higher or lower (in relation to the "active" drug's effects) than one would expect from other trials of similar drugs.

Controlled experiments are used to investigate the effect of a variable on a particular system.[24] Scientific control Scientific controls are a vital part of the scientific method. there were two test groups: 1. but. In this trial. Physicians achieve this with a double-blind study in a clinical trial: two (statistically) identical groups of patients are compared. [1][2] [edit] Examples of controls In testing a drug. those "[treated] by bed-rest alone" (the control group).psychoactive drug. This practice could be biased. In a controlled experiment one set of samples have been (or is believed to be) modified and the other set of samples are either expected to show no change (negative control) or expected to show a definite change (positive control).[23] Another early and until recently overlooked randomized trial was published on strophanthin in a local Finnish journal in 1946. which serves both to curb bias and to isolate the effects of the drug. one of which receives the drug and one of which receives a placebo. Recently. Neither the patients nor the doctor know which group receives the real drug. because those admitting each patient knew to which group that patient would be allocated (and so the decision to admit or not admit a specific patient might be influenced by the experimenter's knowledge of the nature of their illness. it always denotes a placebo of this type. since they can eliminate or minimize unintended influences such as researcher bias. and their knowledge of the group to which they would occupy)."[9] [edit] MRC and randomized trials It used to be thought. those "treated by streptomycin and bed-rest". when it is used. "Neither the experienced investigator nor the naive [subject] is easily fooled on the matter of whether he has received a psychedelic substance or merely a psychoactive placebo such as amphetamine.[20] that the first-ever randomized clinical trial was the trial[21] conducted by the Medical Research Council (MRC) in 1948 into the efficacy of streptomycin in the treatment of pulmonary tuberculosis. and 2. For example. environmental changes and biological variation. based on the order in which they presented for treatment. 117 . an earlier MRC trial on the antibiotic patulin on the course of common colds[22] has been suggested to have been the first randomized trial. The up-to-that-time practice was to allocate subjects alternately to each group. it is important to carefully verify that the supposed effects of the drug are produced only by the drug itself. What made this trial novel was that the subjects were randomly allocated to their test groups. The term "psychoactive placebo" is rare in the literature.

any difference in morbidity between the two groups can be ascribed to the sweetener itself--and no other factor--with much greater confidence. Perhaps the rats were simply not supplied with enough food or water. soil fertility).g. and both groups are observed in the same ways. [edit] Positive and negative control The simplest forms of controls are positive and negative controls. The negative control demonstrates the base-line result obtained when a test does not produce a measurable positive result. A positive control is a procedure that is very similar to the actual experimental test. Eliminating each of these possible explanations individually would be time-consuming and difficult. while the negative control should give very low to no activity. suppose a program that gives out free books to children in subway stations wants to measure the 118 . This mitigates the effect of different soil composition on the yield. The positive control confirms that the basic conditions of the experiment were able to produce a positive result. suppose a researcher feeds an experimental artificial sweetener to sixty laboratory rats and observes that ten of them subsequently die. an experimental control is used to prevent the effects of one variable from being drowned out by the known. often the value of the negative control is treated as a "background" value to be subtracted from the test sample results. The underlying cause of death could be the sweetener itself or something unrelated. but which is known from previous experience to give a positive result. or the rats were under some psychological or physiological stress. For example. even if none of the actual experimental samples produce a positive result. In other cases. greater effects of other variables. The positive control should give a large amount of enzyme activity. Instead. the researcher can use an experimental control.In experiments where crop yield is affected (e. or any other number of variables that may interfere with the experimental design many of which may not be readily obvious. Negative controls confirm that the procedure is not observing an unrelated effect (therefore minimizing false positives). or the water was contaminated and undrinkable. the experiment can be controlled by assigning the treatments to randomly selected plots of land. A negative control is known to give a negative result. For example. Now.[3] Positive controls confirm that the procedure is effective in observing the effect (therefore minimizing false negatives). The two groups are kept in otherwise identical conditions. [edit] Necessity of controls Controls are needed to eliminate alternate explanations of experimental results. For example. and a negative control would be where you do not add any extract. in an enzyme assay to measure the amount of an enzyme in a set of extracts. a positive control would be an assay where you add some of the purified enzyme. or be used as the "100%" value against which the test sample results are weighed. separating the rats into two groups: one group that receives the sweetener and one that does not.

these are called confounding variables. the researchers understand that many other factors probably have a much greater effect on standardized test scores than the free books: household income. In this case. for example. 119 . These p-values must be interpreted in light of the fact that they are a small and selected subset of a potentially large group of p-values. Results of post-hoc analysis should be explicitly labeled as such in reports and publications to avoid misleading readers. a statistical test is effectively performed. This greatly inflates the total number of statistical tests and necessitates the use of multiple testing procedures to compensate. Post-hoc analysis Post-hoc analysis design and analysis of experiments.In practice.effect of the program on standardized test scores. and the extent of parents' education. However.In Latin post-hoc means "after this". refers to looking at the data²after the experiment has concluded²for patterns that were not specified a priori. this is difficult to do precisely and in fact most results of post-hoc analyses are reported as they are with unadjusted p-values. More subtly. each time a pattern in the data is considered. However. It is also known as data dredging to evoke the sense that the more one looks the more likely something will be found. post-hoc analysis is usually concerned with finding patterns in subgroups of the sample. the researchers can either use a control group or use statistical techniques to control for the other variables. In scientific parlance.