M. Steven Evans, M.D. Southern Illinois University School of Medicine You must enable java to see the slides.In the United States, research on human beings is regulated by Federal law. The laws and regulations concerning human research are complex. In practice, their exact meaning is established by (1) the interpretation of Federal agencies such as the Office of Human Research Protections (OHPR) or the Food and Drug Administration (FDA), and (2) by local custom as understood by Institutional Review Boards (IRBs) in the locality where the research is being performed. The local IRB has a crucial role to play for both the subjects and the investigators in human research studies. For the subjects, the IRB helps ensure that the research they will participate in is ethical and reasonable. For the investigators, the IRB assures that his or her study complies with the Federal laws governing human research. |
Laws and regulations governing medical research were enacted only recently. Laws governing some kinds of research, such as vivisection or dissection of cadavers, date to medieval days, but laws concerning research in living human beings date only back to World War II. In the Nuremberg Trials following World War II, the evil of many of the Nazi medical experiments was obvious, but no previous code or philosophy had been developed to address the specific ethical problems encountered in medical research. During the trial of the Nazi doctors statements of principles were developed that it was thought would characterize ethical research. Foremost among these principles, and foremost among the Nazi doctors' lapses, was that research subjects be informed of the nature of the research and to give their voluntary consent. Later examples of bad medical experiments also violated this principle of informed consent. For example, the subjects in the notorious Tuskegee study in the U.S. were not informed that a cure for syphilis had become available, and that continued participation in a medical experiment studying the natural history of untreated syphilis was no longer necessary or reasonable. Some of the Nazi "medical" experiments were hideous and that their ethics was unacceptable is beyond question. Nevertheless, it is interesting that the Nazi physicians were judged by principles that were first clearly stated only after their trial had begun. Judged by these principles, some earlier experiments, such as development of Jenner's smallpox vaccine, would have been ethically unacceptable. In this experiment, Jenner vaccinated boys with cowpox and then exposed them to smallpox to see if they would become infected. They did not! And so today we remember Jenner as one of the most important scientists of history-rather than as a monstrous human being. A less dramatic and more recent example is the development of phenytoin. Phenytoin is the single most important anticonvulsant ever developed, and it is still the most commonly prescribed anticonvulsant in the U.S. After animal experimentation showing that phenytoin was efficacious against maximal electroshock seizures, Merritt and Putnam used it in humans in 1938. It worked! And it was relatively low in side effects--which is fortunate, since it did not receive the preclinical trials that are now thought to be mandatory--with respect to discovery of deadly side effects, the initial patients were the "guinea pigs". |
Nuremberg Code. The Nuremberg Military Tribunal in 1947 developed the Nuremberg Code as a standard by which to judge Nazi medical experiments. This code emphasizes the importance of ten principles that became a part of later standards, including: voluntary consent, capacity to consent, freedom from coercion, comprehension of risks and benefits, minimization of risk and harm, performance of research by qualified investigators using appropriate study designs, and freedom of the subjects to withdraw from the research. Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. Similar recommendations were made by the World Medical Association in this guide first promulgated in 1964. This guide made an additional distinction between therapeutic and non-therapeutic research. Worldwide, this document (most recently revised in South Africa, 1996) is the most commonly referenced ethical standard for human research. In the United States, a separate but very similar ethical standard has been developed and enacted as law. NIH Policies for the Protection of Human Subjects. This was first published in 1966. These policies were given regulatory status in 1974, in part due to public outcry about the notorious Tuskegee medical experiments. These experiments were a many-year study of the natural history of syphilis in untreated black men infected with the disease. Although the experiment may not have been unethical at its start in 1932, its continuation after the development of penicillin was a grievous error. The study was finally ended in 1972. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research. In 1974, the National Research Act was passed, which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. A number of recommendations were produced. The commission's final report, the Belmont Report, was published in 1979. The Belmont Report is the primary "philosophical" basis for current Federal regulations concerning human research, and for Institutional Review Boards established under these regulations. |
The Belmont Report describes three fundamental principles for the ethical conduct of research in human subjects:
The Declaration of Helsinki outlines similar concerns, but also takes pains to clearly distinguish between different types of clinical research. Research that may have therapeutic benefit for the individual subject is distinguished from research that is "purely scientific", and no individual benefit is expected. |
Since much human research is medical research, the Belmont Report distinguishes between medical practice and medical research. The purpose of medical practice is to "provide a diagnosis, preventative treatment or therapy to particular individuals." Unlike medical practice, medical research is "an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge . . . [and it is] usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective." It is the purpose of the activity, not the tools that are used, that determine whether an activity is "research." An "experimental" (in the sense of unapproved or untested) drug or device may be used in order to help a patient. This is not research. In contrast, if part of the purpose is to gather information about safety or efficacy of the drug or device, the activity is research. From The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. In OPRR Reports, April 18, 1979. |
The Belmont Report describes three fundamental principles for the ethical conduct of research in human subjects. The first two principles deal with the ethics of the research as it applies to individual subjects, and the third as it applies to societies as a whole. Respect for persons. The personal dignity and autonomy of individuals should be recognized, and there should be special protections for those with diminished autonomy. This principle is the ethical basis of informed consent. Consent must be voluntary, not coerced in any way, and explicit procedures covering withdrawal of consent should be present. Respect for persons requires "that subjects . . . choose what shall or shall not happen to them." Proper informed consent requires three elements: information, comprehension, and voluntariness. These elements are codified in Federal Policy. Beneficence. There is an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks. The principle of beneficence implies that the patient should have at least the potential to experience a benefit from participating in the study. The potential risks of the study should be minimized, and should be small enough that a "reasonable person" would participate in the study. Justice. The benefits and burdens of research should be distributed equally. Subjects should be fairly selected. This principle concerns the effect of the study on society as a whole. Research is an activity that may have either benefits or burdens, and for one societal group to receive most of either is considered to be against this principle. |
Federal Policy concerning research done under the auspices of the National Institutes of Health, Public Health Service, Department of Health and Human Services, and 13 other Federal Agencies are given in the Code of Federal Regulations 45 CFR 46. Much human research is done without the support of the Federal government, but is intended to be used to support an application to the Food and Drug Administration (FDA). Regulations concerning human research to be submitted to the FDA are covered in 21 CFR 50, 56 and others. Although there are minor wording differences, both FDA and Federal guidelines require local Institutional Review Boards and are identical in the functions and responsibilities assigned to them. |
Most investigators are unfamiliar with the Federal Policy on research in human subjects, but they become very familiar with the Institutional Review Board that oversees their research. An Institutional Review Board (IRB) is a "group that has been formally designated to review and monitor biomedical research involving human subjects . . . .[An] IRB has the authority to approve, require modifications in (to secure approval), or disapprove research." The major function of an IRB "is to review research to assure the protection of the rights and welfare of the human subjects." The purposes, composition, and responsibilities of IRBs are mandated by Federal law. IRB review is required for human studies "conducted, supported or otherwise subject to regulation by any Federal Department or Agency . . . ." An IRB has jurisdiction over research involving human subjects. Research is defined by regulations as "a systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge." Human subjects include "living individual(s) about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information." Some research on human subjects is exempt from Federal regulations. One example is the use of existing data, documents, or specimens, where no identifying information will be recorded that could link subjects to the data. Any institution that receives Federal support for research is required to file an "Assurance" with the Office of Human Research Protections (OHRP), an office in Department of Health and Human Services (DHHS) concerned with implementing regulations on behalf of the Secretary of DHHS. The Assurance certifies that the institution will protect the welfare of human subjects and abide by the ethical principles codified in the Federal Policy. Most institutions, including Southern Illinois University School of Medicine (SIU-SM), Memorial Medical Center, and St. John's Hospital, cite the Belmont Report as the set of principles by which they will abide. The Assurance applies to all research conducted at the institution, whether or not the particular research project is supported by a Federal department or agency. In order to fully comply with their assurances, some institutions may enlarge the jurisdiction of their IRBs to include research that would be exempt under Federal guidelines. The FDA regulations are slightly different from the Federal Policy, and compliance with them is monitored by a system of audits and on-site inspections rather than by submission of a formal assurance. Although an IRB is established (and funded) by a particular local institution, the institution does not control the decision-making of the IRB. Research that has been approved by an IRB may be subject to further institutional review, and possible disapproval, but research that has not been approved by the IRB cannot be approved by the institution. In general, institutions are very concerned that their IRB function correctly and follow Federal Policy, since the IRB is subject to audit by the OHRP and the FDA. Violations found by OHRP may result in suspension or withdrawal of the institution's Federal Assurance, and make the institution ineligible to receive Federal funds. Violations found by the FDA may result in specific sanctions or administrative actions. In the Springfield, Illinois area there are two IRBs to choose from: the Springfield Committee for Research in Human Subjects (SCRIHS), and Triad. SCRIHS was jointly established by the SIU School of Medicine, Memorial Medical Center, and St. John's Hospital, and intended primarily to review research conducted at one of the participating institutions. Triad is a privately-financed IRB. |
An IRB has authority to "approve," "require modifications in (for approval)," or "disapprove" studies that are within its jurisdiction. Even if a study is "disapproved," an IRB does not have the authority to prevent the investigator from doing the research. However, our institutions are bound to assure that all research is performed in compliance with DHHS ethical guidelines, and industry sponsors are obliged to ensure that their research meets equally stringent FDA guidelines. Both sets of guidelines require IRB review. Because of these requirements, institutions and sponsors invariably require IRB approval before an investigator is allowed to begin research using human subjects. The investigator may be able to choose the particular IRB that reviews his or her study, but there are often restrictions. In the Springfield, Illinois area there are two IRBs to choose from, and certain investigators may even be able to use a national IRB. However, for SIU School of Medicine investigators, or for investigators in the Springfield area performing Federally-sponsored research, there is no alternative--prior to beginning the study, all non-exempt human research must be "approved" by SCRIHS. |
An IRB is primarily concerned with the welfare of human subjects of research, not with the research per se. The particular IRB I am most familiar with is SCRIHS. This committee has members with expertise in medicine, law, behavioral medicine, and includes members of the community with expertise in still other areas. Each new protocol is assigned a primary and secondary reviewer, who review their protocols closely. These two reviewers also receive a copy of the investigator's manual, if one is available. The members examine each application carefully to determine whether the study procedures appear safe and reasonable. The members make an assessment of risk and benefit for participating in the study, with the purpose of determining whether a "reasonable person" would participate in the study. In order to make this assessment, the protocol and investigator's manual should carefully describe what is known about the test article. If a drug is being tested, the protocol and investigator's manual should describe previous animal studies and their results, as well as previous human studies and the known effects and side effects of the drug in animals and humans. Research studies reviewed by an IRB are scientific studies. Some IRB members, but not the majority, have scientific expertise. Nevertheless, "scientific merit" is a concern of the committee. The purpose of scientific research is to contribute to "generalizable knowledge," and to do so the research should be designed in such a way that its results will be reliable and valid. If the research proposal uses the scientific method so poorly that it cannot answer the questions it proposes, it will not contribute to generalizable knowledge. This is poor science, and poor science, when done on human beings, is not ethical. Some studies reviewed by an IRB are problematical. If the committee's concern is about scientific merit, the committee may table the protocol and ask for a review by an expert in the field, ask the principal investigator for clarification, or ask the principal investigator to rewrite or amend the protocol. The SCRIHS office is part of the SIU Office of the Associate Dean for Research and Faculty Affairs, and the committee may direct a protocol to the Dean who will convene an ad hoc committee of scientific reviewers. Good scientific research uses the scientific method. Good research contains a clearly stated hypothesis and a clearly stated means for gathering information regarding the hypothesis (i.e., experimental design and methods). A number of different kinds of studies may be valid and ethical--everything from purely descriptive or epidemiological studies, to large multicenter randomized double-blind placebo-controlled clinical trials. No matter what the study design, it should be able to answer the questions it poses. Common scientific mistakes include: 1) not clearly stating an hypothesis; 2) stating an hypothesis that is poorly justified by previous studies or by accepted medical or scientific theory; 3) describing study methods, but not giving a study design; 4) designing a study that cannot test the hypothesis; or 5) testing too few patients or testing too many (a statistical method called power analysis should usually be done to determine the number of subjects that are likely to be needed). Please note that good experimental design can still be an ethical mistake, such as having an untreated placebo group when an efficacious and accepted therapy is available. |
All ethical guidelines emphasize the importance of informed consent. In the Belmont Report, which is the ethical basis for IRBs, informed consent is the main component of the principle of "respect for persons." This respect requires "that subjects . . . choose what shall or shall not happen to them." Proper informed consent requires three elements: information, comprehension, and voluntariness. These elements are codified in Federal Policy. It is routine that study subjects read and sign a written informed consent document, but there is no "national standard" informed consent document. An informed consent must address all the essential elements, but its exact form is dictated by the local IRB. SCRIHS insists on a standard informed consent format whose design ensures that the essential elements for informed consent are routinely presented. The standard SCRIHS informed consent headings are taken directly from the language in Federal Policy, and are reproduced on the face page of the standard SCRIHS form. Each one of these headings covers an essential component of informed consent, so every consent form must have an entry under every standard heading. This method has the advantage of "covering all the bases," but it has the disadvantage of not expressing precisely the SCRIHS interpretation of this language. It is the responsibility of the principal investigator to write a good informed consent document. Some IRBs, such as SCRIHS, have staff who can be of great help in preparing the document properly. They cannot write the document for you, but they can be of great help in making sure your document covers the necessary elements required by the IRB. |
To a certain extent, the interests of the subjects in a study are opposed to those of the investigator. Subjects generally participate in a study because they hope to receive some benefit. Investigators realize this and are tempted to overemphasize potential benefits and minimize potential risks in order to better recruit patients for their studies. In a placebo-controlled trial, there is no benefit to the patient to be expected from the placebo, so there is a temptation for the investigator to not carefully explain what a "placebo" is or the likelihood that the patient will receive one. This is ethically unacceptable. There are many other possible ethical problems. For example: What if the patient is injured by the study? Who "owns" tissues or genetic material obtained from the patient during the study? How will the subjects medical records be kept secure? The IRB will try to ensure that the subjects of the study are informed of the answers to these and any other questions that a reasonable person would want to know before participating in the study. |
IRBs tend to deal with the same problems over and over again. This is my personal list of the top ten repeated problems, developed from experience as committee member and chairman of an IRB in Springfield, Illinois (the Springfield Committee for Research in Human Subjects). These are issues that the IRB is likely to pay close attention to, but most problems can be avoided if the investigators carefully study their protocol and write an informed consent document in the form required by the IRB. For example, failure to cover research-related injury. Some people consider this a moral failure, but it is allowed under government regulation as long as the fact is clearly disclosed to the subjects. If the informed consent document does not make it clear that injury caused by the study will not be covered by the study sponsors, the IRB will insist that the document be revised. Other problems may require protocol modification. For example, a scientifically poor study that cannot, even if completed according to protocol, answer the question it asks, should not be done. |
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Q: The IRB is a pain--do I really have to get approval? A: Yes, if you are planning to do non-exempt research in human subjects. Are you doing research? If your answer is "no" you do not need IRB approval. IRBs do not regulate medical practice, even medical practice using "experimental" or "unapproved" treatments. If the intent of the practitioner is to help an individual patient with an experimental treatment, and there is no intent to collect data to "contribute to generalizable knowledge" (for example, for publication or to demonstrate safety and efficacy to a third party), then the activity is not research. Will your research use human subjects? If your research uses data obtained by interacting with human beings, or by collecting data or specimens from human beings, you are using "human subjects," according to Federal regulations. Is your research "exempt" from IRB review? "Exempt" research is defined in detail in 45 CRF 46(b). Research may be exempt in several circumstances, for example, "collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available, or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects." It is not possible to give a succinct account of research that may be "exempt"--you must refer to the detailed regulations. Q: Ok, so I need IRB approval--but do I have to wait for a committee meeting?A: Usually yes, but you may not have to if your research can be "expedited." Expedited review is done by a SCRIHS subcommittee of two members and the chairman. It does not require a meeting. If approval is recommended by the subcommittee, the chairman can sign off on your protocol indicating approval. The full committee must be formally notified of studies approved by expedited review, which is accomplished by listing these studies in the committee's minutes. A protocol can be formally "disapproved" only by the full review process, not by the expedited review process. Protocols can be expedited for "certain kinds of research involving no more than minimal risk, and for minor changes in approved research." Again, the list of kinds of research that can be expedited is long, but very specific, and few studies qualify. Examples include research done using voice recordings or "collection of hair and nail clippings in a non-disfiguring manner". Research protocols involving children are not eligible for expedited review. Q: Do I need IRB approval just to give my patient a medicine for "compassionate use"?!A: Yes. "Compassionate use" studies are research, and must be submitted for IRB review. In these studies the design is usually simple, but it undergoes full board review, and requires a formal informed consent. Q: But this is an emergency! Do I have to wait for the IRB?!A: Maybe not. "Emergency" use is the use of a test article (e.g., drug) on a human subject in a life-threatening situation in which no standard treatment is available, and in which there is insufficient time to obtain IRB approval for the use. The FDA exempts a single emergency use from IRB review as long as the occurrence is reported to the IRB within five working days. When the IRB receives a report of emergency use, it is obliged to investigate the case carefully and ensure that emergency use was indeed justified. The use will not be justified if the problem is less than life-threatening or if a standard treatment was available. An investigator's belief that an experimental article is better than standard treatment is not sufficient to justify emergency use. Emergency use requires informed consent, except in certain very specific circumstances defined by regulation. There is a new category of research called "emergency research" applying to particular research situations in which it is not possible to obtain effective informed consent. The regulations are meant to begin to allow research in conditions under which obtaining informed consent may be impossible, such as in the acute treatment of severe head trauma. The regulations concerning emergency research are specific and complex. It would be best to contact the IRB office before designing or accepting such a study. Q: What groups have "diminished autonomy"?A: Prisoners, children and the mentally retarded. The term applies to certain special groups of subjects considered especially vulnerable, and perhaps less likely to be able to clearly give an informed consent or informed refusal. Groups meant by the term are: prisoners, children, and the mentally retarded. |