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Protection of Human Subjects in Biomedical Research


Statement of

Mary K. Pendergast
Deputy Commissioner
Senior Advisor to the Commissioner
Food and Drug Administration
Department of Health and Human Services

before

the Subcommittee on Human Resources
House Committee on Government Reform and Oversight

May 8, 1997

INTRODUCTION

Mr. Chairman and Members of the Subcommittee, good morning. I am Mary K. Pendergast, Deputy Commissioner and Senior Advisor to the Commissioner of Food and Drugs, U.S. Food and Drug Administration (FDA). I am pleased to be here today to discuss the Agency's policies with respect to the protection of human subjects in biomedical research. I will discuss the basic structure for human subject protection in the United States, the interconnection between FDA and Department of Health and Human Services (DHHS) regulations, and emerging issues in informed consent, including our exception to the informed consent requirements for those patient populations who are in need of immediate medical intervention but who are unable to give consent because of their medical condition. But first I will set out the protections the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the FDA's regulations afforded to research subjects, and the Agency's mechanisms to monitor and enforce those protections through Institutional Review Boards (IRBs), our Bioresearch Monitoring program, and educational efforts.

FDA'S STATUTORY AND REGULATORY BASIS FOR INFORMED CONSENT

The FD&C Act and its implementing regulations are one part of a complex system of safeguards that has been designed to promote the highest ethical principles described in the post-World War II Nuremberg Code, the World Medical Association's Declaration of Helsinki, professional codes of ethics, and the reports and recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

In the system of safeguards that has evolved over the years, there are multiple levels of protection provided to research subjects. Each participant in a research effort -- the company that sponsors the research, the physician who conducts the research, and the IRB -- is obliged to protect the interests of the people who are taking part in the experiments. The FDA's responsibility is to see that the safeguards are met.

Responsibilities of the Research Sponsor

The sponsors of research -- usually, manufacturers or academic bodies, but sometimes individual physicians -- must select well-qualified clinical investigators, design scientifically-sound protocols, make sure that the research is properly conducted, and make certain that the clinical investigators conduct the research in compliance with informed consent and IRB regulations. The sponsor also has the obligation to make certain that any IRB reviewing one of its studies comports with FDA's IRB regulations. Sponsor obligations are set forth in the FDA's regulations that govern the design and conduct of clinical trials, and the requirements for submission of applications to conduct clinical research (21 CFR Parts 312, 314, 601, 812, 814).

Responsibilities of the Researcher

The primary regulatory obligations of the clinical investigator are to: 1) follow the approved protocol or research plan; 2) obtain informed consent and ensure that the study is reviewed and approved by an IRB that is constituted and functioning according to FDA requirements; 3) maintain adequate and accurate records of study observations (including adverse reactions); and, 4) administer test articles only to subjects under the control of the investigator.

The essential core of FDA's informed consent regulations, 21 CFR Part 50, is that the clinical investigator must obtain the informed consent of a human subject or his/her legally authorized representative before any FDA-regulated research can be conducted. The researcher has to make sure that, whenever possible, the study participants fully understand the potential risks and benefits of the experiment before the experiment begins. The information provided must be in a language understandable to the subject, and should not require the subject to waive any legal rights or release those conducting the study from liability for negligence. Specifically, the clinical investigator must give the following information to research subjects in seeking their informed consent to participate in research:

  • A statement that the study involves research, an explanation of the purposes of the research, the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
  • A description of any reasonably foreseeable risks or discomforts to the subject;
  • A description of any benefits to the subject or to others which may reasonably be expected from the research;
  • A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;
  • A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that FDA may inspect the records;
  • For research involving more than minimal risk, an explanation as to whether any compensation and any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained1;
  • An explanation of whom to contact for answers to pertinent questions about research and research subject's rights, and whom to contact in the event of a research-related injury to the subject; and,
  • A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (21 CFR 50.25(a))

Depending on the nature of the research, other "additional" elements are required if they are appropriate to the research. These additional elements of informed consent include information about the anticipated circumstances under which the investigator may terminate the subject's participation, any additional costs to the subject that may result from participating in the research, the consequences of a subject's decision to withdraw from the study, a statement that the research may involve risks that are currently unforeseeable, a statement that significant new findings will be provided to the subject, and the approximate number of subjects in the study. (21 CFR 50.25(b))

In short, the clinical investigator must tell the human subjects important information about the study and its potential consequences, so that the person can decide whether to be in the experiment. The entire informed consent process involves giving the subject all the information concerning the study that he or she would reasonably want to know; ensuring that the subject has comprehended this information; and finally, obtaining the subject's consent to participate. The process, to be meaningful, should involve an opportunity for both parties, the investigator and the subject, to exchange information and ask questions. It is up to the clinical researcher to make certain that, as best as possible, the person understands the information. To acknowledge that the person has received the information and has consented to the research, FDA also requires the clinical investigator to document in writing that consent was obtained. We recognize that the documentation of informed consent represents only one part of the entire consent process. The consent form itself is an aid to help ensure that a required minimum amount of information is provided to the subject and that the subject consents.

Responsibilities of Institutional Review Boards

An IRB is a group formally designated to review, approve the initiation of, and periodically review the progress of, biomedical research involving human subjects. The primary function of IRBs is to protect the rights and welfare of the people who are in clinical trials.

FDA's regulations, 21 CFR Part 56, contain the general standards for the composition, operation, and responsibility of an IRB that reviews clinical investigations submitted to FDA under sections 505(i), 507(d), and 520(g) of the FD&C Act. IRBs must scrutinize and approve each of the more than 3,000 clinical trials that are conducted on FDA-regulated products in this country each year. IRBs must develop and follow procedures for their initial and continuing review of the integrity of each trial. Among other requirements, IRBs must make sure that the risks to subjects are minimized and do not outweigh the anticipated study benefits, that the selection of participants is equitable, that there are adequate plans to monitor data gathered in the trial and provisions to protect the privacy of subjects and the confidentiality of data. The IRB has the authority to approve, modify, or disapprove a clinical trial. If an IRB decides to disapprove a research activity, it must notify, in writing, the investigator of its decision, state its reasons for the decision, and give the researcher an opportunity to respond in person or in writing. The IRB must approve the informed consent form that will be used. If it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context, the IRB may waive the requirement that informed consent be documented. Where the documentation requirement is waived, however, the IRB may require the investigator to provide the research subjects with a written statement regarding the research. If the researchers fail to adhere to IRB requirements, the IRB has the authority and the responsibility to take appropriate steps, which may include termination of the trial.

An IRB must consist of at least five members with varying backgrounds to promote review of the covered research activities by persons of diverse disciplines. The IRB must have persons qualified in terms of professional experience and expertise. Considerations should be given to cultural, racial, and gender diversity, and sensitivity to such issues as community attitudes. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or physically or mentally disabled persons, the IRB must consider including one or more members primarily concerned with the welfare of those subjects. The IRB must include at least one member whose primary concerns are in scientific areas, one member whose primary concerns are in non-scientific areas, and one member who is not otherwise affiliated with the institution (one person may fulfill multiple roles). No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB.

The IRB is required to conduct continuing review of ongoing research at intervals appropriate to the degree of risk, but not less than once per year. It also has the authority to observe or have a third party observe the consent process and the research. IRBs are not required to register with FDA nor inform FDA when they begin reviewing studies.

HUMAN SUBJECT PROTECTION ACTIVITIES

FDA, which monitors the activities of research sponsors, researchers, IRBs and others involved in the trial, provides an additional layer of protection. We take no human right more seriously than the protection of people enrolled in clinical trials.

FDA's Bioresearch Monitoring Program

In order to protect the rights and welfare of human research subjects and to verify the quality and integrity of data submitted to FDA in support of marketing applications, FDA monitors all aspects of FDA-regulated research through a comprehensive program of on-site inspections and data audits. FDA uses a combination of surveillance, enforcement, and education to achieve regulatory compliance. Under the Agency's Bioresearch Monitoring Program (BIMO), FDA field investigators and headquarters' scientists conduct site visits of research sponsors, clinical investigators, contract research organizations, IRBs, radioactive drug research committees, and non-clinical (animal) laboratories. In Fiscal Year 1996, FDA conducted approximately 1,070 inspections under the program.2

The BIMO program is implemented through several compliance programs: 1) Good Laboratory Practice (GLP) Program (Non-clinical Laboratory); 2) Clinical Investigator Program; 3) Institutional Review Board Program; 4) Sponsor, Contract Research Organization, and Monitoring Program; 5) In Vivo Bioequivalence Program; and, 6) Radioactive Drug Research Committee (RDRC) Program. The Clinical Investigator Program and the IRB Program are the primary programs for ensuring compliance with the informed consent requirements for human subjects in clinical trials.

FDA's Inspections of Clinical Investigators

Under the Clinical Investigator Program, FDA conducts study-specific inspections and audits of physicians and other investigators conducting clinical trials of FDA-regulated products. In Fiscal Year 1996 FDA conducted approximately 700 clinical investigator inspections.

FDA carries out two principal types of clinical investigator inspections: 1) study-oriented inspections; and 2) investigator-oriented inspections. Study-oriented inspections are conducted on studies that are important to product marketing applications, such as new drug applications (NDAs), product license applications (PLAs) for biological products, and premarket approval applications (PMAs) for medical devices, that are pending before the Agency.

The Agency routinely inspects and audits the pivotal studies upon which the Agency intends to base marketing approval of a new product. In these inspections and audits, FDA examines study records and findings, giving particular attention to protocol adherence and data integrity. We also look for documentation of informed consent and IRB review, approval, and continuing review of ongoing studies.

An investigator-oriented inspection may be initiated as a result of complaints received from subjects about alleged human subject protection violations or when a study sponsor or FDA staff raise concerns about an investigator. If a clinical investigator fails in his or her obligations, FDA can reject the study, disqualify the clinical investigator from doing additional studies, impose certain restrictions on carrying out future clinical investigations, and in cases of fraud, pursue criminal prosecution. The names of clinical investigators who are disqualified or restricted are publicly available and can be accessed through FDA's home page on the World Wide Web. From 1993 through 1996, FDA disqualified four clinical investigators and imposed restrictions on the investigational drug use of six other clinical investigators.

FDA's Inspections of IRBs

The primary focus of FDA's IRB Program is the protection of the rights and welfare of research subjects, rather than validating the data obtained from research. FDA performs on-site inspections of IRBs that review research involving products that FDA regulates, including IRBs in academic institutions and hospitals as well as those independent from where the research will be conducted. All IRBs regardless of location or affiliation are required to conform to the same regulations and are inspected in accordance with the same compliance program. The inspectional data show that there are similar findings between types of IRBs. It has been demonstrated, however, that IRBs being reinspected are more often found to be in compliance than those being inspected for the first time.

The frequency of the inspections depends on the performance of the IRB and the number of clinical studies it is monitoring. FDA's approach to these inspections traditionally has emphasized obtaining compliance through education, explanation of requirements, and cooperation but the potential for regulatory or administrative sanctions also is important.

The Agency has a very high standard for the quality of consent forms and applies this stringent standard during its inspections. We look to see whether the consent form includes all the information required by our regulations and whether there are areas in which the consent form could be improved, in our judgment. (We recognize that even a consent form that we find adequate, if submitted to other groups of persons, could be modified to "improve" it further -- so to at least some degree, the review of the adequacy of a consent form is subjective.) One of the reasons why we assign the review of consent documents to IRBs is because the IRB knows the most about its potential subject population and is best able to tailor the consent document to meet the information needs of that subject population.

The most common deficiencies that we find are: 1) lack of clarity about the person to contact if there are questions concerning the research and the research subject's rights in the event of a research related injury; 2) inadequate description of the research procedures to be followed; 3) inadequate description of available compensation if the subject sustains injury as a result of the research; 4) inadequate confidentiality statement; and, 5) inadequate description of alternative procedures that are available to subjects should they choose not to participate in the research.3 A deficiency in the informed consent document does not necessarily mean that the informed consent process was inadequate. It is the interactive information exchange that is most important to the informed consent process. FDA focuses on the consent form during our inspections because it is the best evidence that we have of the basic information that was exchanged during that process.

FDA can impose administrative sanctions when necessary to protect human subjects of research and in cases of significant non-compliance. Significant non-compliance may include inadequate review of studies, inadequate record-keeping practices that are so deficient that IRB review and approval cannot be verified, or not obtaining adequate informed consent from research subjects. FDA's sanctions include withholding approval of new studies that would be conducted at the institution or reviewed by the IRB, or directing that no new subjects be added to ongoing studies until corrections are made. In the most extreme cases of non-compliance, an IRB may be disqualified from serving as an IRB. Since 1993, approximately 59 warning letters have been issued and several consent agreements have been signed. To date, no IRBs have been formally disqualified by FDA, although several have ceased operations following FDA inspections. FDA also may ask the Department of Justice to initiate appropriate civil or criminal proceedings.

The following is an example of an administrative action FDA has taken with respect to an IRB for noncompliance with the Agency's IRB regulations.

In early 1994, FDA sent a warning letter to a major university, citing failure of the university and its IRB to protect adequately the rights and welfare of subjects in research. In this letter the Agency notified the IRB that it was no longer authorized to approve new studies, [under 21 CFR 56.120(b)(1)], and directed that no new patients be added to ongoing studies, [under 21 CFR 56.120(b)(2)].

The university was instructed to: (1) ensure that the IRB receives and acts on all reports of unexpected adverse events in order to protect adequately the rights and welfare of all research subjects; (2) ensure that the IRB and the principal investigators are informed of their mutual responsibilities for initial and continuing review of IND studies, especially the timely submission and review of all progress reports; and (3) ensure that the informed consent documents meet FDA requirements and that the clinical investigator only uses informed consent documents approved by the IRB.

In March 1994, FDA lifted its restrictions against the University after it agreed to correct the problems the Agency had found and documented the plan to accomplish this objective. At that time, FDA gave the university approval to again approve studies and add new patients to ongoing studies.

FDA's Review of Research Conducted Outside of the United States

FDA's protections extend beyond our national borders. All drug, biologic, and medical device studies conducted under an investigational new drug application (IND) or an investigational device application (IDE) are governed by FDA informed consent and IRB requirements. Regardless of the location of the research, our standard is the same.

In general, FDA also accepts foreign safety and efficacy studies that were not conducted under an IND or IDE provided that they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. We recognize that standards for protection of human subjects vary from country to country. If FDA, however, is to accept the data, the conduct of these studies must meet at least minimum standards for assuring human subject protection. Therefore, for studies submitted to FDA which were conducted outside the United States (and not under an IND or IDE), the Agency requires demonstration that such studies conformed with the ethical principles outlined in the Declaration of Helsinki or with the laws and regulations of the country in which the research is conducted, whichever provides greater protection of the human subjects.

Thus, as is evident from the foregoing discussion, there are many different entities which must be involved in the protection of human subjects. FDA works hard to make certain that all of the entities understand their roles and responsibilities and that they live up to the expectations placed on them. The protection of the people of this country who are willing to participate in medical research demands no less.

FDA's Educational Efforts

On our own and in cooperation with other professional and governmental organizations, we strive to inform those conducting and overseeing clinical research of how to meet their responsibilities and why their doing so effectively is important to protecting the rights and welfare of the human subjects who rely on them.

FDA has developed a set of over two dozen information sheets for IRBs and clinical investigators which address human subject protection issues -- including informed consent -- where questions or problems have arisen over the years. Each information sheet package includes the Belmont Report and the Declaration of Helsinki, important historical documents dealing with informed consent which might not be readily available to users, the FDA informed consent and IRB regulations, and a self-evaluation checklist for IRBs, cross-referenced to the regulations. FDA distributes the information sheets at professional conferences and meetings, through an automated facsimile system, and on FDA's home page on the World Wide Web. More than 6,000 copies have been sent directly to IRBs and to individuals who have requested them.

FDA staff frequently handle calls from IRB staff and members, clinical investigators, regulated industry representatives, and staff of other regulatory agencies on specific problem areas and to give explanations of particular points in the regulations. When these contacts raise general issues, they are included in new information sheets. FDA also disseminates its educational message through articles and regular columns in professional journals. FDA's publications, including the Medical Bulletin (distributed to health professionals nationwide) and FDA Consumer, also include educational articles on human subject protection issues.

Professional conferences are an important arena for FDA's educational efforts. FDA recently held a one day national conference on human subject protection that was attended by over 500 people affiliated with IRBs, clinical research studies, and other Federal agencies. Additionally, FDA looks for opportunities to magnify the reach and effectiveness of its educational efforts by working with other organizations. For many years, FDA has cooperated with NIH's Office of Protection from Research Risks in a series of several educational conferences annually. The conferences are cosponsored by universities, medical schools, or other nonprofit institutions and are held in different parts of the country. A longstanding collaboration similarly exists with the premier professional organizations in the IRB field -- Public Responsibility in Medicine and Research and the Applied Research Ethics National Association. On a less regular basis, human subject protection education efforts are made at meetings of other health professional groups and at meetings sponsored by non-profit organizations where sponsors make up a large proportion of the audience.

In addition to their inherent value in focusing attention on the importance of informed consent, FDA's educational efforts support our enforcement and product approval missions. Educated researchers who devote appropriate attention to informed consent and other human subject protections are likely to conduct studies of high quality in other respects as well. Such studies are easier for FDA to review and audit, and approvals can be issued more rapidly. The ultimate beneficiary is the American public, both those who participate as subjects in research and those who are treated with the products approved on the basis of that research.

Interaction Between FDA and Departmental Regulations

Both FDA and the Department of Health and Human Services (HHS) have regulations pertaining to the protection of human subjects (21 Code of Federal Regulation (CFR) Parts 50 and 56 for FDA; 45 CFR Part 46 for HHS). The HHS regulations apply to research that is conducted or supported by HHS4; FDA's regulations apply to human subject research involving products regulated by FDA, whether privately or publicly funded. These FDA-regulated products include, for example, investigational drugs, biologics, and medical devices. The FDA and HHS regulations are essentially identical, with differences only where required to reflect the distinct statutory mandate of the organizations and the focus of FDA regulations.

The two agencies apply the regulations in ways fitting their distinct missions. NIH implements the HHS regulations through assurances made by the institutions where the research is conducted. FDA regulates the investigators who conduct the research and the IRBs which review proposed research studies.

If a research project is conducted or supported by HHS and involves a product regulated by FDA, both sets of regulations will apply. In addition, most large research institutions receiving grant and contract support from HHS have agreed to review all research involving human subjects conducted at the institution in accordance with the HHS regulations regardless of the source of the funding for any particular study. The two sets of regulations are complementary and together they set forth criteria that are needed to protect research subjects.

FDA regulates clinical research of investigational drugs, biologics, antibiotics and medical devices under sections 505(i), 507(d) and 520(g) of the FD&C Act. FDA first imposed informed consent requirements on January 8, 1963, pursuant to the 1962 amendments to the FD&C Act, which required that informed consent be obtained in most, but not all, research involving drugs. Later, in 1976, Congress imposed, through the Medical Device Amendments, an informed consent requirement for research involving medical devices, which was similar, but not identical, to the informed consent requirement for drugs. In 1981, FDA promulgated comprehensive informed consent regulations which applied the most recent statutory requirements to all FDA regulated research (21 CFR Part 50).

In 1981, FDA and HHS simultaneously promulgated new regulations establishing standards governing the composition, operation, and responsibilities of Institutional Review Boards (21 CFR Part 56, for FDA and 45 CFR Part 46, for HHS). These regulations established a common framework for the operations of IRBs that review research funded by HHS and research conducted under FDA regulatory requirements. In 1991, the "common rule" (modeled after the core provisions of the HHS regulations) was adopted by HHS, FDA and 14 other Federal departments and agencies that conducted, supported or regulated research involving human subjects. FDA modified its regulations to conform to the common rule to the extent permitted by its statutes. Last year, FDA published a draft guideline -- "Good Clinical Practice: Consolidated Guideline" under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance, while not a regulation, defines what is good clinical practice and provides a unified international standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.

LIMITED EXCEPTIONS TO THE INFORMED CONSENT REQUIREMENTS

Having discussed the system for human subject protection, it is important to recognize that there are limited circumstances when informed consent is not obtained from a human subject or his or her representative. There are three "exceptions" to FDA's informed consent requirements. These exceptions are: 1) for a physician to preserve the life of an individual patient; 2) for the conduct of a narrow class of research in emergency settings; and 3) for use by the Department of Defense (DoD) of specific investigational products in combat exigencies.

The FD&C Act specifically requires that investigators inform subjects receiving drugs under an IND that the drugs (and biologics) are investigational and "obtain the consent of such human beings or their representatives, except where they deem it not feasible, or in their professional judgement, contrary to the best interests of such human beings" (Section 505 and 520). The Medical Device Amendments of 1976 provided that the sponsor of clinical investigations must "assure that informed consent will be obtained from each human subject (or his representative). . . except where subject to such conditions as the Secretary may prescribe, the investigator conducting or supervising the proposed clinical testing of the device determines in writing that there exists a life-threatening situation involving the human subject. . . which necessitates the use of such device and it is not feasible to obtain informed consent from the subject and there is not sufficient time to obtain informed consent from the subject and there is not sufficient time to obtain such consent from his representative" (Section 520(g)(3)(D)). The three exceptions to the informed consent requirements that FDA has promulgated into regulation meet the standards described in those two statutory sections.

Preserving the Life of the Patient

According to the first exception (21 CFR 50.23 (a) and (b)) which has been in effect since 1981, informed consent of the subject or his/her legally authorized representative is required unless the investigator and a physician who is not otherwise participating in the clinical investigation, certify in writing, before the test article's use, that:

  1. The subject is confronted by a life-threatening situation necessitating the test article's use.
  2. Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject (for example, if the subject is unconscious). In contrast, a subject's inability to speak a particular language is not considered an inability to communicate.
  3. Time is not sufficient to obtain consent from the subject's legal representative.
  4. No alternative method of approved or generally recognized therapy provides an equal or greater likelihood of saving the subject's life.

The first three requirements are contained in the Medical Device Amendments. The fourth requirement was added by FDA to prevent routine reliance on the exception.

The regulatory requirement for this exception 'applies to individual situations and not to categories of studies as a whole (46 FR 8945, January 27, 1981), and suggests that there should be great confidence in the effectiveness of product, i.e., the situation must necessitate use of the product.

Conduct of Research in Emergency Settings

Because the section 50.23 exception was not formulated to apply to clinical trials, in October 1996 FDA promulgated a limited exception to the informed consent requirement to permit the conduct of a narrow class of research involving subjects in life-threatening situations (21 CFR 50.24). These regulations set forth minimum standards designed to protect individuals who may benefit from emergency research (61 FR 51498, October 2, 1996). At the same time, the Secretary, HHS, announced a comparable waiver of informed consent requirements in certain emergency research subject to the HHS regulations (61 FR 51531, October 2, 1996).

FDA developed this second exception to the informed consent requirements following extensive consultation and deliberation with the ethics and research communities as to whether and how research could be ethically conducted in the acute care/emergency medicine context. In the summer of 1993, the Commissioner of Food and Drugs received letters from the neurology and emergency medicine communities expressing concern about their inability to conduct emergency research in subjects unable to provide informed consent because of conflicting HHS and FDA regulatory requirements. At a May 23, 1994, hearing of the Subcommittee on Regulation, Business Opportunities, and Technology, House Committee on Small Business, problems encountered in securing informed consent of subjects in clinical trials of investigational drugs and medical devices were discussed. At that hearing, Representative Wyden emphasized the need to harmonize the HHS and FDA regulations.

On October 25, 1994, professional and patient organizations and the bioethics community met at the Coalition Conference of Acute Resuscitation and Critical Care Research to discuss this problem further. Following this conference, the Coalition developed a consensus document to resolve some of the issues concerning informed consent and waiver of consent in emergency research. The issue received further broad discussion at a meeting of the Applied Research Ethics National Association (Boston, MA, October 30, 1994) and at a conference sponsored by Public Responsibility in Medicine and Research (Boston, MA, November 1, 1994).

Concurrently and at the direction of HHS, FDA and NIH were working together to harmonize their respective informed consent regulations as they pertained to this emergency research. On January 9-10, 1995, FDA and NIH cosponsored a Public Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances in order to obtain as much public input from the research, legal, ethical, and patient advocacy communities as possible. FDA also sent "Dear Colleague" letters to the IRB community, called the major consumer and minority organizations which we thought would be interested in the proposed rule, and held briefings for the emergency research organizations as well as minority organizations in which questions about the rule could be addressed. It was only after all of these activities that FDA published its proposed rule on September 21, 1995 (60 FR 49086).

FDA received 90 comments in response to the proposed rule. The vast majority of these comments supported the proposal, although frequently the comments contained suggestions or requests for clarification. Of the 16 comments opposed to the proposed rule, the majority were from individuals who concluded that informed consent should not be waived under any circumstances. The comments were addressed in the preamble to the final rule published in October 1996.

The final rule provides access to potentially promising experimental treatments to patients in life-threatening situations. This rule sets forth special protections to human subjects who may benefit from this research, but who are not able to give consent on their own, and for whom a family member or legally authorized representative is not available to either withhold or give consent on the subject's behalf. Clearly, any researcher who can obtain informed consent must do so. Frequently, there are ways to design a study so that one is not confronted with emergency situations in which consent cannot be obtained. But in some cases, a subject cannot give his or her informed consent, for example, when there is a life-threatening emergency and there is no one available who is authorized to consent to an experimental treatment that might save that person's life. In that case, the Belmont Report directs us to protect these individuals with diminished autonomy5. That is what the emergency research rule does. It recognizes the need for rigorously designed studies to obtain data on interventions in acutely life-threatening situations such as cardiac arrest and traumatic brain injury in those cases where existing therapies are either unsatisfactory or unproven and consent is not feasible. Without such studies, new therapies for critically injured patients may never be validated and patients in need of emergency medicine may never receive the benefit of improved treatments. Alternatively, such therapies could become widely used in the practice of medicine without any rigorous demonstration of their safety or effectiveness through clinical trials and emergency medicine physicians may never know whether they are in fact saving lives or harming patients through these interventions.

The emergency research regulation requires the following actions to be accomplished. Each study proposing to invoke this waiver must be submitted to FDA as a separate and clearly identified investigational device exemption (IDE) application or investigational new drug (IND) application. This will permit the Agency to very carefully review each of these studies to help ensure that they meet the narrow criteria of the rule before the study is allowed to proceed. The IRB and a physician free of conflict-of-interest must ensure each of the following for these emergency research activities to proceed:

  • The human subjects are in a life-threatening situation;
  • Available treatments are unproven or unsatisfactory; and
  • Research is necessary to determine the safety and effectiveness of the particular intervention.
  • It is not feasible to obtain informed consent from the subjects as a result of their medical condition or from the subjects' legally authorized representative because the intervention must be administered before they could feasibly be reached, and there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the research.
  • Participation in the research holds out the prospect of direct benefit to the subjects because: the life-threatening situation necessitates intervention; information from appropriate preclinical (animal) studies and related evidence support the potential for the intervention to be beneficial; and the risks associated with the research are reasonable in light of what is known about the condition, the risks and the benefits of current therapy, and what is known about the risks and benefits of the proposed intervention.
  • The research could not practicably be carried out without the waiver. That is, the research could not practicably be carried out in a subject population who could provide informed consent.
  • The protocol must define the length of the potential therapeutic window based on scientific evidence and the researcher must commit to attempting to contact a legally authorized representative for each subject within that window of time and, if feasible, to asking that representative for consent rather than proceeding without it. The researcher must summarize his or her efforts and make this information available to the IRB at the time of continuing review. The "therapeutic window" is the period of time in which the patient must receive the therapeutic intervention if it is to be effective.
  • The IRB must have reviewed and approved informed consent procedures and an informed consent document consistent with FDA's informed consent provisions (21 CFR 50.25). These are to be used with subjects or their legally authorized representatives in situations where their use is feasible.
  • The IRB also must review and approve procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the research.

Additional protections of the rights and welfare of subjects are provided in this rule. These additional protections include:

  • Consultation with representatives of the communities in which the research will be conducted and from which the subjects will be drawn;
  • Public disclosure to both of these communities prior to initiation of the research of plans for the research and its risks and expected benefits;
  • Disclosure to the public of sufficient information following completion of the research to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results; and
  • Establishment of an independent data monitoring committee to exercise oversight of the research.

Because the default in this rule is that, once research has been approved by an IRB, eligible subjects are entered into these studies, the rule expands the number of caring individuals who may object to including a subject in one of these studies. Thus, if consent is not feasible from either the subject or a legally authorized representative, the investigator must commit to attempting to contact within the therapeutic window, the subject's family member (who may not be a legally authorized representative) and asking whether he or she objects to the subject's participation in the research. The investigator's efforts to make this contact must be summarized and made available to the IRB at the time of continuing review.

The IRB also is responsible for ensuring that procedures are in place to inform each subject, legally authorized representative, or family member at the earliest feasible opportunity of the subject's inclusion in the research, the details of the research and other information contained in the consent document, and that they may discontinue further participation of the subject at any time without penalty or loss of benefits to which the subject is otherwise entitled.

These policies establish narrow limits for allowing research without informed consent in certain studies of emergency medical interventions, and harmonize these standards throughout HHS. We believe HHS's new overall approach to emergency research situations may offer the best hope, in an ethical manner, to critically ill, unconscious persons who have no readily available legal representative to give consent and who cannot be successfully treated through conventional means, but might benefit from a promising experimental intervention.

Since the promulgation of the final rule on emergency research, FDA has tracked all INDs and IDEs submitted under this rule. We have committed to an ongoing evaluation of the implementation of this rule to ensure its adequacy for protecting research subjects and to ensure it is appropriately applied. To date, there have been very few submissions under this rule. We have received one IDE application and four IND applications under the emergency research rule. This rule was designed, and is being used, only when it is not feasible to conduct research without a waiver. Thus, this rule is being used as it was designed -- only for that limited class of emergency research which cannot be conducted without a waiver and which meets the stringent criteria built into the rule to protect the research subjects.

This life-threatening situation rule was promulgated in response to growing concern that existing rules were making high quality acute care research activities difficult or impossible to carry out at a time when the need for such research is increasingly recognized. By permitting certain adequate and well-controlled clinical trials to occur that involve human subjects who are confronted by a life-threatening situation and who also are unable to give informed consent because of their medical condition, the Agency expects the clinical trials to allow individuals in these situations access to potentially life-saving therapies and to result in the advancement in knowledge and improvement of those therapies used in emergency medical situations that currently have poor clinical outcome.

Department of Defense Combat Exigencies

The third exception to our informed consent requirements concerns the use of an investigational drug or biologic in certain situations related to military combat. During the months preceding the Persian Gulf War, DoD had discussions with FDA regarding the potential use of specific investigational products in military personnel serving in the Persian Gulf. We also had extensive internal discussions involving technical and policy-level staff, as well as experts from other Federal agencies and academia. It was thought that the products under discussion represented the best preventive measures for providing protection against possible attack with chemical or biological weapons. DoD requested the assistance of FDA in allowing the use of these products in certain battlefield or combat-related situations in which they considered obtaining informed consent "not feasible." FDA gave considerable deference to DoD's judgment and expertise regarding the feasibility of obtaining informed consent under battlefield conditions.

In response to this request, on December 21, 1990, FDA published an interim regulation amending its informed consent regulations. This regulation allowed the Commissioner of FDA to determine, upon receipt of an appropriate application from DoD, that obtaining informed consent from military personnel for use of a specific investigational drug or biologic would not be feasible in certain circumstances, and to grant a waiver from the requirement for obtaining such consent.

The exemption extended, on a case-by-case basis, only to investigational drugs (including antibiotic and biological products, including those for protection against chemical and biological warfare agents) for use in a specific military operation involving combat or the immediate threat of combat. A request from DoD for an informed consent waiver must include the justification for the conclusion (made by physicians responsible for the medical care of the military personnel involved) that: 1) the use is required to facilitate the accomplishment of the military mission; 2) the use would preserve the health of the individuals and the safety of other personnel, without regard for any individual's preference for alternate treatment or no treatment; and, 3) the request contains documentation to indicate that the protocol has been reviewed and approved by a duly constituted IRB for the use of the investigational drug without informed consent.

Each application for waiver from the informed consent requirements was assessed by the appropriate FDA review division, and by the Agency's Informed Consent Waiver Review Group (ICWRG). The ICWRG included senior management of the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Office of General Counsel, the Office of Health Affairs, and NIH's Office of Protection from Research Risks. The ICWRG core was supplemented by technical experts as appropriate for the particular investigational drug being considered for exception. The ICWRG considered DoD's justification supporting the request for the waiver and the reviewing division's evaluation of the available safety and efficacy data. The ICWRG requested additional supporting information in some cases, and required changes in the information to be provided to the troops in several rounds of iterative exchanges with DoD. The ICWRG then made a recommendation to the Commissioner regarding whether or not to grant the waiver. The Commissioner made a decision on the application and informed DoD in writing.

Under this regulation, waivers were granted for two products during Operation Desert Storm/Shield--pyridostigmine bromide and botulinum toxoid vaccine. Although FDA had concluded that informed consent was not feasible, FDA did obtain DoD's agreement to provide accurate, fair, and balanced information to those who would receive the investigational products. To do this, DoD developed information leaflets on both products with FDA's input and these leaflets received final FDA approval. Following the cessation of combat activities, the Assistant Secretary of Defense for Health Affairs notified the Commissioner in a March 1991 letter that DoD considered the two waivers granted under the interim rule to be no longer in effect. He also informed the Commissioner that DoD had ultimately decided to administer the botulinum toxoid vaccine on a voluntary basis.

Since that time, the Presidential Advisory Committee on Gulf War Veterans' Illnesses has recommended that we "solicit timely public and expert comment on any rule that permits waiver of informed consent for use of investigational products in military exigencies." (Final Report, page 52.) FDA has carefully evaluated the committee's recommendations as well as other information that has come to its attention. FDA has engaged in discussions within the Agency, with DoD, and with others on this important topic. As a result of these discussions, the Agency will solicit public comment in line with the committee's report. This public comment will be directed towards whether the FDA should finalize the interim rule, modify it, or eliminate it completely.

CONCLUSION

The first layer of the subjects' protection is provided by the medical research sponsor. It is the responsibility of the sponsor to design the research study to be ethically and scientifically sound, select qualified researchers, provide them with the information they need to properly conduct the research study, and ensure proper monitoring of the study. The second layer of protection is provided by the researcher, whose professional and civic obligation is to conduct ethical research and make sure that the study participants are apprised of, and fully understand, the potential risks and benefits of the research. The third layer of protection is provided by IRBs. It is the responsibility of the IRBs to develop and follow procedures for initial and continuing review of the integrity of the research and the protection of the rights and welfare of its human subjects. The last layer of protection is provided by FDA, which regulates the organization and procedures of IRBs, researchers, research sponsors, and others involved in clinical trials. These layers of protections are applied to each clinical study to ensure the integrity of the data and in order to protect the rights and welfare of the human subjects of clinical research.

We take very seriously our obligation to protect the rights and welfare of all research subjects who participate in research involving FDA-regulated products. We believe that our regulations and inspection programs are important to help ensure that human research subjects are protected at the same time that vital information on the safety and effectiveness of drugs, biologics, antibiotics, and devices is gathered.

I would be happy to answer any questions you have about FDA's oversight and regulation of research activities.

1"Minimal risk" in both FDA and HHS regulations means that, "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests." (21 CFR 50.3(1), 56.102(i), and 45 CFR 46.102(i)) this definition is a key factor in the HHS regulations in its criteria for when informed consent may be waived. FDA and HHS published a list of categories of research in the 1981` Federal Register that could be reviewed by expedited means when they impart no greater than minimal risk.

2Excludes color additives and radioactive drug research committee inspections, and includes domestic and foreign inspections.

3FDA recently published a final rule requiring informed consent documents to be dated at the time of signature (61 FR 57278, November 5, 1996). Although a common practice, this was not previously required by regulation. This new rule permits FDA to verify that consent was obtained prior to a subject's entry into a study.

4The implementation of these regulations is the responsibility of the National Institutes of Health (NIH).

5The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research stated in The Belmont Report that: "Respect for persons incorporates at least two basic ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy" (44 FR 23192, April 19, 1979). This report was in response to one of the National Commission's mandates, contained in the "National Research Act", P.L. 93-348 (See 42 U.S.C. 218). That mandate was to identify the basic ethical principles underlying clinical research.