I. 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.
II. 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.
A. 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).
B. 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 obtained;
- 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.
C. 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.
III. 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.
A. 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.
The BIMO program is implemented through several compliance programs: 1) Good Laboratory
Practice (GLP) Program (Nonclinical 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 ertain 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 requiremertain 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. 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.
B. 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.
C. 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.
IV. 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 HHS; 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.
V. LIMITED EXCEPTION 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.
A. 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:
- The subject is confronted by a life-threatening situation necessitating the test article's use.
- 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.
- Time is not sufficient to obtain consent from the subject's legal representative.
- 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.
B. 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
researcconsent 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 whoconsent 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 autonomy. 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.
C. 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.
VI. 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 ensu