[Federal Register Volume 66, Number 170 (Friday, August 31, 2001)]
[Notices]
[Pages 45998-46009]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-22038]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES


Notice of Publication of the Executive Summary of the report, 
``Ethical and Policy Issues in Research Involving Research 
Participants'', by the National Bioethics Advisory Commission (NBAC)

SUPPLEMENTARY INFORMATION: The President established the National 
Bioethics Advisory Commission (NBAC) on October 3, 1995 by Executive 
Order 12975 as amended. The functions of NBAC are as follows:

    (a) Provide advice and make recommendations to the National Science 
and Technology Council and to other appropriate government entities 
regarding the following matters:
    (1) The appropriateness of departmental, agency or other 
governmental programs, policies, assignments, missions, guidelines, and 
regulations as they relate to bioethical issues arising from research 
on human biology and behavior; and
    (2) applications, including the clinical applications, of that 
research.
    (b) Identify broad principles to govern the ethical conduct of 
research, citing specific projects only as illustrations for such 
principles.
    (c) Shall not be responsible for the review and approval of 
specific projects.
    (d) In addition to responding to requests for advice and 
recommendations from the National Science and Technology Council, NBAC 
also may accept suggestions of issues for consideration from both the 
Congress and the public. NBAC may also identify other bioethical issues 
for the purpose of providing advice and recommendations, subject to the 
approval of the National Science and Technology Council. The members of 
NBAC are as follows:
Harold T. Shapiro, Ph.D., Chair
Patricia Backlar
Arturo Brito, M.D.
Alexander Morgan Capron, LL.B.
Eric J. Cassell, M.D., M.A.C.P.
R. Alta Charo, J.D.
James F. Childress, Ph.D.
David R. Cox, M.D., Ph.D.
Rhetaugh G. Dumas, Ph.D., R.N.
Laurie M. Flynn*
Carol W. Greider, Ph.D.
Steven H. Holtzman
Bernard Lo, M.D.
Lawrence H. Miike, M.D., J.D.
Thomas H. Murray, Ph.D.
William C. Oldaker, LL.B.
Diane Scott-Jones, Ph.D.
*Resigned on May 10, 2001

Ethical and Policy Issues in Research Involving Human Participants; 
Summary

Protecting Research Participants--A Time for Change

Introduction
    Protecting the rights and welfare of those who volunteer to 
participate in research is a fundamental tenet of ethical research. A 
great deal of progress has been made in recent decades in changing the 
culture of research to incorporate more fully this ethical 
responsibility into protocol design and implementation. In the 1960s 
and 1970s, a series of scandals concerning social science research and 
medical research conducted with the sick and the illiterate underlined 
the need to systematically and rigorously protect individuals in 
research (Beecher 1966; Faden and Beauchamp 1986; Jones 1981; Katz 
1972; Tuskegee Syphilis Study Ad Hoc Advisory Panel 1973). However, the 
resulting system of protections that evolved out of these rising 
concerns--although an improvement over past practices--is no longer 
sufficient. It is a patchwork arrangement associated with the receipt 
of federal research funding or the regulatory review and approval of 
new drugs and devices. In addition, it depends on the voluntary 
cooperation of investigators, research institutions, and professional 
societies across a wide array of research disciplines. Increasingly, 
the current system is being viewed as uneven in its ability to 
simultaneously protect the rights and welfare of research participants 
and promote ethically responsible research.
    Research involving human participants has become a vast academic 
and commercial activity, but this country's system for the protection 
of human participants has not kept pace with that growth. On the one 
hand, the system is too narrow in scope to protect all participants, 
while on the other hand, it is often so unnecessarily bureaucratic that 
it stifles responsible research. Although some reforms by particular 
federal agencies and professional societies are under way,\1\ it will 
take the efforts of both the executive and legislative branches of 
government to put in place a streamlined, effective, responsive, and 
comprehensive system that achieves the protection of all human 
participants and encourages ethically responsible research.
    Clearly, scientific investigation has extended and enhanced the 
quality of life and increased our understanding of ourselves, our 
relationships with others,

[[Page 45999]]

and the natural world. It is one of the foundations of our society's 
material, intellectual, and social progress. For many citizens, 
scientific discoveries have alleviated the suffering caused by disease 
or disability. Nonetheless, the prospect of gaining such valuable 
scientific knowledge need not and should not be pursued at the expense 
of human rights or human dignity. In the words of philosopher Hans 
Jonas, ``progress is an optional goal, not an unconditional commitment, 
and . . . its tempo . . . compulsive as it may become, has nothing 
sacred about it'' (Jonas 1969, 245).
    Since the 1974 formation of the National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research and 
the activities in the early 1980s of the President's Commission for the 
Study of Ethical Problems in Medicine and Biomedical and Behavioral 
Research, American leaders have consistently tried to enhance the 
protections for human research participants. The research community 
has, in large part, supported the two essential protections for human 
participants: independent review of research to assess risks and 
potential benefits and an opportunity for people to voluntarily and 
knowledgeably decide whether to participate in a particular research 
protocol.
    The charter of the National Bioethics Advisory Commission (NBAC), a 
presidential commission created in 1995, makes clear the Commission's 
focus: ``As a first priority, NBAC shall direct its attention to 
consideration of protection of the rights and welfare of human research 
subjects.'' In our first five years, we focused on several issues 
concerning research involving human participants, issuing five reports 
and numerous recommendations that, when viewed as a whole, reflect our 
evolving appreciation of the numerous and complex challenges facing the 
implementation and oversight of any system of protections.\2\ The 
concerns and recommendations addressed in these reports reflect our 
dual commitment to ensuring the protection of those who volunteer for 
research while supporting the continued advance of science and 
understanding of the human condition. This report views the oversight 
system as a whole, provides a rationale for change, and offers an 
interrelated set of recommendations to improve the protection of human 
participants and enable the oversight system to operate more 
efficiently.

Respecting Research Participants

    Whether testing a new medical treatment, interviewing people about 
their personal habits, studying how people think and feel, or observing 
how they live within groups, research seeks to learn something new 
about the human condition. Unfortunately, history has also demonstrated 
that researchers sometimes treat participants not as persons but as 
mere objects of study. As Jonas observed: ``Experimentation was 
originally sanctioned by natural science. There it is performed on 
inanimate objects, and this raises no moral questions. But as soon as 
animate, feeling beings become the subject of experiment * * * this 
innocence of the search for knowledge is lost and questions of 
conscience arise'' (Jonas 1969, 219).
    How, then, should people be studied? For over half a century, since 
the revelations of medical torture under the guise of medical 
experimentation were described at the Nuremberg Trials,\3\ it has been 
agreed that people should participate in research only when the study 
addresses important questions, its risks are justifiable, and an 
individual's participation is voluntary and informed.
    The principles underlying the Belmont Report: Ethical Principles 
and Guidelines for the Protection of Human Subjects of Research 
(Belmont Report) (National Commission 1979) have served for over 20 
years as a leading source of guidance regarding the ethical standards 
that should govern research with human participants in the United 
States. The Belmont Report emphasized that research must respect the 
autonomy of participants, must be fair in both conception and 
implementation, and must maximize potential benefits while minimizing 
possible harms. The report's recommendations provided a coherent 
rationale for the federal policies and rules that created the current 
U.S. system of decentralized, independent research review coupled with 
some degree of federal oversight. But although the Belmont Report is 
rightly hailed as a key source of guidance on informed consent, 
assessment of risk, and the injustice of placing individuals (and 
groups) in situations of vulnerability, the principles the report 
espouses and the regulations adopted as federal policy 20 years ago 
have often fallen short in achieving their overarching goal of 
protecting human research participants. Moreover, since the Belmont 
Report was published, additional concerns have arisen that require 
much-needed attention today.

Ensuring Independent Review of Risks and Potential Benefits

    A central protection for research participants is the guarantee 
that someone other than the investigator will assess the risks of the 
proposed research. No one should participate in research unless 
independent review concludes that the risks are reasonable in relation 
to the potential benefits. In the United States, the Institutional 
Review Board, or IRB, has been the principal structure responsible for 
conducting such reviews.
    Independent review of research is essential because it improves the 
likelihood that decisions are made free from inappropriate influences 
that could distort the central task of evaluating risks and potential 
benefits. Certainly, reviewers should not have a financial interest in 
the work, but social factors may be just as crucial. Reviewers may feel 
constrained because they are examining the work of their colleagues or 
their supervisors, and they should not participate in protocol review 
unless they are able to separate these concerns from their task. All 
reviewers who themselves are members of the research community should 
recognize that their familiarity with research and (perhaps) their 
predilection to support research are factors that could distort their 
judgment.
    Truly independent and sensitive review requires more involvement of 
individuals drawn from the ranks of potential research participants or 
those who can adequately represent the interests of potential research 
participants.
    A critical purpose of independent review is to ensure that risks 
are reasonable in relation to potential personal and societal benefits. 
This is a precondition to offering people the opportunity to volunteer, 
since informed consent alone cannot justify enrollment. When reviewed 
for risks and potential benefits, research studies must be evaluated in 
their entirety. Studies often include different components, however, 
and the risks and potential benefits of each should also be examined 
separately, lest the possibility of great benefit or monetary 
enticement in one component cause potential participants or IRBs to 
minimize or overlook risk in another. No matter what potential benefit 
is offered to individual participants or society at large, the 
possibility of benefit from one element of a study should not be used 
to justify otherwise unacceptable elements.
    In our view, IRBs should appreciate that for some components of a 
study, participants might incur risks with no personal potential 
benefit, for example, when a nondiagnostic survey is included among the 
components of a psychotherapy protocol or when placebos are given to 
some participants in a drug trial. For these elements, there

[[Page 46000]]

should be some limitation on the amount of social and physical risk 
that can be imposed, regardless of the participants' willingness to 
participate or the monetary (or other) enticement being offered. 
Further, the possibility of some benefit from one element of a study 
should not be used to justify otherwise unacceptable elements of 
research whose potential benefits, if any, accrue, solely to society at 
large. If aspects of a study present unacceptable risks, protocols 
should not be approved until these elements are eliminated. If removing 
the risky component would impair the study as a whole, then the entire 
study should be redesigned so that each of its elements presents risks 
that are reasonable in relation to potential benefits.
    Other parts of studies can obscure risks, such as when standard 
medical interventions are compared in a patient population, leading 
some participants and researchers to discount the risks because they 
are associated with known therapies. It is essential that participants 
and investigators not be led to believe that participating in research 
is tantamount to being in a traditional therapeutic relationship. 
Regardless of whether there is the possibility or even the likelihood 
of direct benefit from participation in research, such participation 
still alters the relationship between a professional and the 
participant by introducing another loyalty beyond that to the 
participant, to wit, loyalty to doing good science. It is too often 
forgotten that even though the researchers may consider participants' 
interests to be important, they also have a serious, and perhaps 
conflicting, obligation to science.
    Years of experience with the current system of independent review 
have demonstrated that there are enduring questions about how to arrive 
at such impartial judgments and how to go about deciding when potential 
benefits justify risks that are incurred solely by participants or the 
community from which they come. In recent years, increasing strains on 
the system have undermined the practice of independent review. IRBs are 
over-burdened by the volume of research coming before them, a strain 
that is compounded by concerns about training of IRB members and 
possible conflicts of interest. In addition, the constantly changing 
nature of research challenges existing notions about what constitutes 
risks and potential benefits.
    Because IRBs are so central to the current oversight system, they 
need better guidance on how to review and monitor research, how to 
assess potential benefits to research participants and their 
communities, and how to distinguish among levels of risk. This report 
provides such guidance in the following areas: determining the type of 
review necessary for minimal risk research; ensuring that research 
participants are able to make voluntary decisions and are appropriately 
informed prior to giving consent; providing adequate protections for 
privacy and confidentiality; identifying appropriate measures needed 
when participants are susceptible to coercion or are otherwise placed 
in vulnerable situations; and monitoring ongoing research. In addition, 
the report recommends that IRB members and staff complete educational 
and certification programs on research ethics before being permitted to 
review research studies.

Obtaining Voluntary Informed Consent

    Even when risks are reasonable, however, no one should participate 
in research without giving voluntary informed consent (except in the 
case of an appropriate authorized representative or a waiver). 
Investigators must make appropriate disclosures and ensure that 
participants have a good understanding of the information and their 
choices, not only at the time of enrollment, but throughout the 
research. Engaging in this process is one of the best ways researchers 
can demonstrate their concern and respect for those they aim to enroll 
in a study. It also serves as the best means for those who do not wish 
to participate to protect themselves.\4\
    Recommendations from our previous reports are reinforced in this 
report, which emphasizes the process of providing information and 
ensuring comprehension rather than the form of documentation of the 
decision to give consent. Both the information and the way it is 
conveyed--while meeting full disclosure requirements--must be tailored 
to meet the needs of the participants in the particular research 
context. In addition, documentation requirements must be adapted for 
varying research settings, and the criteria for deciding when informed 
consent is not necessary must be clarified so that participants--rights 
and welfare are not endangered.
    The decision to participate in research must not only be informed, 
it must be voluntary. Even when risks are reasonable and informed 
consent is obtained, it may nonetheless be wrong to solicit certain 
people as participants. Those who are not fully capable of resisting 
the request to become participants--such as prisoners and other 
institutionalized or otherwise vulnerable persons--should not be 
enrolled in studies merely because they are easily accessible or 
convenient. This historic emphasis on protecting people from being 
exploited as research participants, however, has failed to anticipate a 
time when, at least for some areas of medical research, people would be 
demanding to be included in certain studies because they might provide 
the only opportunity for receiving medical care for life-threatening 
diseases.

Making Research Inclusive While Protecting Individuals Categorized as 
Vulnerable

    Vulnerable individuals need additional protection in research. 
Although certain individuals and populations are more vulnerable as 
human participants than others, people whose circumstances render them 
vulnerable should not be arbitrarily excluded from research for this 
reason alone. This includes those viewed as more open to harm (e.g., 
children), more subject to coercion (e.g., institutionalized persons), 
more ``complicated'' (e.g., women, who are considered more biologically 
complicated than men), or more inconvenient (e.g., women with small 
children, who are viewed as less reliable research participants due to 
conflicting demands on time). Calling competent people intrinsically 
``vulnerable'' can be both insulting and misleading. It is not their 
gender or other group designation that exposes them to injury or 
coercion, but rather their situation that can be exploited by ethically 
unacceptable research. That is, it is their circumstances, which are 
situational, that create the vulnerability. At other times it is the 
intrinsic characteristics of the person--for example, children or those 
with certain mental or developmental disorders--that make them 
generally vulnerable in the research setting.
    The response, whenever possible, should not be to exclude people 
from research, but instead to change the research design so that it 
does not create situations in which people are unnecessarily harmed. To 
do otherwise is to risk developing knowledge that helps only a subset 
of the population. To the extent that the results are not 
generalizable, the potential societal benefits that justify doing the 
research are attenuated. Research participants must be treated equally 
and with respect. Whenever possible, research should be designed to 
encourage the participation of all groups while protecting their rights 
and welfare.
    To accomplish this, we recommend that rather than focusing 
primarily on

[[Page 46001]]

categorizing groups as vulnerable, investigators and IRBs should also 
recognize and avoid situations that create susceptibility to harm or 
coercion. Such situations may be as varied as patients being recruited 
by their own physicians; sick and desperate patients seeking enrollment 
in clinical trials; participants being recruited by those who teach or 
employ them; or studies involving participants with any characteristic 
that may make them less likely to receive care and respect from others 
(e.g., convicted criminals or intravenous drug users). In these 
circumstances, rather than excluding whole groups of people, 
researchers should design studies that reduce the risk of exploitation, 
whether by using a different method of recruitment, by using a 
recruiter who shares the participants' characteristics, or by some 
other technique. This is not always easy. It requires researchers to 
consider carefully their research design and the potential pool of 
participants. At times, it will mean anticipating that otherwise 
seemingly benign situations may become more complex because a 
particular participant or group of participants will be unusually 
susceptible to harm or manipulation in this situation. At other times, 
the nature of the vulnerability may require using a different research 
design. Ethical research does not avoid complexity. Rather, it 
acknowledges the full range and realities of the human condition.

Compensating for Harms

    Despite all these precautions, however, some research participants 
might be harmed. Participants who are harmed as a direct result of 
research should be cared for and compensated. This is simple justice. 
The fact that they offered to participate in no way alters the view 
that mere decency calls for us to take care of these volunteers. 
Unfortunately, this is a greater challenge than it might appear. For 
those who endure harm while participating in research, it is often very 
difficult to separate injuries traceable to the research from those 
that stem from the underlying disease or social condition being 
studied. For others, appropriate care and compensation would be far 
beyond the means of the researchers, their sponsors, and their 
institutions. Two decades ago, the President's Commission for the Study 
of Ethical Problems in Medicine and Biomedical and Behavioral Research 
called for pilot studies of compensation programs--a recommendation 
that was not pursued. It is time to reconsider the need for some type 
of compensation program and to explore the possible mechanisms that 
could be used were one to be adopted. Regardless of individual motives, 
research participants are providing a service for society, and justice 
requires that they be treated with great respect and receive 
appropriate care for any related injuries. It should always be 
remembered that it is a privilege for any researcher to involve human 
participants in his or her research.

Establishing a Comprehensive, Effective, and Streamlined System

    In the United States, government regulations, professional 
guidelines, and the general principles highlighted in the Belmont 
Report (1979) form the basis of the current system of protections. In 
the earliest stages of adoption, the federal regulations were 
fragmented and confusing. Even today, they apply to most--but not all--
research funded or conducted by the federal government, but have 
inconsistent and sometimes no direct application to research funded or 
conducted by state governments, foundations, or industry. They apply to 
medical drugs and devices and vaccines approved for interstate sale, 
but not to some medical innovations that would remain wholly within 
state borders. And they apply to other research only when the 
investigators and their institutions volunteer to abide by the rules.
    A comprehensive and effective oversight system is essential to 
uniformly protect the rights and welfare of participants while 
permitting ethically and scientifically responsible research to proceed 
without undue delay. A fundamental flaw in the current oversight system 
is the ethically indefensible difference in the protection afforded 
participants in federally sponsored research and those in privately 
sponsored research that falls outside the jurisdiction of the Food and 
Drug Administration (FDA). As a result, people have been subjected to 
experimentation without their knowledge or informed consent in fields 
as diverse as plastic surgery, psychology, and infertility treatment. 
This is wrong. Participants should be protected from avoidable harm, 
whether the research is publicly or privately financed. We have 
repeated this assertion throughout our deliberations, and 
recommendations in this regard appear in four previous reports (NBAC 
1997; NBAC 1999a; NBAC 1999b; NBAC 2001).
    In this report, we recommend that the protections of an oversight 
system extend to the entire private sector for both domestic and 
international research. A credible, effective oversight system must 
apply to all research, and all people are entitled to the dignity that 
comes with freely and knowingly choosing whether to participate in 
research, as well as to protection from undue research risks. This is 
consistent with our 1997 resolution that no one should be enrolled in 
research absent the twin protections of independent review and 
voluntary informed consent.
    Even when current protections apply, the interpretation of the 
federal regulations can vary unpredictably, depending on which federal 
agency oversees the research. Even the most basic, common elements of 
the federal rules took a decade to develop into regulations, because 
there was no single authority within the government to facilitate and 
demand cooperation and consistency. There still is no such single 
authority.\5\ This has slowed the diffusion of basic protections and 
made it almost impossible to develop consistent interpretations of the 
basic protections or those relevant to especially problematic research, 
such as studies involving children or the decisionally impaired. Nor 
has there been a unified response to emerging areas of research, such 
as large-scale work on medical records and social science databases or 
on stored human biological materials.
    Today's research protection system cannot react quickly to new 
developments. Efforts to develop rules for special situations, such as 
research on those who can no longer make decisions for themselves, have 
languished for decades in the face of bureaucratic hurdles, and there 
is no reason to believe that efforts to oversee other emerging research 
areas will be any more efficient. In addition, the current system 
leaves people vulnerable to new, virtually uncontrolled experimentation 
in emerging fields, such as some aspects of reproductive medicine and 
genetic research.
    Indeed, some areas of research are not only uncontrolled, they are 
almost invisible. In an information age, poor management of research 
using medical records, human tissue, or personal interview data could 
lead to employment and insurance discrimination, social stigmatization, 
or even criminal prosecution.\6\ The privacy and confidentiality 
concerns raised by this research are real, but the federal response has 
often been illusory. There is almost no guidance and certainly no 
coordination on these topics. The time has come to have a single source 
of guidance for these emerging areas, one that would be better 
positioned to effect change across all divisions of the government and 
private sector, as well

[[Page 46002]]

as to facilitate development of specialized review bodies, as needed.
    In this report we propose a new independent oversight office that 
would have clear authority over all other segments of the federal 
government and extend protections to the entire private sector for both 
domestic and international research. A single office would decide how 
to introduce consistency or reforms, and only that office would develop 
mechanisms to provide specialized review when needed. We recognize the 
challenges to such a proposal. For example, an independent office might 
lack the political support accorded an existing cabinet-level 
department. Although assigning one department, such as the Department 
of Health and Human Services (DHHS), the role of ``first among equals'' 
would allow it to advocate forcefully for uniform rules across the 
government, without special provisions it would not have the authority 
to require other departments to comply, nor is it certain to escape the 
temptation to develop rules premised on a traditional, biomedical model 
rather than the wider range of research to be covered.
    Federal research protections should be uniform across all 
government agencies, academe, and the private sector, but they should 
be flexible enough to be applied in widely different research settings 
or to emerging areas of research. Furthermore, any central coordinating 
body should be open to public input, have significant political or 
legal authority over research involving human participants--whether in 
the public or private sector--and have the support of the executive and 
legislative branches of government.

Education as the Key to Promoting Local Responsibility

    Currently, federal protections depend on a decentralized oversight 
system involving IRBs, institutions, investigators, sponsors, and 
participants. We endorse the spirit and intent of this approach, 
specifically its contention that the ethical obligation to protect 
participants lies first with researchers, their sponsors, and the IRBs 
that review their research. Protecting research participants is a duty 
that researchers, research institutions, and sponsors cannot delegate 
completely to others or to the government. In addition, merely adhering 
to a set of rules and regulations does not fulfill this duty. Rather, 
it is accomplished by acting within a culture of concern and respect 
for research participants.
    It is unrealistic to think that ethical obligations can be fully 
met without guidance and resources. To help researchers and IRBs 
fulfill their responsibilities, the federal government should promote 
the development of education, certification, and accreditation systems 
that apply to all researchers, all IRB members and staff, and all 
institutions. These tools should help researchers craft and IRBs review 
studies that pose few problems and to know when their work requires 
special oversight. Today, investigators and IRBs are rightly confused 
over issues as basic as which areas of inquiry should be reviewed and 
who constitutes a human participant.
    Education is the foundation of the oversight system and is 
essential to protecting research participants. In all of our reports, 
we have highlighted the need to educate all those involved in research 
with human participants, including the public, investigators, IRB 
members, institutions, and federal agencies. In Cloning Human Beings 
(1997), we recommended federal support of public education in 
biomedical sciences that increasingly affect our cultural values. In 
Research Involving Persons with Mental Disorders That May Affect 
Decisionmaking Capacity (1998), we called for practice guidelines and 
ethics education on special concerns regarding this population. In 
Ethical and Policy Issues in International Research: Clinical Trials in 
Developing Countries (2001), we recommended measures to help developing 
countries build their capacity for designing and conducting clinical 
trials, for reviewing the ethics and science of proposed research, and 
for using research results after a trial is completed.
    In this report, we again acknowledge the inadequacy of educational 
programs on research ethics in the United States. This deficiency 
begins at the highest level within the federal oversight system and 
extends to the local level at individual institutions. We recommend 
that investigators and IRB members and staff successfully complete 
educational programs on research ethics and become certified before 
they perform or review research, that research ethics be taught to the 
next generation of scientists, and that research ethics be included in 
continuing education programs.

Clarifying the Scope of Oversight

    Many areas of scientific inquiry are ``research,'' and many of 
these involve human participants, but only some need federal oversight, 
while others might be better regulated through professional ethics, 
social custom, or other state and federal law. For example, certain 
types of surveys and interviews are considered research, but they can 
be well managed to avoid harms without federal oversight, as the risks 
are few and participants are well situated to decide for themselves 
whether to participate. On the other hand, certain studies of medical 
records, databases, and discarded surgical tissue are often perceived 
as something other than human research, even when the information 
retrieved is traceable to an identifiable person. Such research does 
need oversight to avoid putting people at risk of identity disclosure 
or discrimination without their knowledge. Federal policies should 
clearly identify the kinds of research that are subject to review and 
the types of research participants to whom protections should apply. 
When research poses significant risks or when its risks are imposed on 
participants without their knowledge, it clearly requires oversight. 
However, meaningless or overly rigid oversight engenders disdain on the 
part of researchers, creates an impossible and pointless workload for 
IRBs, and deters ethically sound research from going forward.

Ensuring That the Level of Review Corresponds to the Level of Risk

    Even within areas of research that need oversight, many individual 
studies will involve little or no risk to participants. Although 
current federal policies allow for some distinction between research 
involving minimal risk and research involving more than minimal risk, 
the distinction operates mostly in terms of how the research will be 
reviewed--that is, how procedures are to be followed. But the 
distinction should be based on how the research is pursued, how the 
participants are treated, and how the work is monitored over time. 
Overall, the emphasis should be on knowing how to protect participants 
rather than on knowing how to navigate research regulations. Instead of 
focusing so much on the period during which a research design is 
reviewed, oversight should also include an ongoing system of education 
and certification that helps researchers to anticipate and minimize 
research risks. Oversight should also make it easier for researchers to 
collaborate with their colleagues here and abroad without the burden of 
redundant reviews. Research review and monitoring should be intensified 
as the risk and complexity of the research increase and at all times 
should emphasize protecting participants rather than following rigid 
rules. In addition, the review process should facilitate rather than 
hinder collaborative research among institutions and across

[[Page 46003]]

national boundaries, provided that participants are protected.

Providing Resources for the Oversight System

    Creating a system that protects the rights and welfare of 
participants and facilitates responsible research demands political and 
financial support from the federal government as well as the presence 
of a central coordinating body to provide guidance and oversee 
education and accreditation efforts. The oversight system should be 
adequately funded at all levels to ensure that research continues in a 
manner that demonstrates respect and concern for the interests of 
research participants.

Summary of Recommendations

    This report proposes 30 recommendations for changing the oversight 
system at the national and local levels to ensure that all research 
participants receive the appropriate protections. The adoption of these 
recommendations, which are directed at all who are involved in the 
research enterprise, will not only lead to better protection for the 
participants of research, but will also serve to promote ethically 
sound research while reducing unnecessary bureaucratic burdens. 
Achieving these goals will, in turn, restore the respect of 
investigators for the system used to oversee research, support the 
public's trust in the research enterprise, and enhance public 
enthusiasm for all research involving human beings.

Scope and Structure of the Oversight System

    The entitlements due to all research participants of a prior 
independent review of risks and potential benefits and the opportunity 
to exercise voluntary informed consent are the most basic and essential 
protections for all research participants. However, not all research 
participants receive these entitlements and not all are protected by 
the existing oversight system. The commitment to protect participants 
should not be voluntary, nor should requirements be in place for only 
some human research. Extending current protections to all research, 
whether publicly or privately funded, and making uniform all federal 
regulations and guidance cannot be accomplished within the current 
oversight system, in which no entity has the authority to act on behalf 
of all research participants. Thus, to facilitate the extension of the 
same protections to all humans participating in research, a unified, 
comprehensive federal policy promulgated and interpreted by a single 
office is needed.
    Recommendation 2.1: The federal oversight system should protect the 
rights and welfare of human research participants by requiring 1) 
independent review of risks and potential benefits and 2) voluntary 
informed consent. Protection should be available to participants in 
both publicly and privately sponsored research. Federal legislation 
should be enacted to provide such protection.
    Recommendation 2.2: To ensure the protection of the rights and 
welfare of all research participants, federal legislation should be 
enacted to create a single, independent federal office, the National 
Office for Human Research Oversight (NOHRO), to lead and coordinate the 
oversight system. This office should be responsible for policy 
development, regulatory reform (see Recommendation 2.3), research 
review and monitoring, research ethics education, and enforcement.
    Recommendation 2.3: A unified, comprehensive federal policy 
embodied in a single set of regulations and guidance should be created 
that would apply to all types of research involving human participants 
(see Recommendation 2.2).
    Determining whether particular research activities involving human 
participants should be subject to a federal oversight system has been a 
source of confusion for some time. No regulatory definition of covered 
research can be provided that has the sensitivity and specificity 
required to ensure that all research activities that include human 
participants that should be subject to oversight are always included 
and all activities that should be excluded from oversight protections 
are always excluded. Clarification and interpretation of the definition 
of what constitutes research involving human participants will 
invariably be required if the oversight system is to work effectively 
and efficiently. Moreover, there will always be cases over which 
experts disagree about the research status of a particular activity. 
One of the important leadership roles the proposed oversight office 
should fulfill is that of providing guidance on determining whether an 
activity is research involving human participants and is therefore 
subject to oversight.
    Recommendation 2.4: Federal policy should cover research involving 
human participants that entails systematic collection or analysis of 
data with the intent to generate new knowledge. Research should be 
considered to involve human participants when individuals (1) are 
exposed to manipulations, interventions, observations, or other types 
of interactions with investigators or (2) are identifiable through 
research using biological materials, medical and other records, or 
databases. Federal policy also should identify those research 
activities that are not subject to federal oversight and outline a 
procedure for determining whether a particular study is or is not 
covered by the oversight system.
    The proposed federal office should initiate a process in which 
representatives from various disciplines and professions (e.g., social 
science, humanities, business, public health, and health services) 
contribute to the development of the definition and the list of 
research activities subject to the oversight system.

Level of Review

    Although the definition of research involving human participants 
should be applied to all disciplines, the risks differ both 
qualitatively and quantitatively across the spectrum of research. 
Therefore, the oversight system should ensure that all covered research 
is subject to basic protections'such as a process of informed 
consent'with the exceptions of the specified conditions for which these 
protections can be waived, including protection of privacy and 
confidentiality and minimization of risks. Because the proposed 
oversight system may include more research activities, it is more 
critical than ever that review mechanisms and criteria for various 
types of research are suited to the nature of the research and the 
likely risks involved. More specific guidance is needed for review of 
different types of research, including appropriate review criteria and 
IRB composition. For example, procedures other than full board review 
could be used for minimal risk research, and national level reviews 
could supplement local IRB review of research involving novel or 
controversial ethical issues.
    Recommendation 2.5: Federal policy should require research ethics 
review that is commensurate with the nature and level of risk involved. 
Standards and procedures for review should distinguish between research 
that poses minimal risk and research that poses more than minimal risk. 
Minimal risk should be defined as the probability and magnitude of 
harms that are normally encountered in the daily lives of the general 
population (see Recommendation 4.2). In addition, the federal 
government should facilitate the creation of special, supplementary 
review bodies for research that involves novel or controversial ethical 
issues.

[[Page 46004]]

Education, Certification, and Accreditation

    Protecting the rights and welfare of research participants is the 
major ethical obligation of all parties involved in the oversight 
system, and to provide these protections, all parties must be able to 
demonstrate competence in research ethics'that is, conducting, 
reviewing, or overseeing research involving human participants in an 
ethically sound manner. Such competence entails not only being 
knowledgeable about relevant research ethics issues and federal 
policies, but also being able to identify, disclose, and manage 
conflicting interests for institutions, investigators, or IRBs. 
Finally, the oversight system must include a sufficiently robust 
monitoring process to provide remedies for lapses by institutions, 
IRBs, and investigators.
    Recommendation 3.1: All institutions and sponsors engaged in 
research involving human participants should provide educational 
programs in research ethics to appropriate institutional officials, 
investigators, Institutional Review Board members, and Institutional 
Review Board staff. Among other issues, these programs should emphasize 
the obligations of institutions, sponsors, Institutional Review Boards, 
and investigators to protect the rights and welfare of participants. 
Colleges and universities should include research ethics in curricula 
related to research methods, and professional societies should include 
research ethics in their continuing education programs.
    Recommendation 3.2: The federal government, in partnership with 
academic and professional societies, should enhance research ethics 
education related to protecting human research participants and 
stimulate the development of innovative educational programs. 
Professional societies should be consulted so that educational programs 
are designed to meet the needs of all who conduct and review research.
    Educating all parties in research ethics and human participant 
protections is effective only when it results in the necessary 
competence for designing and conducting ethically sound research, 
including analyzing, interpreting, and disseminating results in an 
ethically sound manner. Such competence, however, cannot be assumed to 
follow from exposure to an educational course or program. As the 
complexion of research continues to change and as technology advances, 
new and challenging ethical dilemmas will emerge. And, as more people 
become involved in research as investigators or in roles that are 
specifically related to oversight, it becomes increasingly important 
for all parties to be able to demonstrate competence in the ethics of 
research involving human participants.
    Although accreditation and certification do not always guarantee 
the desired outcomes, these programs, which generally involve experts 
and peers developing a set of standards that represents a consensus of 
best practices, can be helpful in improving performance. Therefore, the 
choice of standards for these programs and the criteria for evaluating 
whether an institution has met them are critically important. 
Accreditation and certification programs should emphasize providing 
education and assuring that appropriate protections are in place, while 
avoiding excessively bureaucratic procedures.
    Recommendation 3.3: All investigators, Institutional Review Board 
members, and Institutional Review Board staff should be certified prior 
to conducting or reviewing research involving human participants. 
Certification requirements should be appropriate to their roles and to 
the area of research. The federal government should encourage 
organizations, sponsors, and institutions to develop certification 
programs and mechanisms to evaluate their effectiveness. Federal policy 
should set standards for determining whether institutions and sponsors 
have an effective process of certification in place.
    Recommendation 3.4: Sponsors, institutions, and independent 
Institutional Review Boards should be accredited in order to conduct or 
review research involving human participants. Accreditation should be 
premised upon demonstrated competency in core areas through 
accreditation programs that are approved by the federal government.

Assessing and Monitoring Compliance

    Assessing institutional, IRB, and investigator compliance can help 
to ensure that standards are being followed consistently. Current 
mechanisms for assessment include assurances of compliance issued by 
DHHS and several other federal departments, site inspections of IRBs 
conducted by FDA, other types of site inspections for participant 
protection, and institutional audits. In addition, some institutions 
have established ongoing mechanisms for assessing investigator 
compliance with regulations. However, institutions vary considerably in 
their efforts and abilities to monitor investigator compliance, from 
those that have no monitoring programs to those that conduct random 
audits. Assessing the behavior of investigators is an important part of 
protecting research participants and should be taken seriously as a 
responsibility of each institution. Investigators, IRBs, and 
institutions should discuss the many practical issues involved in 
monitoring investigators as they conduct their research studies and 
provide input into the regulatory process.
    Recommendation 3.5: The process for assuring compliance with 
federal policy should be modified to reduce any unnecessary burden on 
institutions conducting research and to register institutions and 
Institutional Review Boards with the federal government. The assurance 
process should not be duplicative of accreditation programs for 
institutions (see Recommendation 3.4).
    Recommendation 3.6: Institutions should develop internal mechanisms 
to ensure Institutional Review Board compliance and investigator 
compliance with regulations, guidance, and institutional procedures. 
Mechanisms should be put in place for reporting noncompliance to all 
relevant parties.

Managing Conflicts of Interest

    A research setting that involves human participants necessarily 
creates a conflict of interest for investigators who seek to develop or 
revise knowledge by enrolling individuals in research protocols to 
obtain that knowledge. Overzealous pursuit of scientific results could 
lead to harm if, for example, investigators design research studies 
that pose unacceptable risks to participants, enroll participants who 
should not be enrolled, or continue studies even when results suggest 
they should have been modified or halted. Conflicts of interest can 
also exist for IRB members or the institutions in which the research 
will be conducted. Thus, it is important to address prospectively the 
potentially harmful effects on participants that conflicts of interest 
might cause.
    Organizations, particularly academic institutions, should become 
more actively involved in managing investigators' and IRB members' 
conflicts of interest and increase their efforts for self-regulation in 
this arena. IRB review of research studies is one method for 
identifying and dealing with conflicts of interest that might face 
investigators. By having IRBs review research studies prospectively and 
follow an IRB-approved protocol, investigators and IRBs together can 
manage conflict between the investigators' desire to advance scientific 
knowledge and to protect the

[[Page 46005]]

rights and welfare of research participants. Financial and other 
obvious conflicts for IRB members, such as collaboration in a research 
study, are often less difficult to identify and manage than some of the 
more subtle and pervasive conflicts. Guidance should be developed to 
assist IRBs in identifying various types of conflict.
    Recommendation 3.7: Federal policy should define institutional, 
Institutional Review Board, and investigator conflicts of interest, and 
guidance should be issued to ensure that the rights and welfare of 
research participants are protected.
    Recommendation 3.8: Sponsors and institutions should develop 
policies and mechanisms to identify and manage all types of 
institutional, Institutional Review Board, and investigator conflicts 
of interest. In particular, all relevant conflicts of interest should 
be disclosed to participants. Policies also should describe specific 
types of prohibited relationships.

IRB Membership

    Appropriate composition of IRB membership ensures that research 
studies are reviewed with the utmost regard for protecting the rights 
and welfare of research participants. Current federal regulations 
require that each IRB have ``at least one member who is not otherwise 
affiliated with the institution and who is not part of the immediate 
family of a person who is affiliated with the institution'' (45 CFR 
46.107(d); 21 CFR 56.107(d)). The regulations also require that each 
IRB include ``at least one member whose primary concerns are in 
scientific areas and at least one member whose primary concerns are in 
nonscientific areas.'' Some have raised the concern of whether only 1 
unaffiliated member on an IRB is sufficient to avoid institutional 
influence, especially when IRBs have 15 to 21 members on average. In 
addition, unaffiliated members do not have to be present for an IRB to 
conduct review and approve research studies. Thus, IRBs can approve 
research with only institutional representation present as long as a 
nonscientist and a quorum are also present. IRBs should strive to 
complement their membership by having clearly recognizable members who 
are unaffiliated with the institutions, members who are nonscientists, 
and members who represent the perspectives of participants. However, it 
is difficult to require that IRBs increase the presence and 
participation of more unaffiliated members to reduce the influence of 
institutional interests on IRB decisionmaking, because finding them can 
be difficult. Currently, there are no rules or guidance that describe 
criteria for meeting the definition of an unaffiliated member, that 
specify how long such members should serve, or that provide guidance 
regarding under what circumstances they may be removed or what payment 
should be provided. Institutions should be careful to select 
unaffiliated members who are truly separated from the institution, 
except for their role on the IRB. Procedures for the selection and 
removal of unaffiliated members should be established in a way that 
empowers the independent voices of those members. In addition, 
providing reasonable payment to IRB members who are otherwise 
unaffiliated with the institution can be a valuable way to strengthen 
these members' role.
    Recommendation 3.9: Federal policy should establish standards and 
criteria for the selection of Institutional Review Board members. The 
distribution of Institutional Review Board members with relevant 
expertise and experience should be commensurate with the types of 
research reviewed by the Institutional Review Board (see Recommendation 
3.10).
    Recommendation 3.10: Institutional Review Boards should include 
members who represent the perspectives of participants, members who are 
unaffiliated with the institution, and members whose primary concerns 
are in nonscientific areas. An individual can fulfill one, two, or all 
three of these categories. For the purposes of both overall membership 
and quorum determinations 1) these persons should collectively 
represent at least 25 percent of the Institutional Review Board 
membership and 2) members from all of these categories should be 
represented each time an Institutional Review Board meets (see 
Recommendation 3.9).

Guidance for Assessing Risks and Potential Benefits

    In addition to protecting the rights and welfare of research 
participants, it is equally important to protect them from avoidable 
harm. Thus, an IRB's assessment of the risks and potential benefits of 
research is central to determining whether a research study is 
ethically acceptable. Yet, this assessment can be a difficult one to 
make, as there are no clear criteria for IRBs to use in judging whether 
the risks of research are reasonable in terms of what might be gained 
by the individual or society. IRBs should be able to identify whether a 
clear and direct benefit to society or the research participants might 
result from participating in the study. However, IRBs should be 
cautious in classifying procedures as offering the prospect of direct 
benefit. In fact, if it is not clear that a procedure also offers the 
prospect of direct benefit, IRBs should treat the procedure as one 
solely designed to answer the research question(s). A major advantage 
of this approach is that it avoids justifying the risks of procedures 
that are designed solely to answer the research question(s) based on 
the likelihood that another procedure in the protocol would provide a 
benefit.
    Recommendation 4.1: An analysis of the risks and potential benefits 
of study components should be applied to all types of covered research 
(see Recommendation 2.4). In general, each component of a study should 
be evaluated separately, and its risks should be both reasonable in 
themselves as well as justified by the potential benefits to society or 
the participants. Potential benefits from one component of a study 
should not be used to justify risks posed by a separate component of a 
study.

Minimal Risk

    Determining whether a study poses more than minimal risk is a 
central ethical and procedural function of the IRB. The definition of 
minimal risk in federal regulations (45 CFR 46.102(i); 21 CFR 
56.102(i)) provides an ambiguous standard by which risks involved in a 
research study are compared to those encountered in daily life. 
However, it is unclear whether this applies to those risks found in the 
daily lives of healthy individuals or those of individuals who belong 
to the group targeted by the research. If it refers to the individuals 
to be involved in the research, then the same intervention could be 
classified as minimal risk or greater than minimal risk, depending on 
the health status of those participants and their particular 
experiences. According to this understanding, the standard for minimal 
risk is a relative one.
    This report recommends that IRBs use a standard related to the 
risks of daily life that are familiar to the general population for 
determining whether the level of risk is minimal or more than minimal, 
rather than using a standard that refers to the risks encountered by 
particular persons or groups. These common risks would include, for 
example, driving to work, crossing the street, getting a blood test, or 
answering questions over the telephone. Thus, research would involve no 
more than minimal risk when it is judged that the level of risk is no 
greater than that encountered in the daily lives of the general 
population.
    Recommendation 4.2: Federal policy should distinguish between 
research

[[Page 46006]]

studies that pose minimal risk and those that pose more than minimal 
risk (see Recommendation 2.5). Minimal risk should be defined as the 
probability and magnitude of harms that are normally encountered in the 
daily lives of the general population. If a study that would normally 
be considered minimal risk for the general population nonetheless poses 
higher risk for any prospective participants, then the Institutional 
Review Board should approve the study only if it has determined that 
appropriate protections are in place for all prospective participants.

Evaluating Vulnerability

    All segments of society should have the opportunity to participate 
in research, if they wish to do so and if they are considered to be 
appropriate participants for a given protocol. However, some 
individuals may need additional protections before they can fully 
participate in the research study; otherwise they might be more 
susceptible to coercion or exploitation. Individuals might be 
considered vulnerable within the research context because of intrinsic 
characteristics (e.g., they are children or have mental illness or 
retardation) or because of the situation in which they find themselves 
(e.g., they are impoverished, unemployed, or incarcerated). Recognizing 
various types of vulnerability and providing adequate safeguards can 
prove challenging for IRBs.
    Appropriate and specific safeguards should be established to 
protect persons who are categorized as vulnerable. Once safeguards are 
established, investigators should not exclude persons categorized as 
vulnerable from research involving greater than minimal risk because 
this would deprive them of whatever potential direct benefits they 
might receive from the research and deprive their communities and 
society from the benefit of the knowledge such research might generate.
    Recommendation 4.3: Federal policy should promote the inclusion of 
all segments of society in research. Guidance should be developed on 
how to identify and avoid situations that render some participants or 
groups vulnerable to harm or coercion. Sponsors and investigators 
should design research that incorporates appropriate safeguards to 
protect all prospective participants.

Emphasizing the Informed Consent Process

    Rather than focusing on the ethical standard of informed consent 
and what is entailed in the process of obtaining informed consent, IRBs 
and investigators have followed the lead of the federal regulations and 
have tended to focus on the disclosures found in the consent form. 
However, from an ethics perspective, the informed consent process, not 
the form of its documentation, is the critical communication link 
between the prospective participant and the investigator throughout a 
study, beginning when the investigator initially approaches the 
participant. Informed consent should be an active process through which 
both parties share information and during which the participant at any 
time can freely decide whether to withdraw from or continue to 
participate in the research. It is time to place the emphasis on the 
process of informed consent to ensure that information is fully 
disclosed, that competent participants fully understand the research in 
order to make informed choices, and that decisions to participate or 
not are always made voluntarily.
    Recommendation 5.1: Federal policy should emphasize the process of 
informed consent rather than the form of its documentation and should 
ensure that competent participants have given their voluntary informed 
consent. Guidance should be issued about how to provide appropriate 
information to prospective research participants, how to promote 
prospective participants' comprehension of such information, and how to 
ensure that participants continue to make informed and voluntary 
decisions throughout their involvement in the research.

Waiver of Informed Consent

    Obtaining voluntary informed consent should not be a requirement 
for every research study. In fact, waiving the informed consent process 
is justifiable in research studies that include no interaction between 
investigators and participants, such as in studies using existing 
identifiable data (e.g., studies of records) and in studies in which 
risks generally are not physical. In these kinds of research, risks are 
likely to arise from the acquisition, use, or dissemination of 
information resulting from the study and are likely to involve threats 
to privacy and breaches in confidentiality. The criteria for waiving 
informed consent in such instances should be revised, so that if such 
studies have protections in place for both privacy and confidentiality, 
IRBs may waive the requirement for informed consent.
    Recommendation 5.2: Federal policy should permit Institutional 
Review Boards in certain, limited situations (e.g., some studies using 
existing identifiable data or some observational studies) to waive 
informed consent requirements if all of the following criteria are met:
    (a) All components of the study involve minimal risk or any 
component involving more than minimal risk must also offer the prospect 
of direct benefit to participants;
    (b) The waiver is not otherwise prohibited by state, federal, or 
international law;
    (c) There is an adequate plan to protect the confidentiality of the 
data;
    (d) There is an adequate plan for contacting participants with 
information derived from the research, should the need arise; and
    (e) In analyzing risks and potential benefits, the Institutional 
Review Board specifically determines that the benefits from the 
knowledge to be gained from the research study outweigh any dignitary 
harm associated with not seeking informed consent.

Documentation of Informed Consent

    Although the federal regulations may have been intended to reflect 
a legal standard for documentation of informed consent, NBAC is aware 
of no case law in which a signed, written consent form is required. To 
fulfill the substantive ethical standard of informed consent, depending 
on the type of research proposed, it may be more appropriate to use 
other forms of documentation, such as audiotape, videotape, witnesses, 
or telephone calls to participants verifying informed consent and 
participation in the research study.
    Recommendation 5.3: Federal policy should require investigators to 
document that they have obtained voluntary informed consent, but should 
be flexible with respect to the form of such documentation. Especially 
when individuals can easily refuse or discontinue participation, or 
when signed forms might threaten confidentiality, Institutional Review 
Boards should permit investigators to use other means of verifying that 
informed consent has been obtained.

Protecting Privacy and Confidentiality

    Privacy and confidentiality are complex and poorly understood 
concepts in the context of some research. Privacy refers to the ways 
and circumstances under which investigators access information from 
participants. Because privacy concerns vary by type and context of 
research and the culture and individual circumstances of participants, 
investigators should be well informed

[[Page 46007]]

and mindful of the cultural norms of the participants. In addition, 
investigators should be aware of the various research procedures and 
methods that can be used to respect privacy. Needed is a clear, 
comprehensive regulatory definition of privacy along with guidance for 
protecting privacy in various types of research.
    Like privacy concerns, concerns about confidentiality vary by the 
type and context of the research. No one set of procedures can be 
developed to protect confidentiality in all research contexts. Thus, 
IRBs and investigators must tailor confidentiality protections to the 
specific circumstances and methods used in each specific research 
study. Further, IRBs and investigators are encouraged to consider the 
use of strong confidentiality protections, which can also reduce some 
of the violations associated with privacy. A clear, comprehensive 
definition of confidentiality is needed, along with guidance for 
protecting confidentiality in various types of research.
    Recommendation 5.4: Federal policy should be developed and 
mechanisms should be provided to enable investigators and institutions 
to reduce threats to privacy and breaches of confidentiality. The 
feasibility of additional mechanisms should be examined to strengthen 
confidentiality protections in research studies.

Monitoring of Ongoing Research

    Continual review and monitoring of research that is in progress is 
a critical element of the oversight system. Such review is necessary to 
ensure that emerging data or evidence have not altered the risks/
potential benefits assessment so that risks are no longer reasonable. 
In addition, mechanisms are needed to monitor adverse events, 
unanticipated problems, and changes to the protocol. IRBs can do a 
better job in this area with the appropriate guidance and some 
restructuring of the review and monitoring process.
    Currently, the requirement of continuing review is overly broad. 
The frequency and need for continuing review vary depending on the 
nature of research, with some protocols not requiring continuing 
review. In research involving high or unknown risks, the first few 
trials of a new intervention may substantially affect what is known 
about the risks and potential benefits of that intervention. Even if 
the knowledge does not warrant changes in study design, it may warrant 
changes in the information presented to prospective and enrolled 
participants.
    On the other hand, the ethics issues and participant protections 
necessary in minimal risk research are unlikely to be affected by 
developments from within or outside the research--for example, research 
involving the use of existing data or research that will no longer 
involve contact with participants because it is in the data analysis 
phase.
    Continuing review of such research should not be required because 
it is unlikely to provide any additional protection to research 
participants and merely increases the burden of IRBs. However, because 
minimal risk research does involve some risk, IRBs may choose to 
require continuing review. In these cases, other types of monitoring 
may be more appropriate, such as assessing investigator compliance with 
the approved protocol or reporting of protocol changes and 
unanticipated problems. Clarifying the nature of the continuing review 
requirements would allow IRBs to better focus their efforts on 
reviewing riskier research and would increase protections for 
participants where they are most needed.
    Recommendation 6.1: Federal policy should describe how sponsors, 
institutions, and investigators should monitor ongoing research.
    Recommendation 6.2: Federal policy should describe clearly the 
requirements for continuing Institutional Review Board review of 
ongoing research. Continuing review should not be required for research 
studies involving minimal risk, research involving the use of existing 
data, or research that is in the data analysis phase when there is no 
additional contact with participants. When continuing review is not 
required, other mechanisms should be in place for ensuring compliance 
of investigators and for reporting protocol changes or unanticipated 
problems encountered in the research.
    Recommendation 6.3: Federal policy should clarify when changes in 
research design or context require review and new approval by an 
Institutional Review Board.

Adverse Event Reporting

    Assessing adverse events reports can be a major burden for IRBs and 
investigators because of the high volume and ambiguous nature of such 
events and the complexity of the pertinent regulatory requirements. 
Investigators have reported frustration in attempting to understand 
what constitutes an adverse event, the required reporting times, and to 
whom adverse events should be reported. The regulations need to be 
simplified, and one set of regulations should be available for safety 
monitoring. Regulations and guidance should be written so that 
investigators and sponsors understand what constitutes an adverse 
event, what type of event must be reported within what time period, and 
to whom it should be reported. In addition, regulations and guidance 
should be clear regarding whose responsibility it is to analyze and 
evaluate adverse event reports and should describe the required 
communication and coordination channels for these reports among IRBs 
and safety monitoring entities, such as Data Safety Monitoring Boards, 
investigators, sponsors, and federal agencies.
    Recommendation 6.4: The federal government should create a uniform 
system for reporting and evaluating adverse events occurring in 
research, especially in multi-site research. The reporting and 
evaluation responsibilities of investigators, sponsors, Institutional 
Review Boards, Data Safety Monitoring Boards, and federal agencies 
should be clear and efficient. The primary concern of the reporting 
system should be to protect current and prospective research 
participants.

Review of Cooperative or Multi-Site Research Studies

    One of the greatest burdens on IRBs and investigators is the review 
of multi-site studies. Requiring multiple institutions to review the 
same protocol is unnecessarily taxing and provides no additional 
protection to participants. In addition, such review poses problems in 
the initial stages of review as well as in the continual review and 
monitoring stages and is especially problematic in the evaluation of 
adverse events in clinical research. Innovative and creative 
alternative mechanisms and processes for reviewing protocols in multi-
site research are needed. To allow for such projects and to support a 
change in the current system toward a more flexible review system, 
federal policy should be clear about the functions that must be 
performed, but be less restrictive about who performs each function.
    Recommendation 6.5: For multi-site research, federal policy should 
permit central or lead Institutional Review Board review, provided that 
participants' rights and welfare are rigorously protected.

Compensation for Research-Related Injuries

    Participants who volunteer to be in a research study and are harmed 
as a direct result of that study should be cared for and compensated. 
However, no adequate database exists that describes the number of 
injuries or illnesses that are suffered by research

[[Page 46008]]

participants, the proportion of these illnesses or injuries that are 
caused by the research, and the medical treatment and rehabilitation 
expenses that are subsequently borne by the participants. It may be 
argued that regardless of the magnitude of the problem, the costs of 
research injuries should never be borne by participants. If individuals 
are injured by research participation, those who benefit from the 
research (e.g., institutions and sponsors) bear some obligation to 
compensate those who risked and suffered injury on their behalf. At 
this time, injured research participants alone bear both the cost of 
lost health and the expense of medical care, unless they have adequate 
health insurance or successfully pursue legal action to gain 
compensation from the specific individuals or organizations that were 
involved in conducting the research.
    A comprehensive system of oversight of human research should 
include a mechanism to compensate participants for medical and 
rehabilitative costs resulting from research-related injuries.
    Recommendation 6.6: The federal government should study the issue 
of research-related injuries to determine if there is a need for a 
compensation program. If needed, the federal government should 
implement the recommendation of the President's Commission for the 
Study of Ethical Problems in Medicine and Biomedical and Behavioral 
Research (1982) to conduct a pilot study to evaluate possible program 
mechanisms.

The Need for Resources

    Adopting the recommendations made in this report will generate 
additional costs for institutions, sponsors, and the federal government 
(through the establishment of a new federal oversight office). Sponsors 
of research, whether public or private, should work together with 
institutions carrying out the research to make the necessary funds 
available.
    Recommendation 7.1: The proposed oversight system should have 
adequate resources to ensure its effectiveness and ultimate success in 
protecting research participants and promoting research:
    (a) Funds should be appropriated to carry out the functions of the 
proposed federal oversight office as outlined in this report.
    (b) Federal appropriations for research programs should include a 
separate allocation for oversight activities related to the protection 
of human participants.
    (c) Institutions should be permitted to request funding for 
Institutional Review Boards and other oversight activities.
    (d) Federal agencies, other sponsors, and institutions should make 
additional funds available for oversight activities.

Future Research

    This report raises many questions about ethical issues that cannot 
be answered because of insufficient or nonexistent empirical evidence. 
Current thinking about ethical issues in research--such as analysis of 
risks and potential benefits, informed consent, privacy and 
confidentiality, and vulnerability--would greatly benefit from 
additional research. Deserving of more study, for example, are 
questions regarding the development of effective approaches for 
assessing cognitive capacity, for evaluating what participants want to 
know about research, and for determining how to ascertain best 
practices for seeking informed consent. Clearer and more effective 
guidance could be developed from a stronger knowledge base. In general, 
understanding the ethical conduct of research would be advanced by 
increased interdisciplinary discussion that would include biomedical 
and social scientists, lawyers, and historians.
    Recommendation 7.2: The federal government, in partnership with 
academic institutions and professional societies, should facilitate 
discussion about emerging human research protection issues and develop 
a research agenda that addresses issues related to research ethics.

Notes

    1. For example, the Office for Human Research Protections is 
implementing a new process by which institutions assure future 
compliance with human participant protections. The Institute of 
Medicine has recently issued a report on accreditation standards for 
IRBs (IOM 2001). Public Responsibility in Medicine and Research has 
established training programs and has co-founded a new organization, 
the Association for the Accreditation of Human Research Protection 
Programs.
    2. To date, NBAC has issued five reports: Cloning Human Beings 
(NBAC 1997), Research Involving Persons with Mental Disorders That 
May Affect Decisionmaking Capacity (NBAC 1998), Ethical Issues in 
Human Stem Cell Research (NBAC 1999a), Research Involving Human 
Biological Materials: Ethical Issues and Policy Guidance (NBAC 
1999b), and Ethical and Policy Issues in International Research: 
Clinical Trials in Developing Countries (NBAC 2001).
    3. United States v. Karl Brandt et al., Trials of War Criminals 
Before the Nuremberg Military Tribunals Under Control Council Law 
10. Nuremberg, October 1946--April 1949. Volumes I-II. Washington, 
DC: U.S. Government Printing Office.
    4. There are, of course, some circumstances in which consent 
cannot be obtained and in which an overly rigid adherence to this 
principle would preclude research that is either benign or 
potentially needed by the participant him or herself. Thus, NBAC 
endorses the current exceptions for research that is of minimal risk 
to participants and for potentially beneficial research in emergency 
settings where no better alternative for the participants exists. 
NBAC also urges attention to emerging areas of record, database, and 
tissue bank research in which consent serves only as a sign of 
respect and in which alternative ways to respect participants do 
exist (NBAC 1999b; 21 CFR 50.24). In a previous report, the 
Commission made recommendations regarding persons who lack 
decisionmaking capacity and from whom informed consent cannot be 
obtained (NBAC 1998).
    5. Porter, J., Testimony before NBAC. November 23, 1997. 
Bethesda, Maryland. See McCarthy, C.R., ``Reflections on the 
Organizational Locus of the Office for Protection from Research 
Risks.'' This background paper was prepared for NBAC and is 
available in Volume II of this report.
    6. See Goldman, J., and A. Choy, ``Privacy and Confidentiality 
in Health Research'' and Sieber, J., ``Privacy and Confidentiality: 
As Related to Human Research in Social and Behavioral Science.'' 
These background papers were prepared for NBAC and are available in 
Volume II of this report. See also Ferguson v. City of Charleston 
121 S. Ct. 1281. (2001).

References

Beecher, H.K. 1966. ``Ethics and Clinical Research.'' New England 
Journal of Medicine 274(24):1354-1360.
Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of 
Informed Consent. New York: Oxford University Press.
Institute of Medicine (IOM). 2001. Preserving Public Trust: 
Accreditation and Human Research Participant Protection Programs. 
Washington, DC: National Academy Press.
Jonas, H. 1969. ``Philosophical Reflections on Experimenting with 
Human Subjects.'' Daedalus 98:219-247.
Jones, J.H. 1981. Bad Blood: The Tuskegee Syphilis Experiment. New 
York: The Free Press.
Katz, J. 1972. Experimentation with Human Beings. New York: Russell 
Sage Foundation.
National Bioethics Advisory Commission (NBAC). 1997. Cloning Human 
Beings. 2 vols. Rockville, MD: U.S. Government Printing Office.
------. 1998. Research Involving Persons with Mental Disorders That 
May Affect Decisionmaking Capacity. 2 vols. Rockville, MD: U.S. 
Government Printing Office.
------. 1999a. Ethical Issues in Human Stem Cell Research. 3 vols. 
Rockville, MD: U.S. Government Printing Office.
------. 1999b. Research Involving Human Biological Materials: 
Ethical Issues and Policy Guidance. 2 vols. Rockville, MD: U.S. 
Government Printing Office.
------. 2001. Ethical and Policy Issues in International Research: 
Clinical Trials in Developing Countries. 2 vols. Bethesda, MD: U.S. 
Government Printing Office.

[[Page 46009]]

National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (National Commission). 1979. 
Belmont Report: Ethical Principles and Guidelines for the Protection 
of Human Subjects of Research. Washington, DC: U.S. Government 
Printing Office.
    Tuskegee Syphilis Study Ad Hoc Advisory Panel. 1973. Final 
Report. Washington, DC: U.S. Department of Health, Education, and 
Welfare.


FOR FURTHER INFORMATION ABOUT THE REPORT CONTACT: Marjorie A. Speers, 
Ph.D., Acting Executive Director, National Bioethics Advisory 
Commission, or to obtain copies of the report contact the NBAC office 
at 6705 Rockledge Drive, Suite 700, Bethesda, Maryland 20892-7979, 
telephone number (301) 402-4242, fax number (301) 480-6900. Copies may 
also be obtained through the NBAC website: www.bioethics.gov.

    Dated: August 27, 2001.
Glen D. Drew,
Acting Executive Director, National Bioethics Advisory Commission
[FR Doc. 01-22038 Filed 8-30-01; 8:45 am]
BILLING CODE 4167-01-P