[Federal Register Volume 66, Number 94 (Tuesday, May 15, 2001)]
[Notices]
[Pages 26856-26866]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-12142]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Reports and Guidance Documents; Availability, etc.: Ethical and 
Policy Issues in International Research; Clinical Trials in Developing 
Countries

SUMMARY: Notice of Publication of the Executive Summary of the report, 
``Ethical and Policy Issues in International Research: Clinical Trials 
in Developing Countries'', 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:

[[Page 26857]]

    (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.

Ethical and Policy Issues in International Research: Clinical 
Trials in Developing Countries; Executive Summary

Introduction

    In recent years, the increasingly global nature of health research, 
and in particular the conduct of clinical trials involving human 
participants (1), has highlighted a number of ethical issues, 
especially in those situations in which researchers or research 
sponsors from one country wish to conduct research in another country. 
The studies in question might simply be one way of helping the host 
country address a public health problem, or they might reflect a 
research sponsor's assessment that the foreign location is a more 
convenient, efficient, or less troublesome site for conducting a 
particular clinical trial. They might also represent a joint effort to 
address an important health concern faced by both parties.
    As the pace and scope of international collaborative biomedical 
research have increased during the past decade, long-standing questions 
about the ethics of designing, conducting, and following up on 
international clinical trials have reemerged. Some of these issues have 
begun to take center stage because of the concern that research 
conducted by scientists from more prosperous countries in poorer 
nations that are more heavily burdened by disease may, at times, be 
seen as imposing ethically inappropriate burdens on the host country 
and on those who participate in the research trials. The potential for 
such exploitation is cause for a concerted effort to ensure that 
protections are in place for all persons who participate in 
international clinical trials.
    As with other National Bioethics Advisory Commission (NBAC) 
reports, several issues and activities prompted the Commission's 
decision to address this topic. First, several members of the public 
suggested that NBAC's mandate to examine the protection of the rights 
and welfare of human participants in research extends to international 
research conducted or sponsored by U.S. interests. In this respect, one 
particular dimension of research conducted internationally has 
attracted a great deal of attention, namely whether the existing rules 
and regulations that normally govern the conduct of U.S. investigators 
or others subject to U.S. regulations remain appropriate in the context 
of international research, or whether they unnecessarily complicate or 
frustrate otherwise worthy and ethically sound research projects.
    A second circumstance--the changing landscape of international 
research--also is relevant. Increasingly, scientists from developing 
countries are becoming more involved as collaborators in research, as 
many of the countries from which these investigators come have 
developed their capacity for technical contributions to research 
projects and for appropriate ethical review of research protocols. 
Although the source of funding for such collaborative research is 
likely to continue to be the wealthier, developed countries, 
collaborators from developing countries are seeking--justifiably--to 
become fuller and more equal partners in the research enterprise. 
Finally, the current landscape of international research also reflects 
the growing importance of clinical trials conducted by pharmaceutical, 
biotechnology, and medical device companies. Some observers believe 
that market forces have pressured private companies to become more 
efficient in the conduct of research, which may--absent vigilance--
compromise the protection of research participants. Although the 
extent, relevance, and force of these pressures are widely debated, it 
is clear that such pressures can exist regardless of the funding 
source.

Scope of This Report

    This report discusses the ethical issues that arise when research 
that is subject to U.S. regulation is sponsored or conducted in 
developing countries, where local technical skills and other key 
resources are in relatively scarce supply. Within this context, the 
Commission's attention was focused on the conduct of clinical trials 
involving competent adults, in particular those trials--such as Phase 
III drug studies--that can lead to the development of effective new 
treatments. Complex and important ethical concerns are likely to be 
more pressing in clinical trials than in many other types of research 
investigations; thus, the focus of this report has been limited 
accordingly. Although much of the discussion in this report is relevant 
to other types of research, the particular characteristics of research 
endeavors other than clinical trials probably merit their own ethical 
assessment.
    This report centers on the principal ethical requirements 
surrounding the conduct of clinical trials conducted by U.S. interests 
abroad, and in particular the need for such trials to be directly 
relevant to the health needs of the host country. Other major topics 
addressed include ethical issues surrounding the choice of research 
designs, especially in situations where a placebo control is proposed 
when an established effective treatment is known to exist; issues 
arising in the informed consent process in cultures whose norms of 
behavior differ from those in the United States; what benefits should 
be provided to research participants and by whom after their 
participation in a trial has ended; and what benefits, if any, should 
be made available to others in the host community or country. Finally, 
it makes recommendations about the need for developed countries to 
assist developing countries in building the capacity to become fuller 
partners in international research. Until this goal can be met, 
however, recommendations are made regarding how the United States 
should

[[Page 26858]]

proceed in settings in which systems for protecting human participants 
equivalent to those of the United States have not yet been established.

Essential Requirements for the Ethical Conduct of Clinical Trials

    Many of the ethical concerns regarding the treatment of human 
participants in international research are similar to those raised in 
conjunction with research conducted in the United States (2). They 
include, among others, choosing the appropriate research question and 
design; ensuring prior scientific and ethical review of the proposed 
protocol; selecting participants equitably; obtaining voluntary 
informed consent; and providing appropriate treatment to participants 
during and after the trial. These concerns are consistent with 
principles endorsed in many international research ethics documents.
    NBAC believes that two types of ethical requirements--substantive 
and procedural--must be carefully considered and distinguished when 
human research is conducted, regardless of the location. The principles 
embodied in the ``Belmont Report: Ethical Principles and Guidelines for 
the Protection of Human Subjects of Research'' serve as a foundation 
for the substantive ethical requirements incorporated into the system 
of protection of human participants in the United States. The ``Belmont 
Report'' sets forth three basic ethical principles, which provide an 
analytical framework for understanding many of the ethical issues 
arising from research involving human participants: respect for 
persons, beneficence, and justice. NBAC believes that in order to be 
ethically sound, research conducted with human beings must, at a 
minimum, be consistent with the ethical principles underlying the 
``Belmont Report''. In addition, ethically sound research must satisfy 
a number of important procedural requirements, including prior ethical 
review by a body that is competent to assess compliance with these 
substantive ethical principles. U.S. research regulations also set 
forth more specific rules to guide ethics review committees (3) (and 
researchers) in their work. NBAC believes that when conducting clinical 
trials abroad, U.S. researchers and sponsors should comply with these 
substantive ethical requirements for the protection of human research 
participants.
    Recommendation 1.1 lists protections that should be provided for 
individuals participating in U.S. government-sponsored clinical trials, 
whether conducted domestically or abroad (4). Although existing U.S. 
law and regulations impose limits on the extent to which non-federally 
funded research is subject to oversight, the Commission believes that 
these requirements should extend to all clinical trials, regardless of 
who sponsors or conducts them.

Recommendation 1.1

    The U.S. government should not sponsor or conduct clinical trials 
that do not, at a minimum, provide the following ethical protections:
    (a) prior review of research by an ethics review committee(s);
    (b) minimization of risk to research participants;
    (c) risks of harm that are reasonable in relation to potential 
benefits;
    (d) adequate care of and compensation to participants for injuries 
directly sustained during research;
    (e) individual informed consent from all competent adult 
participants in research;
    (f) equal regard for all participants; and
    (g) equitable distribution of the burdens and benefits of research.

Recommendation 1.2

    The Food and Drug Administration should not accept data obtained 
from clinical trials that do not provide the substantive ethical 
protections outlined in Recommendation 1.1.

Responsiveness of the Research to the Health Needs of the 
Population

    Sponsoring or conducting research in developing countries often 
poses special challenges arising from the combined effects of 
distinctive histories, cultures, politics, judicial systems, and 
economic situations. In addition, in countries in which extreme poverty 
afflicts so many, primary health care services generally are 
inadequate, and a majority of the population is unable to gain access 
to the most basic and essential health products and services. As a 
result of these difficult conditions, the people in these countries are 
often more vulnerable in situations (such as clinical trials) in which 
the promise of better health seems to be within reach.
    Whether the research sponsor is the U.S. government or a private 
sector organization, some justification is needed for conducting 
research abroad other than a less stringent or troublesome set of 
regulatory or ethical requirements. Moreover, when the United States 
(or any developed country) proposes to sponsor or conduct research in 
another country when the same research could not be conducted ethically 
in the sponsoring country, the ethical concerns are more profound, and 
the research accordingly requires a more rigorous justification.
    To meet the ethical principle of beneficence, the risks involved in 
any research with human beings must be reasonable in relation to the 
potential benefits. Plainly, the central focus of any assessment of 
risk is the potential harm to research participants themselves (in 
terms of probability and magnitude), although risks to others also are 
relevant. The potential benefits that are weighed against such risks 
may include those that will flow to the fund of human knowledge as well 
as to those now and in the future whose lives may be improved because 
of the research. In addition, some of the benefits must also accrue to 
the group from which the research participants are selected. NBAC 
understands the principle of justice to require that a population, 
especially a vulnerable one, should not be the focus of research unless 
some of the potential benefits of the research will accrue to that 
group after the trial. Thus, in the context of international research--
and particularly when the population of a developing country has been 
sought as a source of research participants--U.S. and international 
research ethics require not merely that research risks are reasonable 
in relation to potential benefits, but also that they respond to the 
health needs of the population being studied. This is because, 
according to the principles of beneficence and justice, only research 
that is responsive to these needs can offer relevant benefits to the 
population.

Recommendation 1.3

    Clinical trials conducted in developing countries should be limited 
to those studies that are responsive to the health needs of the host 
country.

Choosing a Research Design and the Relevance of Routine Care

    Making a determination about the appropriate design for a clinical 
trial depends on various contextual considerations, so that what might 
be an ethically acceptable design in one situation could be problematic 
in another. For example, it might be unethical to conduct a clinical 
trial for a health condition in a country in which that condition is 
unlikely to be found. In comparison, the same trial might be quite 
appropriately conducted where the trial results could be important to 
the local population. A more challenging question is whether a research 
design that could not be ethically implemented in the sponsoring 
country can be ethically justified in a host country when the health 
problem

[[Page 26859]]

being addressed is common to both nations.
    In this report, NBAC is especially interested in exploring the 
following question: Can a research design that could not be ethically 
implemented in the sponsoring, developed country be ethically justified 
in the country in which the research is conducted? In all cases, there 
is an ethical requirement to choose a design that minimizes the risk of 
harm to human participants in clinical trials and that does not exploit 
them. Because the choice of a study design for any particular trial 
will depend on these and other factors, it would be inappropriate--
indeed wrong--to prescribe any particular study design as ethical for 
all research situations. Nevertheless, under certain, specified 
conditions, one or another design can be held to be ethically 
preferable.

Recommendation 2.1

    Researchers should provide ethics review committees with a thorough 
justification of the research design to be used, including the 
procedures to be used to minimize risks to participants.

Providing Established Effective Treatment as the Control

    From the perspective of the protection of human participants in 
research, one of the most critical issues in clinical trial design 
concerns the use and treatment of control groups, which often are an 
essential component in methodologies used to guard against bias. 
Although placebos are a frequently used control for clinical trials, it 
is increasingly commonplace to compare an experimental intervention to 
an existing established effective treatment. These types of studies are 
called active-control (or positive control) studies, which are often 
extremely useful in cases in which it would not be ethical to give 
participants a placebo because doing so would pose undue risk to their 
health or well-being.
    Within the context of active treatment concurrent controls, it is 
useful to consider whether, and if so under what circumstances, 
researchers and sponsors have an obligation to provide an established 
effective treatment to the control group even if it is not available in 
the host country. This report adopts the phrase an established 
effective treatment to refer to a treatment that is established (it has 
achieved widespread acceptance by the global medical profession) and 
effective (it is as successful as any in treating the disease or 
condition). It does not mean that the treatment is currently available 
in that country.
    Investigators must carefully explain and ethics review committees 
must cautiously scrutinize the justification for the selection of the 
research design, including the level of care provided to the control 
group. If in a proposed clinical trial the control group will receive 
less care than would be available under ideal circumstances, the burden 
on the investigator to justify the design should be heavier. 
Furthermore, representatives of the host country, including scientists, 
public officials, and persons with the condition under study, should 
have a strong voice in determining whether a proposed trial is 
appropriate.

Recommendation 2.2

    Researchers and sponsors should design clinical trials that provide 
members of any control group with an established effective treatment, 
whether or not such treatment is available in the host country. Any 
study that would not provide the control group with an established 
effective treatment should include a justification for using an 
alternative design. Ethics review committees must assess the 
justification provided, including the risks to participants, and the 
overall ethical acceptability of the research design.

Community Involvement in Research Design and Implementation

    Over the past three decades, researchers increasingly have 
deliberately involved communities in the design of research. In 
addition, research participants, health advocates, and other members of 
the communities from which participants are recruited have requested, 
and in some cases demanded, involvement in the design of clinical 
trials. By consulting with the community, researchers often gain 
insight about whether the research question is relevant and responsive 
to health needs of the community involved.
    In addition, community consultation can improve the informed 
consent process and resolve problems that arise in this process because 
of the use of difficult or unfamiliar concepts. Such discussions can 
provide insight into whether the balance of benefits and harms in the 
study is considered acceptable and whether the interventions and 
follow-up procedures are satisfactory. Community consultation is 
particularly important when the researcher does not share the culture 
or customs of the population from which research participants will be 
recruited.

Recommendation 2.3

    Researchers and sponsors should involve representatives of the 
community of potential participants throughout the design and 
implementation of research projects. Researchers should describe in 
their proposed protocol how this will be done, and ethics review 
committees should review the appropriateness of this process. When 
community representatives will not be involved, the protocol presented 
to the ethics committee should justify why such involvement was not 
possible or relevant.

Fair and Respectful Treatment of Participants

    The requirement to obtain voluntary informed consent from human 
participants before they are enrolled in research is a fundamental 
tenet of research ethics. It was the first requirement proclaimed in 
the Nuremberg Code in 1947, and it has appeared in all subsequent 
published national and international codes, regulations, and guidelines 
pertaining to research ethics, including those in many developing 
countries.
    Nevertheless, discussion is ongoing about the value and importance 
of particular procedural approaches to informed consent in other 
countries. Problems involving the interpretation and application of the 
requirement to obtain voluntary informed consent--and its underlying 
ethical principles--arise for researchers, ethics review committees, 
and others. In some countries, the methods used in U.S.-based studies 
for identifying appropriate groups for study, enrolling individuals 
from those groups in a protocol, and obtaining informed voluntary 
consent might not succeed because of different cultural or social 
norms. Meeting the challenge of developing alternative methodologies 
requires careful attention to the ethical issues involved in recruiting 
research participants and obtaining their consent, which is necessary 
in order to ensure justice in the conduct of research and to avoid the 
risk of exploitation.

Recommendation 3.1

    Research should not deviate from the substantive ethical standard 
of voluntary informed consent. Researchers should not propose, sponsors 
should not support, and ethics review committees should not approve 
research that deviates from this substantive ethical standard.

[[Page 26860]]

Disclosure Requirements

    The basic disclosure requirements for satisfying the informed 
consent provisions in U.S. research regulations focus on the 
information needed by a potential participant in order to decide 
whether or not to participate in a study. Requirements for disclosure 
of information in the research setting usually exceed those for 
disclosure in clinical contexts. Indeed, the extent of disclosure of 
medical information to patients in clinical settings differs among 
cultures and can influence judgments about the amount and kind of 
information that should be disclosed in research settings. In the 
United States, the requirements for disclosure of information to 
potential participants in research are specific and detailed (45 CFR 
46.116). The Commission has found some evidence that disclosures 
relating to diagnosis and risk, research design, and possible post-
trial benefits are not always clearly presented in clinical trials 
conducted in developing countries, even though the current U.S. 
regulations include such requirements. For example, one disclosure 
requirement in the U.S. regulations focuses on potential benefits: ``a 
description of any benefits to the subject or to others which may 
reasonably be expected from the research'' (45 CFR 46.116(a)(1)). 
Traditionally, such a disclosure has been required to ensure that 
potential participants understand whether there is any possibility that 
the intervention itself might benefit them while they are enrolled in 
the study. There is, however, no specific mention of any possible post-
trial benefits in current U.S. regulations. The Commission believes 
that, because this information is relevant to participants' decisions 
to participate in the trial, prospective participants should be 
informed of the potential benefits, if any, that they might receive 
after the trial is over.

Recommendation 3.2

    Researchers should develop culturally appropriate ways to disclose 
information that is necessary for adherence to the substantive ethical 
standard of informed consent, with particular attention to disclosures 
relating to diagnosis and risk, research design, and possible post-
trial benefits. Researchers should describe in their protocols and 
justify to the ethics review committee(s) the procedures they plan to 
use for disclosing such information to participants.

Recommendation 3.3

    Ethics review committees should require that researchers include in 
the informed consent process and consent documents information about 
what benefits, if any, will be available to research participants when 
their participation in the study in question has ended.

Ensuring Comprehension

    In some cultures, the belief system of potential research 
participants does not explain health and disease using the concepts and 
terms of modern medical science and technology. However, despite this 
potential barrier to adequate understanding, if they are willing to 
devote the time and effort to do so, researchers often are often able 
to devise creative measures to overcome this barrier. Despite the 
acknowledged difficulties of administering tests of understanding, NBAC 
supports the idea of incorporating these tests into research protocols.

Recommendation 3.4

    Researchers should develop procedures to ensure that potential 
participants do, in fact, understand the information provided in the 
consent process and should describe those procedures in their research 
protocols.

Recommendation 3.5

    Researchers should consult with community representatives to 
develop innovative and effective means to communicate all necessary 
information in a manner that is understandable to potential 
participants. When community representatives will not be involved, the 
protocol presented to the ethics review committee should justify why 
such involvement is not possible or relevant.

Recognizing the Role of Others in the Consent Process

    In some cultures, investigators must obtain permission from a 
community leader or village council before approaching potential 
research participants. Yet, it is important to distinguish between 
obtaining permission to enter a community for the purpose of conducting 
research and for obtaining individual informed consent. In their 
reports, NBAC consultants all noted that the role of community leaders 
or elders is an integral part of the process of recruiting research 
participants. Although these reports typically use the terminology of 
consent to refer to the community's permission or a leader's 
authorization for the researchers to approach individuals, NBAC will 
use this term to refer to the permission or authorization given by the 
individual being recruited as a research participant.
    The need to obtain permission from a community leader before 
approaching individuals does not need to compromise the ethical 
standard requiring the individual's voluntary informed consent to 
participate in research. Gaining permission from a community leader is 
no different, in many circumstances, from the common requirement in 
this country of obtaining permission from a school principal before 
involving pupils in research or from a nursing home director before 
approaching individual residents. An ethical problem arises only when 
the community leader exerts pressure on the community in a way that 
compromises the voluntariness of individual consent. In NBAC's view, if 
the political system in a country or the local situation makes it 
impossible for individuals' consent to be voluntary and that fact is 
known in advance, then, because U.S. researchers cannot adhere to the 
substantive ethical standard of informed consent, it would be 
inappropriate for them to choose such settings.

Recommendation 3.6

    Where culture or custom requires that permission of a community 
representative be granted before researchers may approach potential 
research participants, researchers should be sensitive to such local 
requirements. However, in no case may permission from a community 
representative or council replace the requirement of a competent 
individual's voluntary informed consent.

Recommendation 3.7

    Researchers should strive to ensure that individuals agree to 
participate in research without coercion or undue inducements from 
community leaders or representatives.

Family Members

    It is customary although not required in some societies for other 
members of a potential research participant's family to be involved in 
the informed consent process. For example, in cultures in which men are 
expected to speak for their unmarried adult daughters and husbands are 
expected to speak for their wives, a woman may not be permitted to 
consent on her own behalf to participate in research. In most 
instances, the need to involve the family is not intended as a 
substitute for individual consent, but rather as an additional step in 
the process. In many cases, family members may be

[[Page 26861]]

approached before an individual is asked directly to participate in a 
research project. However, seeking permission from family members 
without engaging the potential research participants at all clearly 
departs from the ethical standard of informed consent. On the other 
hand, potential participants might also choose to involve others, such 
as family members, in the consent process. Indeed, involving family or 
community members in the informed consent process need not diminish, 
and might even enhance, the individual's ability to make his or her own 
choices and to give informed consent (or refusal).
    It is often possible to obtain individual informed consent, which 
may require and indeed benefit from the involvement of family or 
community members, while at the same time preserving cultural norms. 
Such involvement ranges from providing written information sheets for 
potential participants to take home and discuss with family members to 
holding community meetings during which information is presented about 
the research and community consensus is obtained. When the potential 
participant wishes to involve family members in the consent discussion, 
the researcher should take appropriate steps to accommodate this 
desire.

Recommendation 3.8

    When a potential research participant wishes to involve family 
members in the consent process, the researcher should take appropriate 
steps to accommodate this wish. In no case, however, may a family 
member's permission replace the requirement of a competent individual's 
voluntary informed consent.

Consent by Women

    A strict requirement that a husband must first grant permission 
before researchers may enroll his wife in research treats the woman as 
subordinate to her husband and as less than fully autonomous. In 
reality, it may be impossible to conduct some research on common, 
serious health problems that affect only women without involving the 
husband in the consent procedures. In such cases, a likely consequence 
would be a lack of knowledge on which to base health care decisions for 
women in that country. The prospect of denying such a substantial 
benefit to all women in a particular culture or country calls for a 
narrow exception to the requirement that researchers use the same 
procedures in the consent process for women as for men, one that would 
allow for obtaining the permission of a man in addition to the woman's 
own consent.

Recommendation 3.9

    Researchers should use the same procedures in the informed consent 
process for women and men. However, ethics review committees may accept 
a consent process in which a woman's individual consent to participate 
in research is supplemented by permission from a man if all of the 
following conditions are met:
    (a) it would be impossible to conduct the research without 
obtaining such supplemental permission; and
    (b) failure to conduct this research could deny its potential 
benefits to women in the host country; and
    (c) measures to respect the woman's autonomy to consent to research 
are undertaken to the greatest extent possible.
    In no case may a competent adult woman be enrolled in research 
solely upon the consent of another person; her individual consent is 
always required.

Minimizing the Therapeutic Misconception

    One barrier to understanding the relevant, important aspects of any 
proposed research is what has been called the therapeutic 
misconception. This term refers to the belief that the purpose of a 
clinical trial is to benefit the individual patient rather than to 
gather data for the purpose of contributing to scientific knowledge. 
The therapeutic misconception has been documented in a wide range of 
developing and developed countries.
    It is important to distinguish the confusion that arises from the 
therapeutic misconception from a related consideration. In the research 
setting, participants often receive beneficial clinical care. In some 
developing countries, the type and level of clinical care provided to 
research participants may not be available to those individuals outside 
the research context. It is not a misconception to believe that 
participants probably will receive good clinical care during research. 
But it is a misconception to believe that the purpose of clinical 
trials is to administer treatment rather than to conduct research. 
Researchers should make clear to research participants, in the initial 
consent process and throughout the study, which activities are elements 
of research and which are elements of clinical care.

Recommendation 3.10

    Researchers working in developing countries should indicate in 
their research protocols how they would minimize the likelihood that 
potential participants will believe mistakenly that the purpose of the 
research is solely to administer treatment rather than to contribute to 
scientific knowledge (see also Recommendation 3.2).

Addressing Procedural Requirements in the Consent Process

    A number of issues may arise during the process of obtaining 
informed consent that require careful scrutiny before determining 
whether voluntary informed consent can be obtained. These include, for 
example, determining when it is necessary to obtain written consent and 
when oral consent should be permitted; when, if ever, it is appropriate 
to withhold important and relevant information from potential 
participants; the need in some cultures to obtain a community leader's 
or a family member's permission before seeking an individual's consent; 
and standards of disclosure for research participants in cultures in 
which people lack basic information about modern science or reject 
scientific explanations of disease in favor of traditional 
nonscientific beliefs.
    In light of the cultural variation that might arise in 
international clinical trials, the Commission was especially interested 
in problems that may arise from expecting researchers in developing 
countries to adhere strictly to the substantive and procedural 
imperatives of the U.S. requirements for informed consent. NBAC was 
particularly interested in exploring ways of dealing with the situation 
that arises when cultural differences between the United States and 
other countries make it difficult or impossible to adhere strictly to 
the U.S. regulations that stipulate particular procedures for obtaining 
informed consent from individual participants. In general, it is 
important to distinguish procedural difficulties from those that 
reflect substantive differences in ethical standards. Clearly, more 
research is needed in this area.

Recommendation 3.11

    U.S. research regulations should be amended to permit ethics review 
committees to waive the requirements for written and signed consent 
documents in accordance with local cultural norms. Ethics review 
committees should grant such waivers only if the research protocol 
specifies how the researchers and others could verify that research 
participants have given their voluntary informed consent.

[[Page 26862]]

Recommendation 3.12

    The National Institutes of Health, the Centers for Disease Control 
and Prevention, and other U.S. departments and agencies should support 
research that addresses specifically the informed consent process in 
various cultural settings. In addition, those U.S. departments and 
agencies that conduct international research should sponsor workshops 
and conferences during which international researchers can share their 
knowledge of the informed consent process.

Access to Post-Trial Benefits

    Discussions of the ethics of research with human beings usually 
center on issues regarding research design and approval and how 
individuals' rights and welfare are protected when they are enrolled in 
research protocols. The same has been true of the U.S. regulations, 
which only tangentially address what happens after a research project 
has ended by requiring that research participants must be informed in 
advance about what compensation, if any, will be provided if they are 
injured during the course of the research. Other questions about what 
should happen after a trial is completed are left unaddressed by U.S. 
guidelines.
    Thus, central questions in the context of international research 
include the following: What benefits (in the form of a proven, 
effective medical intervention) should be provided to research 
participants, and by whom, after their participation in a trial has 
ended, and what, if anything, should be made available to others in the 
host community or country? Although these questions are relevant in 
terms of the ethical assessment of research--regardless of where the 
research is conducted--they are being posed with special force, 
especially regarding serious diseases that affect large numbers of 
people in developing countries. Therefore, the question of what 
benefits, if any, research sponsors should make available to 
participants or others in the host country at the conclusion of a 
clinical trial is particularly significant for those who live in 
developing countries in which neither the government nor the vast 
majority of the citizenry can afford the intervention resulting from 
the research. Of course, this is especially germane when a drug is 
proven to be effective in a clinical trial.
    An ethically relevant feature that distinguishes most developing 
from developed countries is the lack of access to adequate health care 
by a large majority of the population. Many developed countries have 
long provided universal access to primary health care through a 
national health service or government-based insurance system. However, 
in the developing world, especially in the poorest countries in Africa 
and Asia, substantially fewer health care services are available (if 
any), and where they are available, access is severely limited. Access 
to health care is an important issue in research ethics, because an 
ethically appropriate clinical trial design requires an assessment of 
the level and nature of care or treatment available outside the 
research context, as well as any possible future health benefits that 
might arise from the research.
    Recognizing that it is sometimes difficult to distinguish research 
from treatment when routine health care is inadequate or nonexistent, 
it cannot be denied that it may be difficult for participants, whose 
health status may be altered by their participation in a clinical 
trial, to distinguish between participating in research and receiving 
clinical care. Consequently, if all interventions by the research team 
cease at the end of a trial, participants may experience a loss and 
feel that the researchers in their clinical role have abandoned them. 
This sense of loss can take several forms, the starkest of which arises 
when participants are left worse off at the conclusion of the trial 
than they were before the clinical trial began. Being worse off does 
not mean that they were harmed by the research. It can simply mean that 
their medical condition has deteriorated because they were in what 
turned out to be the less advantageous arm of the protocol. Such an 
outcome--particularly when participants are worse off than they would 
have been had they received standard treatment or if they had been in 
the other arm of the trial--underlines the extent to which any research 
project can depart from the Hippocratic goal of ``first, do no harm,'' 
despite the best intentions and efforts of all concerned. When such a 
result occurs, efforts to restore participants at least to their 
pretrial status could be regarded as attempts to reverse a result that 
would otherwise be at odds with the ethical principles of 
nonmaleficence and beneficence.
    Ironically, people who have benefited from an experimental 
intervention may also experience a loss if the intervention is 
discontinued when the project ends. It might be said that this is a 
risk the participant accepted by enrolling in the trial. But 
participants who are ill when they enter the research protocol may not 
be able to appreciate fully how they will feel when they face a 
deterioration in their medical condition (once the trial is completed) 
after having first experienced an improvement, even if the net result 
is a return to the status quo ante. One of the ways to mediate or 
reduce the burden of such an existential loss (the experience of loss 
as perceived by the research participant) and to sustain an appropriate 
level of trust between potential participants and the research 
enterprise is to continue to provide to research participants an 
intervention that has been shown to be efficacious in the clinical 
trial if they still need it once the trial is over.

Recommendation 4.1

    Researchers and sponsors in clinical trials should make reasonable, 
good faith efforts before the initiation of a trial to secure, at its 
conclusion, continued access for all participants to needed 
experimental interventions that have been proven effective for the 
participants. Although the details of the arrangements will depend on a 
number of factors (including but not limited to the results of a 
trial), research protocols should typically describe the duration, 
extent, and financing of such continued access. When no arrangements 
have been negotiated, the researcher should justify to the ethics 
review committee why this is the case.

Providing Benefits to Others

    Once it is recognized that research projects should sometimes 
arrange to provide post-trial benefits to participants, a question 
arises about the justice of differentiating between former trial 
participants and others in the host community who need similar medical 
treatments. Is the distinction between former research participants and 
those who were not merely arbitrary? Applying a competing concept of 
justice, typically referred to as the principle of fairness--treat like 
cases alike, and treat different cases differently--to this situation 
requires a consideration of whether family members (or others) who 
suffer from the same illness as the participants should be treated as 
``like cases'' with respect to receiving an effective treatment. 
Similarly, are the claims to treatment of people who were eligible for 
and willing to participate in a clinical trial but who for any number 
of reasons were not selected comparable to the claims of those who were 
selected? Or are such cases not sufficiently similar because 
participants undertook the risks and experienced the inconveniences of 
the research?
    In NBAC's view, the relevant distinction between research 
participants and these other groups of

[[Page 26863]]

individuals is that research participants are exposed to the risks and 
inconveniences of the study. Moreover, a special relationship exists 
between participants and researchers that does not exist for others. 
These are the ethical considerations that support the argument to 
provide effective interventions to research participants after a trial 
is completed.
    On what basis then can one justify an ethical obligation to make 
otherwise unaffordable (or undeliverable) effective interventions 
available to members of the broader community or host country? Given 
that global inequities in wealth and resources are so vast, expecting 
governmental or industrial research sponsors to seek to redress this 
particular global inequity is unfair and unrealistic, especially when 
no such requirement exists in other spheres of international 
relationships. Typically, it is not the primary purpose of clinical 
trials to seek to redress these inequities.

Recommendation 4.2

    Research proposals submitted to ethics review committees should 
include an explanation of how new interventions that are proven to be 
effective from the research will become available to some or all of the 
host country population beyond the research participants themselves. 
Where applicable, the investigator should describe any pre-research 
negotiations among sponsors, host country officials, and other 
appropriate parties aimed at making such interventions available. In 
cases in which investigators do not believe that successful 
interventions will become available to the host country population, 
they should explain to the relevant ethics review committee(s) why the 
research is nonetheless responsive to the health needs of the country 
and presents a reasonable risk/benefit ratio.
    These concerns prompt the question of whether research sponsors 
should consider implementing arrangements, such as prior agreements 
(arrangements made before a clinical trial begins that address the 
post-trial availability of effective interventions to the host 
community and/or country after the study has been completed), that 
would allow some of the fruits of research to be available in the host 
country when the research is over. Such arrangements would be 
responsive to the health needs of the host country. The parties to 
these agreements usually include some combination of producers, 
sponsors, and potential users of research products. Although only a 
limited number of prior agreements, either formal (legally binding) or 
informal, are in place in international collaborative research today, 
it is useful to consider what role such agreements should play in the 
future.

Recommendation 4.3

    Wherever possible, preceding the start of research, agreements 
should be negotiated by the relevant parties to make the effective 
intervention or other research benefits available to the host country 
after the study is completed.

Mechanisms to Ensure the Protection of Research Participants in 
International Clinical Trials

    The two principal approaches used to ensure the protection of human 
participants in international clinical trials are (1) relying on 
assurance processes and reviews by U.S. Institutional Review Boards 
(IRBs) to supplement and enhance local measures or determining that a 
host country or host country institution has a system of protections in 
place that is at least equivalent to that of the United States and (2) 
helping host countries build the capacity to independently conduct 
clinical trials and to conduct their own scientific and ethical review. 
In addition, a regulatory provision permits the substitution of foreign 
procedures that afford protections to research participants that are 
``at least equivalent'' to those provided in the Common Rule. 
Clarification of the scope and limits of these mechanisms and their use 
would increase public confidence that a valid system of protections is 
in place for participants in clinical trials conducted abroad.

Negotiating Assurances of Compliance

    U.S. researchers or sponsors and their collaborators often 
encounter difficulties with some of the procedural and administrative 
aspects of the U.S. research regulations or their implementation and at 
times perceive U.S. regulations as unnecessarily rigid. Among the many 
concerns NBAC heard were those relating to the process of negotiating 
assurances. An assurance is a document that commits an institution to 
conduct research ethically and in accordance with U.S. federal 
regulations. An approved assurance is a prerequisite to federally 
conducted or sponsored research.
    In December 2000, the U.S. Office of Human Research Protections 
(OHRP) launched a new Federalwide Assurance (FWA) and IRB registration 
process. The process for filing institutional assurances with OHRP for 
protecting human research participants has been simplified by replacing 
Single, Multiple, and Cooperative Project Assurances with the FWA, one 
for domestic research and one for international research. Each legally 
separate institution must obtain its own FWA, and assurances approved 
under this process would cover all of the institution's federally 
supported human research. The proposed system eliminates the assurance 
documents now in place and replaces them with either a Federalwide 
Domestic Assurance or a Federalwide International Assurance, covering 
all federally supported human research.
    NBAC was encouraged that OHRP is taking these steps to revise and 
simplify the current assurance process. It is not clear at this 
writing, however, whether the new FWA process will eliminate the 
problems and inconsistencies that exist among agencies such as the 
Department of Health and Human Services (DHHS), the Agency for 
International Development, and the Food and Drug Administration (FDA), 
or the difficulties expressed by researchers who are familiar with the 
previous assurance system. Moreover, it should be noted that the 
assurance process itself does not provide a failsafe system of 
protections. Because weaknesses in this system have been noted in 
failures at U.S. research institutions, care should be taken not to 
rely too heavily on this single mechanism to achieve protections 
abroad, especially when it is not clear that OHRP will provide a 
visible presence in the host country (through, for example, site 
visits). However, it will be important to evaluate the success of these 
new initiatives.

Recommendation 5.1

    After a suitable period of time, an independent body should 
comprehensively evaluate the new assurance process being implemented by 
the Office for Human Research Protections.

Ethics Review

    It is now widely accepted that research involving human 
participants should be conducted only after an appropriate ethics 
review has occurred. When research is sponsored or conducted in 
accordance with U.S. research regulations (and within the boundaries of 
these regulations), an appropriately constituted and designated IRB is 
empowered to make these assessments. However, spokespersons from 
developing countries have maintained that those who live in the 
countries in which the research is to be conducted are in the best 
position to decide what is appropriate, rather than those who may be 
unfamiliar with local health needs

[[Page 26864]]

and culture. It is argued that committees that are familiar with the 
researchers, institutions, potential participants, and other factors 
associated with a study are likely to provide a more careful and fully 
informed review than a committee or other group that is geographically 
displaced or distant and that only local committees can exercise the 
kind of balanced and reasoned judgment required to review research 
protocols. The concept of local review has been a cornerstone of the 
U.S. system for protecting human participants. Whether this standard 
can or should be applied to research sponsored or conducted abroad was 
a focus of Commission deliberations.
    NBAC found that the requirement for local review is occasionally 
tested and sometimes weakened when research is conducted in developing 
countries. In some cases, review by a local committee raises the 
potential for conflict of interest--or at least a heightened interest 
in approving research--when it means that valuable research funds would 
flow to a local institution. Although several developing countries have 
instituted national research ethics guidelines, and in some countries, 
ethics review is becoming more established, many difficulties and 
challenges to local review remain, including lack of experience with 
and expertise in ethics review principles and processes; conflict of 
interest among committee members; lack of resources for maintaining the 
committees; the length of time it can take to obtain approvals; and 
problems involved with interpreting and complying with U.S. 
regulations.
    In NBAC's view, efforts to enhance collaboration in research must 
take into account the capacity of ethics review committees in 
developing countries to review research and the need for U.S. 
researchers and sponsors to ensure that their research projects, at the 
very least, are conducted according to the same ethical standards and 
requirements applied to research conducted in the United States. This 
has led NBAC to conclude that when clinical trials involve U.S. and 
foreign interests, these protocols must still be reviewed and approved 
by a U.S. IRB and by an ethics review committee in the host country, 
unless the host country or host country institution has in place a 
system of equivalent substantive ethical protections.
    Ideally, equivalent (although not necessarily identical) systems 
for providing protections to research participants in developing 
countries would exist at both the national and institutional levels. In 
countries in which a system equivalent to the U.S. system exists at the 
national level, some institutions may be incapable of conducting 
research in accordance with that system. However, it is difficult to 
conceive of institutional systems being declared equivalent in the 
absence of an equivalent national system, although it may be possible 
in a few extremely rare cases. When multiple sponsors are participating 
in research, possibly all from developed countries, determining which 
ethics review committees (and how many) are required poses additional 
complexities. Because there may be legitimate reasons to question the 
capacity of host countries to support and conduct prior ethics review, 
NBAC believes that with respect to research sponsored and conducted by 
the United States, it will be necessary for an ethics review committee 
from the host country and a U.S. IRB to conduct a review. The FDA's 
regulatory provisions for accepting foreign studies not conducted under 
an investigational new drug application or an investigational device 
exemption do not address whether the foreign nation's system must meet 
U.S. ethical standards.

Recommendation 5.2

    The U.S. government should not sponsor or conduct clinical trials 
in developing countries unless such trials have received prior approval 
by an ethics review committee in the host country and by a U.S. 
Institutional Review Board.
    However, if the human participants protection system of the host 
country or a particular host country institution has been determined by 
the U.S. government to achieve all the substantive ethical protections 
outlined in Recommendation 1.1, then review by a host country ethics 
review committee alone is sufficient.

Recommendation 5.3

    The Food and Drug Administration should not accept data from 
clinical trials conducted in developing countries unless those trials 
have been approved by a host country ethics review committee and a U.S. 
Institutional Review Board. However, if the human participants 
protection system of the host country or a particular host country 
institution has been determined by the U.S. government to achieve all 
the substantive ethical protections outlined in Recommendation 1.1, 
then review by a host country ethics review committee alone is 
sufficient.

Lack of Resources as a Barrier to Ethics Review

    Ethics review committees in developing countries may have 
difficulty complying with U.S. regulations because they lack the funds 
necessary to carry out their responsibilities. In previous reports, 
NBAC has recognized that there are costs to providing protection to 
human participants in research, and researchers and institutions should 
not be put in the position of having to choose between conducting 
research and protecting participants. Therefore, an additional means of 
enhancing international collaborative research is to make the necessary 
resources available for conducting ethics reviews.

Recommendation 5.4

    Federal agencies and others that sponsor international research in 
developing countries should provide financial support for the 
administrative and operational costs of host country compliance with 
requirements for oversight of research involving human participants.

Equivalent Protections

    Although many countries have promulgated extensive regulations or 
have officially adopted international ethical guidelines invoking high 
standards for research involving human participants, the former Office 
for Protection from Research Risks (OPRR) never determined that any 
guidelines or rules from other countries--even countries such as 
Australia and Canada, where research ethics requirements closely 
parallel (and to some extent exceed) those of the United States'afford 
protections equal to those provided by U.S. regulations. If these 
variations cannot be mediated by joint efforts, difficulties may arise 
in international research that will prevent important and ethically 
sound research from going forward.
    In June 2000, OHRP became the agency responsible for making 
determinations of equivalent protections for DHHS. However, to date, 
OHRP has not provided criteria for determining what constitutes 
equivalent protections or made any such determinations about other 
countries' guidelines. In lieu of having developed a process for making 
equivalent protections determinations, in the past OPRR relied on its 
usual process for negotiating assurances with foreign institutions to 
ensure the adequate protection of human participants.
    Because the number of U.S.-sponsored studies undertaken in

[[Page 26865]]

collaboration with other countries is increasing (including many 
studies that have different procedural requirements), there is a need 
to enhance the efficiency of those efforts through increased 
harmonization and understanding, without compromising the protection of 
research participants. A way must be found to adhere to widely accepted 
substantive ethical principles while at the same time avoiding the 
undue imposition of regulatory procedures that are peculiar to the 
United States.

Recommendation 5.5

    The U.S. government should identify procedural criteria and a 
process for determining whether the human participants protection 
system of a host country or a particular host country institution has 
achieved all the substantive ethical protections outlined in 
Recommendation 1.1.

Building Host Country Capacity To Review and Conduct Clinical 
Trials

    A unique feature of international collaborative research is the 
degree to which economically more prosperous countries can enhance and 
encourage further collaboration by leaving the host community or 
country better off as a result. The kinds of benefits that could be 
realized as a result of the collaboration would depend on local health 
conditions, the state of economic development, and the scientific 
capabilities of the particular host country. The provision of post-
trial benefits to participants or others in the form of effective 
interventions is one option. The appropriateness of providing a benefit 
other than the intervention will depend on the nature of the benefit 
and on the economic and technological state of development of the host 
country. In most cases, offering assistance to help build local 
research capacity is another viable option. These two options are not, 
of course, mutually exclusive. But no matter what form the benefit 
takes, the ultimate goal of providing it is to improve the welfare of 
those in the host country.
    Approaches to capacity building are related to, but not fully 
dependent on, the clarification and improvement of current U.S. 
procedures for ensuring the protection of research participants in 
international clinical trials. Progress can and should occur 
simultaneously in both realms. Capacity building to conduct research 
could include activities undertaken by investigators or sponsors during 
a clinical trial to enhance the ability of host country researchers to 
conduct research (e.g., training and education) or to provide research 
infrastructure (e.g., equipment) so that future studies might proceed. 
Building capacity to conduct scientific and ethics review of studies, 
on the other hand, is primarily a matter of providing training and 
helping to establish systems designed to review proposed protocols and 
sustain mutually beneficial partnerships with other more experienced 
review bodies, including U.S. IRBs.
    To enhance research collaborations between developing and developed 
nations, it is important to increase the capacity of resource-poor 
countries to become even more meaningful partners in international 
collaborative research. Making the necessary resources available for 
improving the technical capacity to conduct and sponsor research, as 
well as the ability to carry out prior ethics review, is one way to 
move forward in this effort.

Recommendation 5.6

    Where applicable, U.S. sponsors and researchers should develop and 
implement strategies that assist in building local capacity for 
designing, reviewing, and conducting clinical trials in developing 
countries. Projects should specify plans for including or identifying 
funds or other resources necessary for building such capacity.

Recommendation 5.7

    Where applicable, U.S. sponsors and researchers should assist in 
building the capacity of ethics review committees in developing 
countries to conduct scientific and ethical review of international 
collaborative research.

Conclusions

    The ethical standards that NBAC is recommending for conducting 
research in other countries are minimum standards. Host countries might 
find it worthwhile to adopt human research participant protections that 
go beyond the protections that are currently provided under the U.S. 
system if these higher standards further promote the rights, dignity, 
and safety of research participants as well as the credibility of 
research results.
    Ethical behaviors and commitments are not barriers to the research 
enterprise. Indeed, ethical behavior is not only an essential 
ingredient in sustaining public support for research, it is an integral 
part of the process of planning, designing, implementing, and 
monitoring research involving human beings. Just as good science 
requires appropriate research design, consideration of statistical 
factors, and a plan for data analysis, it must also be based on sound 
ethical principles. Only then can research succeed in being efficient 
and cost-effective, while at the same time embodying appropriate 
protections for the rights and welfare of human participants. 
Researchers and sponsors should strive to conduct research in the 
United States and abroad in a way that furthers these aspirations, even 
though, regrettably, financial, logistical, and public policy obstacles 
often stand in the way of immediately achieving this goal.
    Although the recommendations in this report focus principally on 
clinical trials conducted by U.S. researchers or sponsors in developing 
countries, it will be important to consider their application to other 
areas of research. However, even though many ethical issues that arise 
in clinical trials also arise in other types of research, the 
relevance, scope, and implications of NBAC's recommendations in other 
types of studies may be very different. Similarly, many of the issues 
and recommendations discussed in this report may equally apply to 
research conducted in the United States.
    The relationships and, ultimately, the level of trust established 
among individuals, institutions, communities, and countries are 
determined by complex and often contradictory social, cultural, 
political, economic, and historical factors. It is essential, 
therefore, that sponsors, the countries from which they come, and 
researchers work together to enhance these collaborations by creating 
an atmosphere that is based on trust and respect. Finally, because 
attention will continue to focus on the ethical and policy issues that 
arise in international research in general and regarding clinical 
trials in particular, this report provides another opportunity for 
ongoing public dialogue about how to provide appropriate protection to 
all research participants.

Notes

    1. In past reports, the Commission has used the term human 
subject to describe an individual enrolled in research. This term is 
widely used and is found in the Federal Policy for the Protection of 
Human Subjects (45 CFR 46). For many, however, the term subject 
carries a negative image, implying a diminished position of those 
enrolled in research in relation to the researcher. NBAC recognizes 
that merely changing terminology cannot achieve the desired goal of 
true participation by individuals who volunteer for research, and 
NBAC does not imply that a truly participatory role is always the 
case. Nevertheless, for purposes of simplicity and from a desire to 
encourage a more equal role for research volunteers, in this report 
the term participants is adopted to describe those who are enrolled 
in research.
    2. An upcoming NBAC report on the oversight of research 
conducted with human

[[Page 26866]]

participants in the United States will address the implications of 
the findings and conclusions of this report in the context of 
domestic research.
    3. In the United States, committees that review the ethics of 
human research protocols are referred to in regulation and practice 
as Institutional Review Boards (IRBs). In other countries, different 
names might be used, such as research ethics committees or ethics 
review committees. In this report, references and recommendations 
that are specific to the United States will refer to these 
committees as IRBs. References and recommendations that refer to 
such committees generally regardless of their geographic location 
will call them ethics review committees.
    4. Although these protections are generally meant to apply to 
all research involving more than minimal risk, there are exceptions 
in certain guidelines for informed consent to be waived in research 
involving minimal risk.

FOR FURTHER INFORMATION ABOUT THE REPORT CONTACT: Eric M. Meslin, 
Ph.D., 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: May 9, 2001.
Eric M. Meslin,
Executive Director, National Bioethics Advisory Commission.
[FR Doc. 01-12142 Filed 5-14-01; 8:45 am]
BILLING CODE 4167-01-P