Executive Summary of Issues in International Research: Clinical Trials in Developing Countries, April 2001
PDF downloads of this summary are available in French and in Spanish.
Contents
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 trouble-some 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 re-emerged. 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 proceed in settings in which
systems for protecting human participants equivalent to those
of the United States have not yet been established.
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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 committees3 (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:
- prior review of research by an ethics review
committee(s);
- minimization of risk to research
participants;
- risks of harm that are reasonable in relation
to potential benefits;
- adequate care of and compensation to
participants for injuries directly sustained during
research;
- individual informed consent from all
competent adult participants in research;
- equal regard for all participants;
and
- 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.
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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.
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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
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.
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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 treatmentto 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.
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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.
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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.
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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 benefitsin 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.
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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.
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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 consentto 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.
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>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 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
famly 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.
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>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:
- it would be impossible to conduct the
research without obtaining such supplemental permission;
and
- failure to conduct this research could deny
its potential benefits to women in the host country;
and
- 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.
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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).
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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 andprocedural 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.
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.
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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.
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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 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 areproven 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 posttrial 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.
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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 for 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.
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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.
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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 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 andby 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 anda 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.
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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.
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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
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.
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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.
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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.
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Footnotes