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A provider who offers contraceptives or other products
to clients should be confident that these products and services have been
proven to be safe and effective through trials that were reliable,
accurate, and had the welfare of the user as the ultimate goal.
This close relationship between research and clinical
practice leads to better services and care for clients, as well as new or
improved reproductive health options – better contraceptives, for
example, or new treatments and preventive strategies for sexually
transmitted infections (STIs).
An essential element of all good research is that it be
done in an ethical manner, with careful planning and procedures to protect
the individuals who participate.
"The basic principles of sound medical ethics have
evolved over time to fulfill an essential need, and that is to protect
people," says Dr. Roberto Rivera, director of FHI’s Office of
International Research Ethics. "These principles protect people who
volunteer to take part in medical and behavioral research – both
quantitative and qualitative studies. These basic principles shape the
ethical safeguards for each study, but the specific protocols involved
must come from close collaboration with several interested groups,
especially from those who best represent the volunteers and who are
members of the community where the research is conducted."
The potential harm that can arise during a medical trial
is often obvious. Volun-teers in research involving contraceptives or
devices or drugs to prevent or treat STIs may face some risk of physical
harm, especially for products in early development. Potential harm to
participants in qualitative studies may be less obvious, but is
nevertheless real. An example would be if the confidentiality of a
participant were not respected, especially during studies examining such
sensitive issues as STIs (including HIV/AIDS), domestic violence, or
sexual behavior and preferences. Such disclosure could expose participants
to social stigma, job loss, or even violence and death.1
Questions raised in social and behavioral studies may be
controversial and often involve personal aspects of a subject’s life,
says Dr. Nancy Williamson, who headed FHI’s Women’s Studies Project (WSP).
During the 1990s, WSP sought a better understanding of family planning
methods and the impact of services through interviews and discussion
groups with women in 14 countries.
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| Protecting the confidentiality of
personal information about research participants is an ethical
responsibility. Above, an FHI staff member carefully handles
research files. |
"Years ago, before I came to FHI, I was involved in
a behavioral study in the Philippines," she recalls. "When the
questionnaires were entered into the databank, and the names of the
participants were put into code, we told the staff to destroy the
questionnaires. I guess we were not specific enough. We probably should
have said, ‘burn the questionnaires.’ A week later, I was at the local
fish market and bought a fish. I was shocked when I saw that the man who
sold the fish to me was carefully wrapping my purchase in a page from the
completed questionnaire! Paper was so valuable in that culture that
somebody must have sold the questionnaires rather than destroyed
them." Such a flaw in the study’s procedures might have widely
exposed personal information about participants.
Basic principles
It is now widely accepted that any type of study
involving humans must be carefully designed and monitored to protect the
physical and psychological well-being of the participants. In addition to
obtaining informed consent from each participant (see "Choices
Must be Informed, Voluntary"), scientists are required to monitor
study participants closely, and have strict procedures for reporting any
adverse experiences. Also, additional safeguards are needed to protect
vulnerable populations, such as children, prisoners, and people with
limited education or mental capacity.
Codes of ethical conduct have evolved from decades of
analysis, debate, and international concurrence from research scientists,
clinical practitioners, policy-makers, and academics.
Three widely accepted ethical principles should guide
the protocols for any study involving humans. Research participants should
expect:
- respect
- beneficence
- justice
In the United States, these principles were articulated
in 1976 by the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research.2
The commission stated that "respect" for
participants incorporates at least two important ethical convictions.
First, people who volunteer for research should be treated as autonomous
agents – people who have self-rule. And second, people who have
diminished self-rule due to age, marital status, mental or physical
impairment, lack of education, incarceration, or financial instability are
entitled to additional precautions.
Participants should also be protected from harm, with
extensive efforts in procedures and study protocols to secure their
well-being – the principle of "beneficence." Beneficence is a
term that typically describes acts of kindness or charity, but is used in
a stronger sense when guiding the ethical design of research. In the
context of research on humans, "beneficence" is a strict
obligation to maximize possible benefits and to minimize possible harm to
participants.
Beneficence places the responsibility of the well-being
of the participant – physically, mentally, and socially – directly on
the researcher conducting the study, and reinforces the ancient maxim of
medical ethics: first, do no harm. Protecting the human research
participant is more important than the pursuit of new knowledge. It takes
precedence over the personal or professional gain of the researchers.
"Justice" is the third principle. Justice
weighs such questions as who will benefit from the research and who will
bear its burdens. Scientists are called upon to design studies that
distribute equally the risks and benefits that participation in the
research would bring. Justice mandates that recruitment and selection of
research participants be done in an equitable manner, and that research
not be done on disadvantaged or vulnerable people in order to benefit the
privileged.
Conducting research largely among the poor in order to
benefit people who are better off is an example of injustice. A widely
publicized example in the United States involved syphilis research
conducted on disadvantaged African-American men from 1932 to 1972. In the
study, Alabama farmers were only told they were under study for "bad
blood." Researchers allowed some participants to go untreated for
syphilis for years after effective treatment had become available, in
order to study effects of the disease on a long-term basis.3 In
1997, President Clinton apologized on behalf of the United States
government to the surviving participants and their families.
The concept of justice also applies to the publishing of
study results. Investi-gators are ethically obligated to present their
findings accurately and fully – including results that may argue against
the study’s hypothesis – in order to protect both the study
participants and people who volunteer for future research on the same
topic, as well as the general public whose access to products or services
may be affected by the outcome of the research.4
Since Hippocrates
The first recorded application of ethical standards to
medical practice is from Hippocrates, who practiced and taught medicine in
ancient Greece. The Hippocratic oath, which is recited by most graduating
medical students to this day, stipulates that physicians should
"first do no harm," that patient confidentiality must be
respected, that physicians should not perform procedures for which they
are not qualified, and that physicians should lead exemplary lives.
As medicine became more advanced over time, physicians
and scientists confronted situations that were no longer neatly addressed
by the oath. In order to develop safe and effective medical procedures and
treatments to combat disease, scientific studies on drugs, devices, and
procedures had to be performed. In recent times, this has meant conducting
research first in the laboratory, then on animals, and eventually on
humans if laboratory and animal studies involving safety issues were
encouraging.
During World War II, German physicians forced
concentration camp inmates and prisoners of war to take part in a variety
of harmful experiments, most of which were medically useless. Many of the
prisoners died from the experiments, or were permanently injured as a
result.
Nazi war criminals, including some of the physicians who
performed these experiments, faced a war crimes tribunal in Nuremberg,
Germany. A result of these trials was the Nuremberg Code, which
established 10 standards of ethical conduct for studies involving human
subjects.
Since the drafting of the Nuremberg Code, other
documents and declarations have amended those principles to include
contingencies that the framers at Nuremberg could not foresee. The
Nuremberg Code and other accords that followed have established
international guidelines to help researchers protect the safety of their
participants.
In 1964, the World Medical Assembly (now known as the
World Medical Association) drafted the Declaration of Helsinki, which
expanded on the basic points of the Nuremberg Code to include concepts
such as the distinction between clinical research combined with
professional care, and nontherapeutic clinical research. The declaration
also stated that informed consent should be obtained in writing, and that
a legal guardian may give written consent in cases where the participant
is legally incompetent.5
The Declaration of Helsinki has undergone revisions
since 1964. One supports a researcher’s right to use new therapeutic
measures to save a life, for example. Another amendment mandates the
establishment of a committee, sometimes known as an institutional review
board (IRB), to oversee studies involving human participants (see "Institutional
Review Boards Help Ensure Safety"). These committees must be
independent of the institution conducting the research.6
Some of the amendments to the Declaration of Helsinki
have been controversial. A revision added in 2000 states that the
"benefits, risks, burdens, and effectiveness of a new method should
be tested against those of the best current prophylactic, diagnostic, and
therapeutic methods. This does not exclude the use of placebo, or no
treatment, in studies where no proven prophylactic, diagnostic, or
therapeutic method exists." Another section adds, "At the
conclusion of the study, every patient entered into the study should be
assured of access to the best proven prophylactic, diagnostic, and
therapeutic methods identified by the study."7
The stipulation regarding the use of a placebo arm* when
a known treatment may indeed exist has resulted in ethical debate,
particularly in countries where the HIV/AIDS epidemic has taken a terrible
toll.8 For example, some antiviral medications, such as
zidovudine, reduce HIV transmission from an infected mother to her
newborn. However, in some studies that sought to determine the efficacy of
reduced doses of the drug, there was a placebo arm that withheld all
treatment. Critics argue that there should be no placebo arm, and that
participants engaging in such trials should be provided with the highest
accepted standard of care or treatment, even when that level of care is
not readily available in the country where the study is conducted.9
However, a placebo arm is sometimes the only way to test
whether or not a treatment is effective. Consequently, a ban on a placebo
arm could prevent the development of a more effective, less costly
treatment since conclusive research needed to obtain regulatory approval
might not otherwise be possible.
The international codes of ethical conduct in research
have been evolving in a climate of worldwide change in attitudes regarding
vulnerable populations. The rights of children, the elderly, indigenous
people, and persons with disabilities are more widely embraced, and this
public recognition of their fundamental rights has resulted in better
family planning and reproductive health care, as well as additional
safeguards for research involving reproductive health.
One example of this changing worldwide attitude can be
seen in the United Nation’s 1994 International Conference on Population
and Development, held in Cairo. Representatives from 179 countries
endorsed a number of statements seeking to protect women and other
vulnerable groups and to enhance their opportunities for equal treatment
and better education. Many of the concepts have been embraced by
nongovernmental organizations and other groups that provide family
planning services or conduct reproductive health research.10
– Ellen Devlin
* In research using a placebo arm, only some of the
participants receive the drug or treatment being studied. Other
participants receive a "placebo," an inert compound or treatment
that is identical in appearance to the experiment drug or treatment. The
purpose is to analyze the experimental approach more accurately, since the
suggestion of receiving any drug or treatment could have an effect.
Comparing experimental treatment with a placebo arm helps remove this
effect.
References
- Guenter D, Esparza J, Macklin R. Ethical
considerations in international HIV vaccine trials: summary of a
consultative process conducted by the Joint United Nations Programme
on HIV/AIDS (UNAIDS). J Med Ethics 2000;26(1):38.
- National Commission for the Protection of Human
Subjects of Research. Belmont Report: Ethical Principles and
Guidelines for the Protection of Human Subjects of Research. U.S.
Department of Health, Education, and Welfare, Office of the Secretary,
1978.
- National Commission for the Protection of Human
Subjects of Research, 6.
- Kommission für Forschungs Partnerschaften mit
Entwicklungslandern. Guidelines for research in partnership with
developing countries. Unpublished report. Kommission für Forschungs
Partnerschaften mit Entwicklungslandern, nd.
- Declaration of Helsinki. Ethical Principles for
Medical Research Involving Human Subjects. Adopted by the 18th
World Medical Association General Assembly, Helsinki, Finland, 1964
and as amended by the 52nd World Medical Association General Assembly,
Edinburgh, Scotland, 2000.
- Declaration of Helsinki.
- Declaration of Helsinki.
- Angell M. The ethics of clinical research in the
Third World. N Engl J Med 1997;337(12):847-49.
- Benatar SR, Singer PA. A new look at international
research ethics. BMJ 2000;321(7264):824-26.
- Report of the International Conference on
Population and Development: Cairo, 5-13 September, 1994. New York:
United Nations, 1995.
Institutional
Review Boards Help Ensure Safety
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An ethics review committee – sometimes referred
to as an "institutional review board" (IRB) – helps
ensure that people participating in a study are protected as much as
possible from any harm resulting from the study. An IRB is composed
of members who are not doing the actual research itself, and the
membership should consist of people who are representative of the
community in which the study is taking place.
The committee’s primary responsibility is to
review study protocols before research begins to make
recommendations concerning the safety and possible risks to human
participants. It also reviews incidents during the study that could
or do affect safety, and recommends how to resolve them.
In the United States, any research conducted using
federal money must be reviewed by an independent ethics review
committee to ensure that research involving human participants is
clearly justified, safely performed, and complies with national and
international codes of research ethics, such as the U.S. Code of
Federal Regulations.1
In 2001, a U.S. government commission made a
series of recommendations to protect the participants in any
research, regardless of whether federal funds were used. For
example, it recommended that informed consent forms explain any
benefits that would be available to participants when the study
ends, and that participants receive an explanation of how any new,
effective interventions will become available to the public. For
research sponsored by the U.S. government in a developing country,
the recommendations would require approval by ethics review
committees in both the host country and the United States. New laws
would be needed for the recommendations to take effect.2
| Guidelines for Selecting
Members of an IRB |
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| Click on the image
to view a larger version. |
Who serves?
Generally, selection of IRB members should meet
certain criteria. These criteria help ensure a diversity of
professional backgrounds, gender, and ethnic groups. In the United
States, federally funded research requires that at least one member
come from a nonscientific background, and that at least one member
not be affiliated with the institution conducting the research.3
Each panel for U.S.-funded research must have at
least five members from varying backgrounds. This diversity helps
ensure that several areas of expertise are given equal weight in any
decision that the committee makes. If the study involves
participants who are particularly vulnerable, such as children,
prisoners, or physically or mentally disabled persons, it is
strongly recommended that at least one member be knowledgeable about
that particular group.
FHI has a panel to apply good ethical designs and
safeguards to all of its human research. This panel, known as the
Protection of Human Subjects Committee (PHSC), is additional to any
ethics review committees in places where research is conducted. An
FHI study at a U.S. medical center, for example, would require
oversight from both FHI’s PHSC and the medical center’s own IRB.
"Our PHSC is made up of eight members and
meets at least four times a year," says David Borasky,
institutional representative to the PHSC at FHI. No FHI staff can
cast a vote in the independent PHSC’s deliberations. "I’m a
member of our PHSC," says Borasky, "but I’m not a voting
member. Basically, the PHSC reviews proposed studies, and votes to
either approve, disapprove, or defer a particular project. It also
reviews ongoing studies to ensure compliance with guidelines
governing protection of human participants during study
implementation."
PHSC members come from varying professional or
social backgrounds in order to ensure an appropriate range of
perspectives. For example, the current PHSC chair is a theologian
who is headmaster of a private school and previously was dean of the
School of Divinity at Duke University in the United States. Other
members include several professionals who are not associated with
FHI’s work outside of their PHSC memberships – an
epidemiologist, an obstetrician/gynecologist, a pediatrician, two
sociologists, a specialist in internal medicine and bioethics, and
an attorney who specializes in health law. The membership represents
different ethnic groups and half of the members are women.
 |
| Community advisory boards, such as this one
in Blantyre, Malawi, evaluate the impact of studies on local
communities. |
In addition to the PHSC, other panels are
sometimes established to advise FHI scientists, including community
advisory boards. For example, in FHI’s Women’s Studies Project
conducted during the 1990s in 14 countries, local advisory groups
were established that included scientists, women’s advocates, and
policy-makers. Some of the research focused on sensitive topics –
such as domestic violence in Bolivia and the Philippines, covert use
of contraceptives by women in Mali, adolescents seeking abortion in
Brazil, and teenagers’ attitudes about sexuality in Jamaica. Consequently,
FHI and local researchers worked closely with local advisory groups
to make sure study participants’ privacy was protected. And at
Iloilo University in the Philippines, an IRB established as part of
the Women’s Studies Project continues today, long after the FHI
project concluded.
Ethical safeguards worldwide
FHI’s PHSC applies U.S. regulations strictly,
even when conducting research in other countries, and even when U.S.
government funds are not used. Coordinating the PHSC’s activities
with ethics review committees in other countries or at other
institutions is part of the process to safeguard participants.
"Usually, it is the study’s local investigator who has the
most contact with the local panels," says Borasky.
Conducting research in other countries can be
challenging. Differences in languages, including local dialects,
levels of literacy, and a variety of local values and cultural
systems must play a role in how to inform potential participants
about the research and its risks, and in shaping other ethical
aspects of a study. Certain cultures may prohibit women from serving
on a local ethics review committee, thus defeating the U.S. standard
that requires gender diversity. In most resource-poor countries,
administrative expertise, well-staffed facilities, and access to
information are limited, making it difficult for a local panel to
perform effectively.4
"During the past few years, there has been an
increasing recognition of the need to strengthen the capacity of
developing countries to conduct the ethics review of projects,"
says Dr. Roberto Rivera, director of FHI’s Office of International
Research Ethics.
"FHI is now conducting a strong,
well-organized effort to provide training and curricula that will
help the staff of research organizations in developing countries to
establish ethics review committees," he says. "I believe
FHI is one of the first international organizations to do
this." For example, FHI has prepared a training curriculum for
developing country scientists and policy-makers. Devoting this issue
of Network to the subject is another effort to encourage
well-designed ethical oversight for human research.
"A competent ethics review committee cannot
be established overnight," says Dr. Rivera. "Much care
should be taken that the membership is selected carefully and
mirrors the local population where the research is being conducted.
Sometimes, membership is over-represented by physicians. Alerting
the local people about the importance of membership diversity is the
key to ensuring that as many viewpoints as possible are given equal
weight for the benefit of human participants."
– Ellen Devlin
References
- International Ethical Guidelines for
Biomedical Research Involving Human Subjects. Geneva:
Council for International Organizations of Medical Sciences and
World Health Organization, 1993.
- Ethical and policy issues in research involving
human participants, May 18, 2001. National Bioethics Advisory
Commission, 2001. Available: http://bioethics.georgetown.edu/nbac/human/overvol1.pdf.
- Protection of Human Subjects. Code of
Federal Regulations 40CFR26.107, revised July 1, 2001.
- MacPherson CC. Research ethics committees: a
regional approach. Theo Med Bioethics 1999;20(2):161-62.
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