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.
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. Available: http://www.wma.net/e/policy/b3.htm.
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.
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
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. Con-sequently, 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.
