Correspondence
The Ethics of Research in Developing Countries
N Engl J Med 2000; 343:361-363August 3, 2000
- Article
To the Editor:
The editorial by Dr. Angell (March 30 issue)1 that accompanied our article2 conflated two Rakai Project studies. We conducted a community-based, randomized trial of sexually transmitted disease (STD) control for the prevention of human immunodeficiency virus (HIV) infection in the Rakai district of Uganda,3 involving 15,127 persons. We subsequently performed a secondary analysis of HIV viral load in 415 retrospectively identified couples in which one partner was HIV-positive and one was initially HIV-negative.2
In her editorial, Dr. Angell suggests that the HIV-positive study participants could have easily been treated with antiretroviral drugs. This is incorrect. The STD trial conducted surveys at 10-month intervals in 56 dispersed rural communities between 1994 and 1998. Antiretroviral monotherapy is of limited value,4 combination therapy was not described until 1996,5 and the results of definitive trials were reported only in 1998.6 Most important, neither we nor the Ugandan government had, or currently have, the clinical capacity to manage antiretroviral treatment, including side effects and compliance. The study was approved by four institutional review boards (IRBs) in Uganda and in the United States and was monitored by a data safety and monitoring board of the National Institutes of Health, which included Ugandan representatives. None of these boards recommended the use of antiretroviral agents in this rural setting.
Dr. Angell notes that “in most states it would be expected that caregivers would see that seronegative partners were informed of their special risk,” even if the HIV-seropositive partners had not agreed to the disclosure. Participants in the study in Uganda consented to enrollment as individuals, not as couples, and involuntary disclosure of the results of HIV tests would have breached the confidentiality guaranteed as part of the informed-consent process. Ugandan policy states, “It is the right of the patient to decide who else to inform about their results,”7 because of concern about stigma, discrimination, and violence resulting from involuntary disclosure.7-9 Involuntary disclosure would also have undermined trust in the national program of confidential HIV testing and counseling, a cornerstone of Uganda's successful HIV-prevention policy. We promoted and provided voluntary, confidential, free HIV testing and counseling; strongly encouraged persons who underwent testing to share the results with their partners; offered counseling for couples on request; and provided free condoms and health education. Dr. Angell cites U.S. guidelines recommending involuntary disclosure,10 which were published after the trial ended and which are not uniformly accepted in this country.
Dr. Angell implies that we offered substandard care to the members of the control group in the STD trial. This is incorrect. For example, the results of tests for syphilis were made available in both study groups, with home treatment offered to members of the intervention group and referrals to government clinics, which were stocked with free penicillin by the Rakai Project, offered to members of the control group. Syphilis in pregnant women declined by 70 percent in both groups.2 At the time of each survey, we provided free treatment for symptomatic subjects in both groups. At the end of the trial, members of the control group were offered home-based antibiotic therapy identical to that provided in the intervention group. We agree with Dr. Angell that investigators should “provide better care for human subjects than is generally available in the community.” In both study groups, the care provided far exceeded that available in rural Uganda and in many states in this country.
Dr. Angell questions the relevance of our studies to Uganda. Evaluating the control of STDs for the prevention of HIV infection was directly relevant to Ugandan policy. The secondary finding of reduced rates of HIV transmission with lower viral loads provides an impetus for the development of safe, effective, simple, and affordable strategies (use of antiretroviral agents or vaccines) to control the spread of HIV by reducing viremia. The relevance and ethics of research performed in developing countries need to be addressed in well-informed international forums.
10 ReferencesRonald H. Gray, M.D.
Johns Hopkins University, Baltimore, MD 21205-2196Thomas C. Quinn, M.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892David Serwadda, M.B., Ch.B.
Nelson K. Sewankambo, M.B., Ch.B.
Fred Wabwire-Mangen, M.B., Ch.B.
Makerere University, Kampala, UgandaMaria J. Wawer, M.D.
Columbia University, New York, NY 100321
Angell M . Investigators' responsibilities for human subjects in developing countries. N Engl J Med 2000;342:967-969
Full Text | Web of Science | Medline2
Quinn TC ,Wawer MJ ,Sewankambo N , et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000;342:921-929
Full Text | Web of Science | Medline3
Wawer MJ ,Sewankambo NK ,Serwadda D , et al. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Lancet 1999;353:525-535
CrossRef | Web of Science | Medline4
Concorde: MRC/ANRS randomized double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infectionLancet 1994;343:871-881
CrossRef | Web of Science | Medline5
Montaner JS ,Hogg R ,Raboud J ,Harrigan R ,O'Shaughnessy M . Antiretroviral treatment in 1998. Lancet 1998;352:1919-1922
CrossRef | Web of Science | Medline6
Renaud M, Ait HM, Katlama C, et al. Dynamics of CD4+ T cell recovery in a large cohort treated with highly active antiretroviral therapy at advanced stages of HIV disease. In: Proceedings of the 12th World AIDS Conference, Geneva, June 28–July 3, 1998. abstract.
7
AIDS Control Programme: HIV testing policy. Entebbe, Uganda: Ministry of Health, Health Education Printing Press, 1992:1-8.
8
Temmerman M ,Ndinya-Achola J ,Ambani J ,Piot P . The right not to know HIV-test results. Lancet 1995;345:969-970
CrossRef | Web of Science | Medline9
Zierler S ,Cunningham WE ,Andersen R , et al. Violence, victimization after HIV infection in a US probability sample of adult patients in primary care. Am J Public Health 2000;90:208-215[Erratum, J Public Health 2000;90:447.]
CrossRef | Web of Science | Medline10
HIV partner counseling and referral services — guidance. Bethesda, Md.: Department of Health and Human Services, December 30, 1998.
To the Editor:
In research involving human subjects, ethical principles and standards are for the protection of the subjects. If the intention is to study the subjects for their benefit individually, collectively, and in the community, then the main objective must be to benefit the subjects in their own setting. The intention must be to help the population find a way to cope with the disease burden, not to offer new options that are just as out of reach as those that already exist. Otherwise, it would be difficult to claim that the study was conducted for the benefit of the local population, not for that of other populations.
In the study by Quinn et al., is there any hope that the information gleaned will benefit the population studied? Will members of this population be able to afford viral-load testing? Will adult circumcision be of any benefit? Will this information lead to a reduction in the cost of antiretroviral drugs, making them more affordable in developing countries? These and other questions about the ethical nature of such studies must be answered if the study subjects are not to be seen as being exploited.
Anthony M.A. Mullings, M.B., B.S., D.M.
University of the West Indies, Mona, Kingston 7, Jamaica, West IndiesTo the Editor:
As an AIDS researcher in a “developing” country, I know that new drugs and effective vaccines for HIV infection are urgently needed. However, this urgency is being used to lower the standards established by the Declaration of Helsinki,1,2 which states that the “best proven diagnostic and therapeutic methods” must be provided to all study subjects. A 1999 draft of a document intended as a substitute for the declaration proposes the wording “best proven methods that would otherwise be available to the subject of research.” Thus, if nothing were available, the “best proven” method would be to make nothing available. The researchers' rationale is that poor countries do not provide antiretroviral agents anyway and that their high costs would make the trials too expensive to conduct. The lack of availability of antiretroviral agents is used to justify the performance of placebo-controlled trials even though effective drugs exist. The argument is that such trials are more efficient and less expensive to perform than non–placebo-controlled trials.
Clinical trials should be performed when use of the “best proven” methods can be assured. This approach may delay access to trials for some countries but will be safer and ethical. If at the end of the trial the drug, vaccine, or procedure is found to be effective, it should be made available wherever it is needed. The plan for this provision should be discussed at the outset among all parties. The justification for different ethical standards for poor countries is based on economic grounds, not on ethical or scientific grounds. Such trials should not be permitted.3
3 ReferencesDirceu B. Greco, M.D.
Federal University of Minas Gerais, 30130-100 Belo Horizonte, Brazil1
Brennan TA . Proposed revisions to the Declaration of Helsinki -- will they weaken the ethical principles underlying human research? N Engl J Med 1999;341:527-531
Full Text | Web of Science | Medline2
World Medical Association Declaration of Helsinki. Rev. ed. Somerset West, South Africa: 48th WMA General Assembly, 1996.
3
Greco DB . Clinical trials in “developing countries“: the fallacy of urgency or ethics vs. economics. Bull Med Ethics 1999;150:33-34
Medline
To the Editor:
I am perplexed by the Journal' s publication of the article on HIV transmission by Quinn et al. and Dr. Angell's accompanying editorial. She expresses grave doubts about the study. The statements that “ethical standards should not depend on where the research is performed” and “such a study could not have been performed in the United States” strongly indicate that she considers the study unethical. If so, why did she publish the article?
It seems that the Journal is trying to have it both ways: championing the rights of poor Africans in the editorial while endorsing the study by publishing the report on it. True progress in protecting human subjects in developing countries will require tougher choices.
Norman Hearst, M.D., M.P.H.
University of California, San Francisco, San Francisco, CA 94143To the Editor:
Although ongoing public discussion about the ethics of international research is crucial, we believe that Dr. Angell's editorial did not advance the discussion. The editorial detracted from the policy and prevention implications of the article by Quinn et al. We are concerned that much-needed ethical research on interventions to prevent the further spread of HIV infection in countries where it has a high prevalence will be derailed. Moreover, the ensuing confusion will delay the implementation of effective strategies to prevent HIV infection. Clearly, no one wants this to happen.
We strongly agree that all research conducted in international settings should have relevance to the study participants themselves, as well as to the country in which the research is taking place. In the case of HIV-prevention trials, highly ethical research has led to findings that have helped reduce both sexual and perinatal HIV transmission in such countries as Thailand and Uganda, thus saving many thousands of lives. The facts in the Rakai study are clear. The investigators went to great lengths to adhere to basic principles of ethical research. Furthermore, the study was deemed a high priority by health officials in Uganda.
The finding that HIV transmission was directly related to the viral load serves as a foundation for further research on low-cost, easily administered HIV therapies. This information will help prevent the spread of the virus in countries with the greatest problems in controlling the epidemic.
Willard Cates, Jr., M.D., M.P.H.
Family Health International, Research Triangle Park, NC 27709Thomas J. Coates, Ph.D.
University of California, San Francisco, San Francisco, CA 94105To the Editor:
Dr. Angell's editorial is an articulate summary of the ethical dilemmas posed by the study of HIV transmission in Uganda reported by Quinn et al. However, I am disturbed by her tacit assumption that the Journal, or any other peer-reviewed journal, should be the final arbiter in conflicts over the publication of ethically questionable research.
Undoubtedly, the ethical issues were not considered lightly by the two national agencies and two universities whose IRBs approved the research. For most reports on research involving human subjects, journals accept the authors' assurance that the study was approved by a suitable IRB, with the assumption that the IRB was given complete information. When investigators acknowledge that there are special ethical issues but document reviews by two, three, or more IRBs, journals should not dispute the decision to conduct the research or publish the results. Such a policy would not suggest a cavalier attitude toward the ethical treatment of human subjects but would reflect the recognition that ethical dilemmas should be resolved not by individuals or small groups but by bodies that are more broadly representative of society — the essential role of IRBs.
H. Hunter Handsfield, M.D.
University of Washington, Seattle, WA 98104Author/Editor Response
Dr. Angell replies:
To the Editor: The two parts of the Rakai Project addressed different questions. The first part asked whether the transmission of HIV could be reduced by treating other STDs in a population. To answer that question, the investigators had to treat the two groups of villages differently, so that the experimental villages would have a lower rate of STDs than the control villages. That is exactly what they achieved. Otherwise, they could not have answered the question they asked. I do not question the relevance of that part of the project to Uganda (a point on which I agree with Dr. Mullings), only whether the design of the trial was ethical.
The second part of the project asked whether the heterosexual transmission of HIV is a function of the viral load. The authors retrospectively measured HIV type 1 RNA in 415 couples discordant for HIV. However, as the authors make clear, the results of HIV serologic testing were available to the investigators and the subjects throughout the 40-month study. Since both partners were tested for HIV at 10-month intervals, seronegative partners of seropositive persons could easily have been identified and informed of their special risk. The fact that Ugandan policy advises against this practice does not constitute an ethical argument. Instead, it might suggest a review of the justifications for undertaking the study in a country with such a policy. Furthermore, it is difficult to see the relevance to present-day Uganda of this part of the Rakai Project, unlike the STD part.
I did not specify any particular form of treatment in saying that “the investigators could easily provide the drugs” to HIV-positive study participants, but I meant whatever treatment was offered in developed countries at that time. My point was that I was not persuaded by the argument that participants could be offered less simply because they lived in an underdeveloped country where the best current treatment was not generally available outside a research study. Furthermore, I do not agree with the implication by Gray et al. that a study, once launched, cannot be altered or even halted when other work identifies important new treatments.
In answer to Dr. Handsfield, I believe that an ethical review of a study is similar to a scientific review. No one involved should fail to call attention to scientific flaws on the grounds that it is someone else's business to do so. An editor should not publish a paper if he or she believes it is fatally flawed, either scientifically or ethically. In answer to Dr. Hearst, although I did have important reservations about the study, I did not believe the issues were so clear-cut that I was willing to override the judgments of the peer reviewers and other editors on my staff. These issues need further debate, and that is happening here.
Marcia Angell, M.D.
- Citing Articles (2)
Citing Articles
1
Daniel T Halperin, Richard G Wamai, Helen A Weiss, Catherine Hankins, Kawango Agot, Quarraisha Abdool Karim, Olive Shisana, Robert C Bailey, Bilonda Betukumesu, John Bongaarts, Kasonde Bowa, Richard Cash, Ward Cates, Mamadou Otto Diallo, Sibongile Dludlu, Nathan Geffen, Mark Heywood, Helen Jackson, Patrick Kalambayi Kayembe, Saidi Kapiga, Poloko Kebaabetswe, Leon Kintaudi, Jeffrey D Klausner, Suzanne Leclerc-Madlala, Khanya Mabuza, Mzamani Benjamin Makhubele, Kenneth Micheni, Brian J Morris, Antonio de Moya, Johanna Ncala, Innocent Ntaganira, Obrian F Nyamucherera, Emmanuel Oladipo Otolorin, Jean William Pape, Mannasseh Phiri, Helen Rees, Monica Ruiz, Jorge Sanchez, Sharif Sawires, Esther Salang Seloilwe, David M Serwadda, Geoffrey Setswe, Nelson Sewankambo, Dudu Simelane, François Venter, David Wilson, Godfrey Woelk, Nompumelelo Zungu. (2008) Male circumcision is an efficacious, lasting and cost-effective strategy for combating HIV in high-prevalence AIDS epidemics. Future HIV Therapy 2:5, 399-405
CrossRef2
Paul Farmer, Nicole Gastineau Campos. (2004) New Malaise: Bioethics and Human Rights in the Global Era. The Journal of Law, Medicine & Ethics 32:2, 243-251
CrossRef
