THE MONDAY REVIEW (May 11, 1998 - Issue #2) 15. HIV, AZT, AND THE ETHICS OF THIRD WORLD CLINICAL TRIALS Deborah Hellman (University of Maryland) presents a short review of a medical research ethics problem that first came to public attention last year. We have attached a series of reports that appeared during the past year in SCIENCE-WEEK to give a fuller account, but here is the essence of Hellman's piece: "The CDS (US Centers for Disease Control) and the National Institutes of Health (US) chose to compare the short-course therapies with placebos. This method promised to show clearly and indisputably whether the new treatment was better than nothing and by how much. But it also meant handing out a useless pill for a fatal disease even though researchers already had a drug they believed would work." The blurb for the Hellman article states: "Eighteen babies who could probably have been saved recently contracted HIV from their mothers as part of a test of a cheaper AIDS prevention treatment that might save thousands of lives. Was it worth it?" (The New Republic 27 Apr 98) (The Monday Review 11 May 98) ------------------- Related Background: ETHICS OF PLACEBO-CONTROLLED 3RD WORLD STUDIES REVISITED The New England Journal of Medicine has now published a collection of 19 letters from 41 researchers and clinicians in 7 countries concerning the journal's condemnation last year of placebo-controlled trials in underdeveloped countries of a drug (zidovudine) to prevent transmission of HIV from pregnant women to their fetuses, and of another study involving placebo- controlled trials of preventive therapy for tuberculosis in HIV- infected people in Uganda. The US National Institutes of Health and the US Centers for Disease Control were and/or are intimately involved in these studies, but the heads of these two federal agencies (H. Varmus and D. Satcher) apparently declined to respond to any of the letters directly addressing their public statements. This is a complex subject that cannot be done justice in a few lines, but the problems addressed by people on all sides of these issues are of extreme importance to the current and future development of international medical research ethics, and this collections of letters in the NEJM will be a classic collection for a long time to come. (New England J. Med. 19 Mar 98) ------------------- Related Background: HIV TRIALS CONTROVERSY AND TRANSMISSION IN PREGNANT WOMEN We have had a number of reports in this publication about a controversy concerning ethical aspects of anti-HIV drug trials in undeveloped countries, the controversy, in brief, focusing on the use of placebos when the placebo groups might benefit consider- ably from the test drug, and when such research placebo protocols in drug trials involving a drug known to be efficacious are not allowed in the industrialized nations. Now a US-funded drug trial in Thailand, designed to test the drug AZT in pregnant women as an agent against transmission of HIV from the women to their newborn children, has been halted early and declared to demonstr- ate that administration of AZT during the final weeks of preg- nancy does indeed reduce the transmission of HIV to newborn children by 50%. The drug was already known to do this in con- junction with other drugs in an expensive regimen, but this trial was designed to determine if AZT is useful alone in an inexpens- ive regimen as opposed to a placebo. Those who support such placebo trials say the speedy conclusion of the research was facilitated by the placebo controls, while those who oppose such research continue to argue that the use of placebos in this instance was unnecessary and unethical, and that data comparable to the Thailand trial have been available since 1994. QY: Eliot Marshall (Science 27 Feb 98) ------------------- Related Background: A PROBLEMATIC DOUBLE STANDARD IN BIOETHICS During the past year, a schism of sorts has developed among bioethicists and people concerned with bioethics. The particular focus has been the protocols of AIDS research in so-called developing countries, but the issue concerns more than AIDS, and indeed pertains to any clinical research involving human subjects in such regions. The problem is essentially as follows: Consider two countries A and B. A is rich and B is poor, and in both countries, the same serious lethal disease is rampant. A drug treatment exists, affordable by the government of the rich country but not affordable by the government of poor country. In the rich country, research guidelines prohibit protocols that involve withholding drug treatment from patients diagnosed with the disease; in the poor country, since the drug is unavailable, no such guidelines exist. Some clinical researchers in the poor country wish to focus on assessment of locally available treatment methods, particularly preventive methods involving vaccines, but the country is too poor for these research efforts. The rich country is also interested in vaccine research, but such research is now difficult to do in the rich country because the ethical requirements of drug treatment in the rich country have "contaminated" the patient population so that it is difficult if not impossible to assess the effectiveness of a vaccine. Research teams from the rich country therefore collaborate with research teams in the poor country to carry out the relevant vaccine research in the poor country, the protocol involving the withholding of the life-saving drug treatment from the control patient group with the rationalization that the drug is not available in the poor country anyway. Such, it appears, is the ethical problem now facing the international medical research community. Are clinical researchers to do their research with human patients with two standards of ethics, one standard for rich countries and another standard for poor countries? One has the feeling this is one of those questions whose answer one way or the other will be a defining moment in the history of bio- ethics. In a family, if one member is ill, the members of the family usually pool resources. The same occurs in a group, a tribe, or a country. But it does not yet occur on an internat- ional scale, which means patients in poor countries are denied access to life-saving drugs because they do not have the requis- ite cash to pay for the pills they need. Pills -- not hospitals or expensive machines or expensive facilities for state-of-the- art surgery. This is people dying for lack of a pill that exists in plenty in one place but not in another place. The editors of the New England Journal of Medicine not long ago condemned research protocols based on such disparities, but there are clinicians in both rich and poor countries who say a double standard is indeed required if any progress is to be made. ... ... E. Mbidde (Makerere Univ., UG), in an editorial in the journal Science, calls for a double standard and states that "a discussion of ethical principles in biomedical research that ignores the socioeconomic heterogeneity of society is not ethical and not worth holding", and that the International Ethical Guidelines for Biomedical Research Involving Human Subjects, in place since 1993, will in their present form "delay development of badly needed vaccines and treatment regimens." QY: Edward Mbidde, Uganda Cancer Institute, Makerere University, UG (Science 9 Jan 98) ------------------- Related Background: AIDS RESEARCH IN POOR COUNTRIES: BIOETHICS REVISITED B. Bloom (Albert Einstein College of Medicine, US), in a review of international ethical issues in research in AIDS vaccines, the review appearing in the same issue of Science as the editorial mentioned in the previous report, concludes it is necessary to clarify the existing guidelines to make clear what is attainable for implementation in developing countries whose health care resources are severely constrained. The author mentions only in passing the editorial in the New England Journal of Medicine last year that began the public discussion. QY: Barry R. Bloom (Science 9 Jan 98) ------------------- Related Background: NADER GROUP CALLS AIDS TRIALS UNETHICAL Ralph Nader's Public Citizen's Organization has charged that international AIDS therapy trials in developing countries are unethical. The basis of the accusation is that patients given placebos rather than the drug AZT are compromised by not re- ceiving the most effective treatment for the disease. Health officials state that on the contrary the studies are ethical and are vital for international treatment of the AIDS epidemic. Nader held a press conference on 22 April. (Science-Week 1 May 97) ------------------- Related Background: ETHICAL DILEMMAS IN THIRD WORLD CLINICAL RESEARCH It is not often that a leading scientific journal publishes an eight page front article and in the same issue of the journal also publishes eight pages of editorial matter most of which calls the front article an example of unethical research. But that is exactly what happened last week in connection with a study of drug therapy against tuberculosis in patients already infected with HIV. The reported study, by Christopher C. Whalen et al (Case Western Reserve University, US; other installations in US and UG), took place in Uganda, and included a placebo group of HIV infected individuals who were not given any anti-tubercul- osis drug therapy at all (the drugs isoniazid, rifampin, pyrazin- amide) even though these drugs have been shown in other studies to have preventive action against tuberculosis in people who carry tuberculosis antibodies. In the editorial matter, presented in three separate pieces by 5 physicians, Marcia Angell, the Executive Editor of the journal, calls into question the ethics of the Whalen study. It appears the justification of the Whalen study by its authors was the desire to glean definitive data con- cerning the expected effectiveness of the known anti-tuberculosis drugs in HIV infected patients in both the U.S. and Africa. Angell states: "An essential condition for a randomized clinical trial comparing two treatments for a disease is that there be no good reason for thinking one is better than the other." Everyone apparently agrees that the study could not possibly have been carried out in the U.S. because it would be prohibited by current U.S. regulations. These prohibitions evidently do not exist in Uganda. (New England J. Med. 18 Sep 97) ------------------- Related Background: HEAD OF NIH COMMENTS ON CLINICAL STUDIES IN THIRD WORLD There is evidently a flap brewing concerning U.S. management of clinical studies of diseases in developing countries in which placebo groups are used as controls, the placebo groups receiving no medication at all, even if such medication is available and known to have therapeutic value. Such placebo studies in the U.S. are not allowed, but they are allowed in many developing countr- ies, and in the September 18th issue of the respected New England Journal of Medicine a paper reporting such a study in Uganda by a U.S. managed research team of the clinical effectiveness of three anti-tuberculosis drugs in HIV infected Ugandans was published. In the same issue of the journal, as many pages as the report were devoted by the journal to editorial criticism of the ethics involved. Now Harold Varmus, head of the U.S. National Institutes of Health, which was involved in the Uganda study, and David Satcher of the U.S. Centers for Disease Control and Prevention, which was also involved in the Uganda study, have an article in that journal defending such studies in developing countries. The crux of the Varmus-Satcher position is apparently as follows: "The most compelling reason to use a placebo controlled study is that it provides definitive answers to questions about the safety and value of an intervention in the setting in which the study is performed, and these answers are the point of the research." One wishes Varmus and Satcher would have in the very next sentence considered why, despite this "compelling" reason, such placebo studies are not permitted in the U.S. The evident answer is that in the U.S., the "compelling" reason has not been found compell- ing enough. So that is the fundamental question: Why the applic- ation of one ethical standard in the U.S. and another ethical standard in Uganda? And this is the question addressed by the editorial matter in the 18th September issue of the journal. The New England Journal of Medicine has announced it will later publish responses to the Varmus-Satcher article by Marcia Angell, Executive Editor of the journal, who with others previously criticized the reported Uganda study. (Our first report of the Uganda study is in the SCIENCE-WEEK/SCIENCE-REPORT issue of 26 Sep 1997) QY: H. Varmus, National Institutes of Health, Bethesda MD 20892-0148 US (New England J. Med. 2 Oct 97) ------------------- Related Background: ESTIMATED 20 MILLION INFECTED WITH AIDS IN SUB-SAHARAN AFRICA There is perhaps too much of a tendency in many quarters to think of a plague only as a state of affairs in which people drop dead in expensive restaurants and get hauled away in trucks containing piles of bodies. Our current plague, although not as dramatic as some plagues of the past, is no less an international calamity. The United Nations AIDS Program recently released a report containing the following: -- In 1997, 5.8 million people worldwide were newly infected with HIV. -- The number of new HIV infections this year rose 9% over 1996. -- The total number of infected adults is now a little under 30 million, about 1% of the world's adult population. -- This year, the total number of people infected with HIV increased by 13% -- More than 20 million people in sub-Saharan Africa are infected with HIV, which is 7% of that adult population. -- This year, 2.3 million people worldwide will have died of AIDS, the consequent stage of HIV infection. -- In South and Southeast Asia, 6 million people are infected with HIV. -- In Latin America, 1.3 million people are infected with HIV. -- In North America, 860,000 people are infected with HIV. -- In Western Europe, 150,000 people are infected with HIV. (Nature 27 Nov 97)