Miércoles 12 de Julio de 2006, Ip nº 161

Ends and means
Por Jessica Winter

LAST MARCH, Harper's Magazine published an article by journalist Celia Farber called ``Out of Control: AIDS and the Corruption of Medical Science." The piece focused on the death of 33-year-old Joyce Ann Hafford, a pregnant, HIV-positive woman in Tennessee who died of liver failure after enrolling in a clinical trial of the drug nevirapine, manufactured by the German pharmaceutical company Boehringer-Ingelheim and intended to prevent transmission of HIV from mother to child. The article also examined a troubled long-term study of nevirapine in Uganda.

To judge by the outcry that followed the article's appearance-it stirred general condemnation and point-by-point rebuttals from scientists, physicians, activists, and Farber's fellow journalists-one might have imagined that the venerable left-leaning magazine had run an essay by a climate-change naysayer or a proponent of creationism. In fact, Farber is perhaps the only established American journalist who, in her Harper's piece and throughout her career, has seriously questioned the proof that HIV causes AIDS, despite overwhelming and decisive scientific evidence to the contrary.

But that's only part of the story. ``Out of Control" now forms a chapter of Farber's new book, ``Serious Adverse Events: An Uncensored History of AIDS" (Melville House). The book won't reopen the case on AIDS causation, nor should it. But it's a useful entry point into a broader debate on the methods and motivations of the pharmaceutical industry and the medical establishment at large in the development of AIDS drugs. What was largely obscured amid the Harper's controversy is that the main characters in this story face choices and risks that crystallize some of the most important issues in medical ethics today.

Drug research that involves human subjects is fraught with moral and practical dilemmas, but these are compounded when it comes to AIDS studies, for a number of reasons. Unlike more equal-opportunity diseases such as heart disease and cancer, AIDS hits hardest among the poorest and most vulnerable people and communities, both here and abroad.

In the US, HIV disproportionately afflicts low-income and minority women (Joyce Hafford was an African-American single mother of a 14-year-old). And AIDS is far more deadly in Third World nations than it is in the affluent West. Studies of AIDS drugs in resource-poor countries have drawn criticism for skirting ethical standards and exploiting defenseless patients, as investigative journalist Sonia Shah observes in her new book, ``The Body Hunters: How the Drug Industry Tests Its Products on the World's Poorest Patients" (New Press), which is arriving in bookstores the same week as Farber's.

What's more, because AIDS can be passed on from mother to baby, researchers must gather data from subjects who would rarely be allowed to participate in other drug trials: pregnant women and their unborn children. Potential subjects are often under great psychological and economic stress, in addition to the physical stress of pregnancy. Their ability to give informed consent may therefore be compromised. The prospect of taking potentially toxic drugs to fend off HIV infection can seem both terrifying and necessary to a woman concerned about the future health of her child.

These pressing ethical issues are of global and local significance. The pharmaceutical giant Bristol-Myers Squibb, which recently announced plans to build a $1.1 billion biotechnology production facility in Devens, will soon be recruiting HIV-positive pregnant women in Boston for a trial to determine adequate dosing regimens of antiretroviral drugs to prevent mother to child transmission. The company will also recruit subjects for two sites in South Africa, where AIDS drug research in local populations have been a divisive topic for a decade.

In advanced clinical drug trials, such as Bristol-Myers Squibb's proposed project and the nevirapine studies in Uganda, the researcher must tread a fine line: between protecting vulnerable groups from undue research risks and, at the same time, ensuring their participation. If you don't test pregnant women, for example, how can you develop drugs to help them?

``After a while, the idea that you're protecting vulnerable subjects actually gives them the worse end of the bargain," says Daniel Wikler, a professor of ethics and population health at the Harvard School of Public Health. Researchers, Wikler adds, must balance the pursuit of knowledge with the patient's well-being. ``There are two missions: One is a scientific mission and one is a therapeutic mission," he says.

Where those two missions diverge-and especially when those missions are influenced by economic considerations-is where the medical establishment must confront vexing questions. How does medical science draw a line between research subject and AIDS patient when they are one and the same person? Is it possible to balance the interests of science, patients, and industry? And how does that balance tilt at a time when so many trials are conducted in the developing world?

Central to the design of an ethical drug trial is the principle of ``equipoise," which means that the researcher is truly uncertain about which arm of the study-the control group or the experimental group-will experience greater benefit. Adhering to this principle ensures that researchers will not knowingly administer inferior treatments to subjects when an effective treatment has already been established.

Equipoise can be lost over the course of a trial. In 1994, researchers halted a trial studying the efficacy of the AIDS drug AZT in preventing mother to child transmission of HIV-the early results were so promising that they determined it would be unethical not to provide the control group with the same treatment that was proving so effective in the experimental group. (Last year, a study of the breast cancer drug Herceptin was ended early under similar circumstances.)

Finding equipoise can be especially difficult, or even impossible, when studies involve patients in deprived countries, as is often the case with AIDS-related medications. Both Farber's ``Serious Adverse Events" and Shah's ``Body Hunters" give scathing accounts of the nevirapine trials in Uganda, which were funded by the National Institutes of Health. The study was the focal point of a controversy dating back to 1997, and one that still reverberates in biomedical and bioethical circles.

In the Uganda trial, short courses of AZT and nevirapine were tested on HIV-positive pregnant women against a placebo, even though a long-course AZT regimen had been proven to make deep cuts in the rate of transmission. Some observers argued that both the placebo and the abbreviated regimens were not unethical because poor patients in Uganda would normally receive no treatment at all. Yet others insisted that researchers had a moral obligation to provide the best known treatment to the control group, regardless of what was currently feasible in Uganda.

In The New England Journal of Medicine, then-editor-in-chief Marcia Angell wrote of the Uganda trials, ``It seems as if we have not come very far from Tuskegee after all," referring to the infamous 1932-1972 study in which treatment for syphilis was knowingly withheld from poor black men in a government-funded research program.

The 1964 Declaration of Helsinki, which is a kind of Hippocratic oath for researchers, would seem to back up Angell's view. The declaration holds that the interests of science cannot come before the interests of the individual subject, and is often interpreted as giving human research subjects the right to the highest available standard of care available. But adapting the Helsinki principles to the age of globalized medicine has proven to be highly problematic. In resource-poor countries such as those of sub-Saharan Africa, basic medical supplies, manpower, and expertise are often in gravely short supply; the ``standard of care," in other words, may be terrible, or nonexistent.

``We can clean up the water supply, provide ancillary care, set up hospitals to give intravenous therapy, make a rule that women are not allowed to breast-feed-we can do all that, but you might as well save the plane fare and conduct the study in Boston, because the results will only be relevant in Boston," says Robert J. Levine, a professor and bioethics expert at the Yale School of Medicine.

This seems to have been the thinking underlying the Uganda trial. Under pressure from critics, researchers eventually dropped the placebo arm of the nevirapine study, but they did not offer subjects the proven long-course drug regimen. The ethical justification was that the long course was too expensive and difficult to administer in Uganda, but the cheaper, easier short course, while probably not as effective, might be a pragmatic alternative. ``They were trying to come up with a treatment that would prevent transmission of AIDS in thousands of babies in the only way that Ugandans could afford," Wikler said.

The Uganda AIDS controversy remains significant thanks to the pharmaceutical industry's continuing presence throughout sub-Saharan Africa and other Third World regions. The FDA has ``approved or tentatively approved" 20 AIDS-related products under the President's Emergency Plan for AIDS Relief, which mostly targets sub-Saharan African countries. In addition to the African work of Bristol-Myers Squibb and Boehringer-Ingelheim, Glaxo-Smith-Kline is now conducting seven clinical trials in 13 resource-poor countries involving 6,000 patients, specifically for prevention of mother to child transmission of HIV.

Big Pharma's presence in the developing world is heartening to some observers, since treatments benefiting desperately poor, low-status patients don't necessarily translate into big financial returns for this extremely profitable industry. But others note that the companies aren't just being magnanimous-and that it's impossible to consider the ethics of aids drug trials without factoring in economics.

``There's a public relations benefit for the pharmaceutical companies to be seen doing the right thing in the Third World," says Jerry Avorn, chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women's Hospital and the author of ``Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs" (2004). ``Sub-Saharan Africa is also seen as a more cost-effective and hassle-free environment for clinical trials, and those findings can then be used for marketing in the US."

Others note that opting for sub-Saharan Africa means that the study will be held to less stringent standards of safety and bookkeeping and allow researchers to enroll subjects who are much less likely to sue if things go wrong.

For Farber, the development of AIDS drugs has become a matter of padding the Big Pharma bottom line, with the profit motive trickling down to the researchers themselves. In ``Serious Adverse Events," she writes that researchers ``stand to gain enormously if a trial yields a commercially successful drug, in terms of patents, royalties, credit, and prestige. The bigger their names get, the more money they attract from industry to push new drugs through trials."

Shah's ``The Body Hunters" draws a two-pronged conclusion about Big Pharma: that it is too aggressive about ``body-hunting" vulnerable patients to test some drugs-ones that can be marketed in the West-but not aggressive enough in researching and providing others, particularly those with less profit potential. She cites the example of Gilead Sciences and their patented AIDS drug, tenofovir, which they tested in clinical trials in several sub-Saharan African countries as well as in Thailand and Cambodia, attracting charges of exploitation by some activists. Gilead has faced criticism from Doctors Without Borders for not yet delivering on its 2002 promise to provide a cheap generic version of the FDA-approved tenofovir to developing nations.

``The ethical dilemmas here are already very difficult before you bring conflicts of interest and profit motive into it," says Wikler. Yet tempting though it may be, it doesn't simplify matters to cast Big Pharma as the bogeyman. ``The presupposition is that the pharmaceutical companies' primary incentive is to make money," says Yale's Levine, ``but if we get carried away with acting on presumptions that they're not honorably motivated, we may end up removing incentives to developing drugs."

  02/07/2006. Boston.com.