Medical Examiner


Coming to a clinical trial near you.

In July 2004, AIDS activists trashed a Gilead Sciences exhibit booth at the international AIDS conference in Bangkok, Thailand, because of a proposed study of the company’s drug tenofovir. The trial sought to assess whether tenofovir, arguably the safest AIDS drug on the market and already approved by the Food and Drug Administration, could prevent infection if given in daily doses. The proposed subjects were volunteer HIV-negative Cambodian sex workers. No matter. AIDS advocates objected because they thought the company was taking advantage of a vulnerable population and failing to offer the women medication if they became infected. Helping to lead the “zap” was ACT UP Paris, which splashed fake blood on the Gilead booth, hung a large banner that read “Closed Due to Death,” and plastered the walls with signs that said “Sex Workers Infected by Gilead” and “Gilead Prefers Us HIV+.”

The protest against Gilead is one example of pharmanoia, the extreme distrust of drug research and development that’s sweeping the world. As Joep Lange, head of the International AIDS Society at the time of the Bangkok meeting recently wrote, the protest was based on “uninformed demagogy” and threatened to derail “arguably the most important studies for those at high risk of acquiring HIV infection around the globe.” When Cambodian President Hun Sen pulled the plug on the study a month after the protest, he added his own uninformed demagogy to the fracas.

To be sure, major drug companies and the battalions of academic researchers on their payrolls deserve intense scrutiny. And they have received it, in this story in Bloomberg News about questionable clinical trials in Miami and in these stories in the New York Times about a defective heart device, which were honored this week by the George Polk journalism awards. Also justifiably unsparing is the Washington Post’s 2000 series “The Body Hunters,” which critically examined Pfizer’s experiments with Trovan on Nigerian children who had meningococcal meningitis, and the recent hammering of Merck for its decision not to report heart problems in trials of Vioxx. But as Big Pharma becomes the new Big Tobacco, some critics wildly exaggerate—see Celia Farber’s article on AIDS and the corruption of medical science in the March issue of Harper’s—turning shades of moral gray into black.

Consider other recent narratives that involve AIDS and the testing of drugs on humans. In John le Carré’s The Constant Gardener and the movie based on it, a big drug company and its affiliates cover up the toxicities of an experimental tuberculosis drug that they’re testing on Kenyan AIDS patients. They then murder the people who try to expose their wrongdoing. Le Carré writes in an author’s note: “by comparison with reality, my story was as tame as a holiday postcard.” In fact, the plot is so over the top, it’s a hoot. In January, the Toronto Globe and Mail, Canada’s leading daily, ran an article titled “Sex Slaves for Science?” featuring Salome Simon, a woman described as “a medical guinea pig” who participated in a long-running Canadian program that’s hunting for clues to develop an AIDS vaccine. Simon volunteered for the study. She can leave it at any time. And the researchers provide her with free medical care, as well as counseling about how to avoid infection. (Read more about this study.) Here are two other examples of drug R & D criticism run amok.

By overplaying unproved but sensational misdeeds, Big Pharma’s watchdogs obscure serious ones—like the inane lawsuit that 39 drug makers filed against the South African government in 1998 to block it from making generic versions of anti-HIV drugs. The scattershot approach also draws attention away from a critical and increasingly complicated issue that AIDS has pushed to the fore: What do researchers owe people who volunteer to test new medicines and devices?

There’s a fundamental rule of thumb for the ethics of conducting human biomedical studies: Don’t behave like a Nazi. It was the cruel and deadly Nazi experiments on concentration-camp prisoners that led to the 1947 Nuremberg Code, which spelled out 10 core principles for human experiments. These include the requirement that research subjects must freely join a study with full knowledge of the risks and that researchers must make every effort to minimize unnecessary mental or physical suffering. After the Nuremberg Code came several, more specific canons—the Declaration of Helsinki, guidelines from the Council for International Organizations of Medical Sciences, and the Belmont Report—that together  spell out the international ethical tenets for human research.

The AIDS epidemic has spotlighted the ethics of clinical research like no disease in history. Early on, AIDS activists demanded a voice in drug R & D; today they sit on influential panels that help governments set research guidelines and evaluate the worth of HIV-fighting drugs. AIDS also brings ethics to the forefront because it preys on ostracized groups—sex workers, gay men, minorities, drug users, migrants. And when powerful but expensive anti-HIV drug cocktails became available, the developed world was forced to recognize that patents and profits were standing in the way of reaching the vast majority of the HIV infected.

Should researchers conducting a study that aims to prevent HIV infection be required to provide anti-HIV drugs to participants who become infected during the trial, for reasons that have nothing to do with it? No official guidelines address this difficult question, which was central to the protests surrounding the abandoned study in Cambodia. In a sophisticated exchange between two bioethicists a few years ago, one, Ruth Macklin of Albert Einstein College of Medicine, argued that researchers have this “moral obligation.” The other, Charles Weijer of the University of Western Ontario, countered that in “moral theory, causation is a necessary condition of compensatory claims.” In other words, the researchers had no obligation to provide treatment unless their trial caused the infection.

Weijer also argued that providing anti-HIV drugs to subjects was an “undue inducement” because it might lead poor people to volunteer. There is “something strange about this worry,” wrote Ezekiel Emanuel, the chief bioethicist at NIH, in the Lancetlast July. “No person would become HIV positive just to get antiretroviral drugs,” Emanuel and his co-authors reasoned. If someone joins a trial because of the offer of anti-HIV drugs, they concluded, then the inducement is not undue.

Last May, an unusual meeting of activists, researchers, and bioethicists convened at the Bill and Melinda Gates Foundation to hash out the questions raised by the protest over the Cambodia trial. The group’s report, “Building Collaboration to Advance HIV Prevention,” wisely asserts that providing anti-HIV drugs to people who become infected during a prevention trial “is steadily becoming a question of logistics and implementation rather than a hot topic of ethical debate.” This has major implications for ongoing tenofovir pre-exposure prophylaxis experiments, as well as trials of AIDS vaccines and topical gels and creams known as microbicides. Indeed, as the report notes, several large sponsors of AIDS vaccine trials now have promised to help make sure that people infected during studies receive the medicines.

The ethical canons haven’t changed. But as the price of anti-HIV drugs has plummeted from $15,000 per person a year to a few hundred dollars, major international efforts are under way to bring these medicines to poor people. In essence, increased access to drugs revealed that the ethical quandary came down to cost, not right or wrong.

Researchers from wealthy countries typically provide research subjects in poor ones better health care. They also train colleagues and bring medical equipment that remains in use long after studies end. But there are financial and practical limits to what they can offer. No ethical manifesto, however, spells out precisely how much is enough. The unstated message of “Building Collaboration” is that researchers and communities that participate in clinical studies have to negotiate this bottom line.

AIDS has ushered in an ethos in which more and more people, especially in desperately poor countries, want to know what’s in it for them to participate in a clinical trial. They want some say in establishing what researchers call the risk/benefit ratio. These are reasonable demands. But pharmanoia makes them harder to hear.