Drug Trials and Error

Conspiracy theories about big pharma would amuse, if they were not a matter of life and death.

In March, Harper’s magazine, ordinarily classy, bohemian, and reliably well written and reported, went ape. The venerable journal published an account of clinical drug trials that was more baleful (and more fantastic) than that painted by John le Carré in his 2000 novel The Constant Gardener, where pharmaceutical companies and governments murderously collude to hide the truth about an experimental drug.

The Harper’s story, “Out of Control,” by Celia Farber, is an extraordinary, overheated document. Farber is a polemicist, notorious for advancing the “Duesberg hypothesis”: the argument, proposed by University of California, Berkeley, virologist Peter Duesberg, that HIV does not cause AIDS. Instead, as Farber writes in Harper’s, “It could very well be the case that HIV is a harmless passenger virus that infects a small percentage of the population and is spread primarily from mother to child.” Like Duesberg, Farber believes that in the United States and Europe, AIDS sufferers have poisoned themselves: “many cases of AIDS are the consequence of heavy drug use, both recreational (poppers, cocaine, methamphetamines, etc.) and medical (AZT, etc.).” In Africa, she argues, AIDS is a kind of confidence game played by pharmaceutical companies and national governments: she uncritically offers up Duesberg’s position that “AIDS in Africa is best understood as an umbrella term for a number of old diseases, formerly known by other names, that…do not command high rates of international aid.” Duesberg (and, we presume, Farber) consequently believes that all anti-HIV medications are poisonous shams promoted by self-serving researchers, executives, and activists: “If toxic AIDS therapies were discontinued, [Duesberg] says, thousands of lives could be saved virtually overnight.”

Of course, the epidemiological evidence does not support the Duesberg hypothesis. Most virologists, and nearly all AIDS researchers, accept that HIV causes AIDS. Farber’s own views of HIV and AIDS drugs seem political, informed by an idiosyncratic set of dislikes: of AIDS activists, of big business, of pharmaceutical and recrea-tional drugs, and of something called “the scientific-medical complex.”

Farber’s assault on what she calls “the HIV theory of AIDS” is not new: she has been writing approvingly of Duesberg since the late 1980s. What is novel in “Out of Control” is her criticism of an HIV drug trial, called HIVNET 012, that took place in -Kampala, Uganda, in the late 1990s. Just how drug trials in the poor world should be managed is a real question, and a highly topical one. The same month that Harper’s unleashed Farber, Wired magazine published “A Nation of Guinea Pigs,” a story by Jennifer Kahn that addresses the outsourcing of drug trials to India. Portrayals of corrupt or dubious medical research have suddenly become a media genre, one that draws upon popular distrust of the motives and methods of pharmaceutical companies (a psychology that science writer Jon Cohen has dubbed “pharmanoia”).

HIVNET 012, funded by the National Institutes of Health, found that a brief, inexpensive regimen of a drug called nevirapine- – one shot for a mother at the beginning of labor and one for her infant shortly after birth – could dramatically reduce rates of mother-to-child transmission of the virus. But problems with HIVNET 012 have since come to light: audits and reviews have found that record keeping was sloppy, and adverse events were underreported by trial investigators. Farber believes that these failures suggest a conspiracy to promote drugs that are toxic.

To further discredit HIVNET 012 and support her argument that anti-HIV drugs are deadly, Farber also tells the story of Joyce Ann Hafford, an HIV-positive, pregnant mother in Tennessee, who in 2003 entered another drug trial called PACTG 1022, designed to test anti-HIV drugs on pregnant women. While taking nevirapine in combination with other drugs, and for a longer time than the HIVNET 012 subjects did, Hafford developed terrible symptoms, including rashes, nausea, pain, and breathing trouble. She died soon after giving birth, probably from drug toxicity. Farber asserts that the trial was unethical, that nevirapine is unacceptably dangerous and useless, and that Hafford “never had AIDS, or anything even on the diagnostic scale of AIDS.” She implies that Hafford was probably not even HIV positive.

The clinical trial in which Joyce Ann Hafford enrolled did find nevirapine to have greater-than-expected toxicity when used in combination with other drugs in a particular regimen. These results were reported and published and led to a revision in Federal Drug Administration guidelines for the drug’s use. Hafford’s death, in which nevirapine was almost certainly a contributing cause, was a tragedy. It does not follow, however, that the risks of nevirapine will always outweigh the benefits, or that the drug is never a good treatment. HIV is a potentially fatal virus, and some of the treatments capable of holding it in check have dangerous side effects (as is also true of some anticancer regimens, such as chemotherapy). It should also be noted that Farber’s claim that Hafford did not have AIDS or was not HIV positive is not substantiated.

Farber’s treatment of HIVNET 012 is equally cavalier. She writes, “Although HIVNET was designed to be a randomized, placebo-controlled, double-blind, Phase III trial of 1,500 mother/infant pairs, it wound up being a no-placebo, neither double- nor even single-blind Phase II trial of 626 mother/infant pairs.” She implies that this degradation in standards occurred because the Ugandans were corrupted by “the lucrative promise of AIDS drug research” and is scandalized that the results of the study were “received rapturously.” She concludes, “With the results of the study now published in The Lancet, Boehringer [a German pharmaceutical company]…pressed for FDA approval to have nevira-pine licensed for use in preventing the transmission of HIV in pregnancy.”

By implication, therefore, HIVNET led to the death of Joyce Ann Hafford.

Most of these claims are false or misleading. HIVNET 012 was, in fact, a randomized, single-blind phase III trial – that is, a trial primarily designed to study the efficacy of a new drug (in this case, nevirapine), where patients randomly receive either the new drug or the standard treatment for a disease (here, AZT). It was not double blind, because the drug administration procedures were different in the two arms of the trial; but while phase III trials are, ideally, double blind, the FDA does not absolutely require them to be. Similarly, placebos, while desirable, are not strictly necessary to yield scientifically valid trial results. In the case of HIVNET 012, hospital clinicians resisted giving patients placebos, allowing AZT to stand in their place for purposes of control: they wanted to provide treatments to sick people.

But HIVNET 012 was certainly flawed; NIH itself acknowledges as much. In 2004, the agency therefore requested an evaluation of the trial results from the Institute of Medicine (IOM), an independent, quasi–academic body that advises government agencies and researchers. The IOM concluded that HIVNET 012’s conclusions were valid. It agreed that investigators’ files had been messy (in part because the hospital in Kampala flooded during the investigation) and that some adverse events had gone unreported (both in patients taking nevirapine and in those taking AZT). But the IOM determined that the data on rates of HIV infection and survival did indicate the benefit of the nevira-pine regimen to the newborns.

In any case, HIVNET 012’s flaws are not relevant. At least five other studies have now confirmed the safety and benefits of the drug. Indeed, as a group of renowned AIDS experts, including Robert Gallo, the codiscoverer of the HIV virus, wrote recently in response to Farber’s article, “Not a single life-threatening event related to short-course nevirapine has been recorded in mother or child in tens of thousands of such uses around the world.” Ultimately, Farber’s contentions are skewed by her assumptions. To someone who believes HIV is benign, what would be a good anti-HIV drug or trial?

Jennifer Kahn’s Wired story poses different and less easily answered questions about clinical trials in the poor world. Her account of drug trials in India indulges in its own kind of excess: she claims that “India, the brilliant hub of outsourced labor, was positioning itself in a newly lucrative role: guinea pig to the world.” But Kahn’s piece is genuinely thought-provoking. It profiles a quiet doctor named S. P. Kalantri who works in Sevagram, a town in the -middle of India, in order to ask whether clinical trials in the poor world are inescapably morally compromised.

Kalantri explains that he and his hospital are receiving a growing number of requests from pharmaceutical companies looking for test sites for drugs in their development pipelines. On the one hand, he notes, impoverished patients enrolling in these trials can receive a “health care windfall,” including regular physical exams and access to medication that may help them. But the problem, Kalantri says, is that patients are often quite passive and tend not to question their doctors’ recommendations, making it harder to ensure uncoerced, informed consent. And regrettably, the drugs being tested in India often have little relevance to their recipients’ most pressing medical problems. For instance, -Kalantri’s hospital is currently part of a trial to determine whether a drug called Aggrenox can help to forestall second strokes. Arguably, many other potential thera-pies would be more helpful to the people of Sevagram. And even those that are helpful may turn out to be too expensive for them.

In “A Nation of Guinea Pigs,” Kahn worries that payments to hospitals and doctors, which are meant to cover the costs of running and overseeing a trial, sometimes serve as bribes, encouraging improper human experimentation. She questions whether trials in remote areas receive proper oversight, from either the Indian government or foreign institutions. (Indeed, pharmaceutical trials that do not receive government funding are overseen by commercial institutional review boards, which are paid by the companies they are supposed to be monitoring – an obvious conflict of interest.) Kahn does not demonstrate specific wrongdoing or scandal. But she clearly explains the perverse incentives that might encourage unethical behavior.

There are, however, very strong medical, scientific, and economic arguments for conducting clinical trials in the poor world. The drugs tested might be intended for the population testing them; the trials might benefit from genetic diversity; or the trials, usually the most expensive part of the drug development process, might be cheaper. Given that clinical trials will be conducted in the poor world, what would be a better system?

The ethical requirements for human research were established by international agreements such as the 1964 Helsinki declaration. They include various commonsense rules: for instance, physicians ought to consider the health and well-being of subjects above other considerations; any adverse effects that occur during the course of a study should be scrupulously monitored, reported, and treated; researchers must fully communicate potential risks and benefits; and subjects must not be coerced into participating. Most importantly, the subjects of a trial should bene-fit personally from the results of the research (that is, they should not be induced to participate in a trial for solely economic reasons).

But obvious difficulties arise in interpreting these principles and applying them in impoverished settings. A common dilemma is, Just what constitutes excessive inducement? If researchers pay for their subjects’ transportation and lunch, or reimburse them for missing a day of work, is that a bribe? What if they offer direct payments?

Informed consent is particularly elusive in places where patients are not well educated and where doctors’ authority looms large. Informed-consent agreements are lengthy, bureaucratic documents. One recent improvement is to supplement documents with -visual aids and require patients to answer a brief quiz to ensure they have really comprehended the nature and terms of the transaction. It is important that patients understand they may leave the trial whenever they wish and will -neither be punished nor lose their primary health care.

Among the most vexing questions is, Who should oversee the people who oversee clinical trials? At NIH, where HIVNET 012 has cast a long shadow, there is a growing interest in supporting the work of local ethics committees. But local groups often lack the training and resources to do much. One study, which appears in the March-April issue of IRB: Ethics and Human Research, suggests that many African groups are susceptible to influence and have limited expertise.

A variety of promising initiatives, sponsored by international bodies like the World Health Organization (WHO), may help these groups to grow stronger. WHO is funding projects that teach ethics and provide infrastructure. This sounds sane: American and European private and public institutions cannot provide the oversight required for ethical clinical trials in the poor world, particularly when Ameri-can and European pharmaceutical companies are involved.

Read together, the Farber and Kahn pieces, apparently so different, disturb. While Farber’s malignant vision of clinical trials is obviously unhinged, it does remind us that clinical trials are not without risks for their subjects. Kahn dramatizes another uncomfortable fact: that economic disparity between investigators and subjects in human research creates possibilities for abuse and coercion – possibilities that we do not really know how to manage. Considered in combination, these realities may not justify pharmanoia, but they explain it.

“Out of Control”
By Celia Farber
Harper’s, March 2006

“A Nation of
Guinea Pigs”
By Jennifer Kahn
Wired, March 2006

Amanda Schaffer writes about science and medicine for Slate.

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