The Body Hunters

by Sonia Shah

  “There are a lot of trials where the person isn’t giving anything up and wants to be in the trial,” the FDA’s Robert Temple said to the Washington Post, offering hay fever and migraine drug trials as examples. “The declaration bars them, too. I think that’s paternalistic.” Not just that, either. Temple decreed the revised declaration “scientifically and ethically incorrect.”6

  In fact, just as Temple was doling out snippy quotes about allergy drugs to reporters, the agency was attempting to facilitate a placebo-controlled study in Latin America for a drug to treat fatally lung-impaired infants. There were already four such drugs on the market and the new drug, while easier to manufacture than its rivals, would likely provide no added benefit for patients, by the drugmaker’s own admission. A trial that pitted the new drug against placebo seemed the only way to prove the drug worked at all and get it on the market, but no American parent would enroll in such a trial, risking their dying infant’s life when already approved alternative drugs were available to them. The solution the company proposed was to run the trial at a poor hospital in Latin America instead. In January 2001, the FDA’s Division of Pulmonary and Allergy Drug Products held a workshop to weigh the pros and cons of the proposed trial: “Use of placebo-controls in life threatening diseases: is the developing world the answer?” they dubbed the session.7

  Peter Lurie, who had by then taken up a full-time position at the health watchdog group Public Citizen, raised a stink and forced the FDA to can the idea. Temple was miffed. “There is a certain satisfaction that everybody feels that this trial isn’t happening,” he said. But “those people [who would have been in the study] don’t seem to have gained by this maintenance of principle.” After all, the company was willing to upgrade decrepit hospital facilities in the developing country site to state-of-the-art. “Half of the people would have gotten surfactant and better care” than they would have otherwise, noted Temple. “The other half would get the better care.”8

  In the spring of 2001 the FDA announced that in defiance of two decades of precedent it would not be adopting the latest version of the Declaration of Helsinki into its regulations.9

  Emboldened by the FDA’s circumvention of the undesirably strict Declaration of Helsinki, U.S. researchers and bioethicists attempted a similar dismantling of the even stricter rules governing NIH research on human subjects.

  Unlike trials aimed at FDA approval, which can get away with host country ethics reviews alone, NIH rules require that scientists procure ethics approval for their studies both in the United States and the host country. In November 2000, the National Bioethics Advisory Commission (NBAC), set up in 1995 to advise the U.S. government on ethical issues in biomedicine, started to make noises about dropping the requirement. In a draft version of a 2001 report on clinical trials in developing countries, the NBAC recommended that for overseas research, ethics reviews abroad would suffice on their own.10

  NBAC planned to recommend this change despite evidence in the commission’s own report that such overseas reviews would be unlikely to stop trials no matter how they measured up to the declaration’s edicts. NBAC researchers had found that in Morocco, for instance, there were no ethical review committees, and “the Ministry of Health does not feel that it is necessary.” Turkish officials had “serious reservations” about setting up ethics review committees. Researchers in Haiti said there had been no ethics committees in their country until 1999. Researchers in Uganda revealed that “the notion of an unbiased, uninvested review committee” was still “quite new” to the country. In an NBAC-commissioned anonymous survey, researchers active abroad had been startlingly frank about the ethics committees in developing countries that oversaw their trials. “Whatever happens to the patients, they don’t care too much,” one said. Ethics reviewers are “more concerned about the money,” researchers told NBAC; “they have no control at all”; “they are looking [at] technical [issues] . . . and money, how much are you getting”; and “it is a political approval . . . more about whether we would be spies or . . . real researchers.” The people in charge of the committees “have no idea about this. They just know [ethics] is a word.”11 Overall, one-quarter of clinical trials conducted in developing countries went through no ethical review whatsoever, the survey found.12

  And yet, in its final April 2001 report, the NBAC’s recommendations were, for the most part, noncommittal. On most of the thornier ethical issues confronting researchers, NBAC recommended simply passing the buck to local ethics committees. Researchers should try to provide “established effective treatment” whether or not it is routinely available, the NBAC opined, but if they don’t, they should explain themselves to their ethics committees. Researchers should make “reasonable, good faith efforts” to provide study drugs to subjects after trials end, but if not, again, they should simply present their justifications to their ethics committees. On the question of whether researchers should capture both domestic and foreign ethics approvals, the NBAC recommended that researchers do get both—unless U.S. officials decided that the foreign site was sufficient on its own.13 The NBAC report, noted Yale’s Robert Levine approvingly, “put the world on notice that they [U.S. researchers] don’t intend to comply” with the revised Declaration of Helsinki.14

  In the summer of 2001, an industry-funded outfit, the Drug Information Association, held its annual meeting in Denver, Colorado. The FDA’s Temple joined Caroline Loew, a spokesperson from the industry lobby group PhRMA, in attacking the WMA’s Delon Human in front of a standing-room-only crowd. According to an account of the meeting circulated by a prominent bioethicist, Temple was scathing. The declaration “doesn’t look like a group of suggestions that are worth discussing,” he said. “It looks like a set of principles to be observed. And it says that every doctor has to observe these or he’s not a good person.”

  Loew went straight to the heart of the matter. According to Loew, GlaxoSmithKline, Pfizer, and Merck had all had clinical trials banned by ethics reviewers because of the new Helsinki requirements. “Sooner or later it will be practically impossible to perform placebo-controlled studies for therapeutic confirmatory purposes,” GlaxoSmithKline and AstraZeneca scientists wrote in a trade journal in 2001. “Indeed, it is already now increasingly difficult.” If forced by ethics committees to test their new drugs against already available therapies, “improvement of therapy by degrees”—that is, copycat drugs—“will become impossible,” they said.15 “What we’re seeing is important, ethical clinical research being disrupted,” Loew said, “with the end result that access to innovative new medicine is deferred.”16

  Loew also aired the industry’s objections to Article 30 of the declaration, which requires that research subjects should be assured access to whatever beneficial intervention is identified in the study, and Article 27, which requires that all results from clinical trials be published publicly. Human was overwhelmed. He announced he would convene a work group to reconsider the placebo restriction. His plan was to have “direct meetings with those who are critical,” he said.17

  In the fall of 2001, under pressure from the FDA and PhRMA, Human and the WMA issued a hasty retreat. The WMA revised the declaration yet again, the once elegantly concise document now appended with a wordy footnote “clarifying” the placebo rule. According to the footnote, “in general” placebos should not be used when proven therapy exists, but if placebos are necessary “for compelling and scientifically sound methodological reasons,” or when the condition for which therapy would be withheld is minor, then they were “ethically acceptable.”18

  Lurie was outraged. “Where . . . is the footnote explaining in greater detail how informed consent should be obtained? Or how ethics committees should be constituted? Or how conflict of interest should be reduced or eliminated?” he railed in a 2003 letter to Human.19

  The Helsinki dilutions didn’t stop there, either.

  Industry scientists stepped up their complaints that the Declaration of Helsinki’s requirement that study su
bjects be “assured” of the best intervention as identified in the study was too onerous. “Firstly, none of the methods used in the study may be found to be suitable,” Merck’s Laurence Hirsch and Harry Guess wrote in the British Medical Journal.

  Secondly, a single study can rarely identify “best” treatment. . . . Thirdly, a new drug or device may not be approved until several years after the end of a trial. Consequently, providing as yet unapproved treatment to trial participants on completion of the study may conflict with local regulations. Finally, an offer to provide treatment that is otherwise unavailable on completion of the trial might be considered an undue inducement to potential participants.20

  “It is unrealistic and misleading to suggest that [drugmakers] can ensure access to drugs for any given population,” seconded a paper by PhRMA. “Only local governments, not pharmaceutical companies, can make decisions about initial, and particularly ongoing, access to new drugs. . . . There is a need first to establish an appropriate infrastructure (e.g. roads, transportation, electricity, and water supplies).” Requiring such magnanimous gestures would surely bar drug companies from taking on research into new drugs for those diseases that public health advocates continually complained were neglected, the PhRMA paper warned.21

  On cue, the WMA again convened a working group—this time to draft new language weakening the declaration’s requirement that patients be assured of study drugs after trials end. In September 2004, Helsinki gained another wordy footnote, clarifying that posttrial access to study drugs didn’t have to be “assured,” but merely “identified” and “described” before trials begin.22

  With influential institutions such as UNAIDS, the National Bioethics Advisory Commission, and the WMA on record supporting double standards in medical research, other groups chimed in as well, including the Council for International Organization of Medical Sciences and the European Group on Ethics in Science and New Technologies. According to the new ethics regime, if there is solid scientific reason to believe trial subjects will not be harmed and can possibly benefit, then researchers should feel free to lower their ethical standards for impoverished patients. True, the new consensus might “create an insidious double standard that accepts for the poor what it rejects as unethical for the rich,” defenders noted in a 2004 Journal of Medical Ethics paper, but “even if the position is not the optimal ethical standard, it is at least not clearly unethical.”23

  Ironically, one of the poster children of the standard-of-care debate—Jay Brooks Jackson’s trial pitting nevirapine against placebo and ultra-short course AZT in preventing HIV infections in infants, a study condemned as unethical by Lurie—had meanwhile fallen out of favor. In September 2003, Jackson published his final report on the 012 trial, reporting on how the infants who survived the trial had fared eighteen months down the road. Although the nevirapine had saved more babies from HIV infection compared to the ultra-short course of AZT, it made no difference in saving their lives. After eighteen months the same proportion of babies had died in both groups. It wasn’t clear why, but the fact that their HIV-burdened mothers—who did not receive antiretroviral therapy after the trial ended—had died might have had something to do with it.24 Jackson said he would be checking up on the children again. He expected more of the toddlers in the AZT group to die in a few years’ time. “HIV takes time to kill babies,” he pointed out matter-of-factly.25

  But why bother with single doses of nevirapine anymore, anyway? New York University’s HIV researcher Karen Beckerman asked in the accompanying editorial. American patients had rightly shunned nevirapine as monotherapy back in the early 1990s because of its tendency to produce resistant strains of the virus. In 2001, Jackson’s colleagues noted that nearly 20 percent of the women who received even a single dose of the drug had developed resistant strains of HIV. Likewise, if the infants exposed to the drug contracted HIV because the drug failed to work for them, or because their mothers passed on the virus through breast milk, they’d likely harbor resistant strains of the virus and find themselves dangerously limited in the kinds of therapies they might be able to take.26 The entire class of nevirapine-like drugs could be rendered useless as AIDS treatments for them, Beckerman pointed out.

  Combination antiretroviral therapy would both greatly decrease the chances of their babies catching the bug and would save the lives of mothers. It would also save the babies even if they did get infected—just as it had in the United States for years. With prices finally within reach, and lingering doubts about the ability of impoverished people to faithfully adhere to the regimen vanquished, there was no longer any need for “suboptimum” preventive techniques, she wrote. Single-dose nevirapine and other such second-rate solutions “no longer have a justifiable place in the front lines of global struggle against HIV/AIDS.”27

  Just as Helsinki was diluted in order to allow the kinds of trials that had brought the world single-dose nevirapine to prevent HIV infection in infants, the scientific consensus in favor of that treatment started to turn. In July 2004, South African health officials advised clinicians to stop administering nevirapine as an HIV prevention drug.28

  Today AIDS researchers continue to justify giving substandard care to their test subjects in developing countries, in places where local standard of care is comparably poor. The trials Jackson planned in 2003 to launch in China were illustrative. Most revolved around experiments upon intravenous drug users, some of the most downtrodden people in Chinese society, their contaminated needles the source of at least half of the HIV infections in the country. The best current methods of helping intravenous drug users—clean needles and substitution drugs such as buprenorphine and methodone, for example—are routinely administered in Western countries. Not so in China, at the time Jackson planned to launch his studies. There, before 2004, the government had been known to throw illegal drug users into hospitals, force them into hard labor, and even execute them.29

  And so, in Jackson’s studies, the best proven methods would not be on offer. In one study Jackson would enroll Chinese intravenous drug users, comparing how some given nevirapine to prevent HIV infections fared against others given nothing but placebo.30 In another he’d simply enroll them in a trial and count how many came down with HIV. In yet another he’d offer them all counseling, but give buprenorphine to only some and track how many became infected with HIV compared to those given placebo. None of the subjects who contracted HIV during the course of the trials would get antiretroviral therapy from the researchers. The Chinese government didn’t offer it either.31

  In 2001, NIH officials had suggested that Jackson might consider offering all of his Chinese subjects antiretrovirals and substitution therapies, treatment that would undoubtedly save many of their lives. Jackson objected. “American-style treatment programs are impractical at this point in China,” he said. “It’s unrealistic—even unethical—to think that we could provide Western standards of care to everyone in the world.”32

  In 2004, he was proved wrong, when the Chinese government announced it would offer free HIV testing to everyone in the country and antiretroviral treatment to all who needed it.33 In 2005, officials announced their intention to legalize the use of methadone to treat intravenous drug users and step up needle-exchange programs. Meanwhile, the World Health Organization added both methadone and buprenorphine to its list of “essential medicines,” drugs so crucial to public health that they should be available to all.34

  Whether or not Jackson would be able to conduct his trial with nevirapine in China—as of 2005, the trial was in limbo—the arguments so staunchly forwarded in its favor had crumbled fast indeed.

  VaxGen’s trials of its tepid HIV vaccine in the United States and Thailand had, by early 2003, predictably failed. A smaller trial of an Aventis vaccine had a similarly weak showing, interim results revealed in 2002, leading researchers to give up on their plans for a larger trial testing the vaccine in the United States. And yet, in September 2003, NIH researchers chose to plow ahead with a tria
l that had been planned before the bad results: a massive trial in Thailand of a combination of the two failed vaccines.35

  Critics such as Cornell University’s John Moore and AIDS advocacy groups Treatment Action Group and Gay Men’s Health Crisis complained loudly. Such data would likely render papers, grants, and scientific satisfaction, but had only a tenuous link to the search for an effective vaccine, they said. Many earlier vaccines had proven effective without scientists ever figuring out how they worked at all. But the researchers exhibited a steely determination to extract some usable data from the trial.36

  By early 2005, ten thousand of a needed sixteen thousand subjects had been rounded up for the vaccine trial. Would the thousands of Thai subjects be informed that between the conception of the trial and its start date, both halves of the experimental vaccine they were being given had been shown ineffective? Local newspapers seemed oblivious, predicting that “the AIDS vaccine work programme will definitely be a success.”37 Lancet editor Richard Horton asked one of the safety monitors of the trial about “the propriety of continuing” the experiment. The monitor’s response was evasive, as Horton later described in the New York Review of Books. “Good question,” the monitor said, smiling anxiously.38

  At the same time, Thai AIDS activists watched prevention campaigns in the country shrivel. “We spent millions of dollars for this no-hope project rather than spending that money on providing antiretroviral drugs for patients,” complained one.39

  As double standards in research ethics for poor people become increasingly acceptable in the research community, new arguments rationalizing the stripping down of subject protections have come into vogue. A popular one dismisses concern about defenseless test subjects as paternalistic. Nobody is forcing Thai sex workers or Chinese drug users to enroll in these experiments, goes the argument. They’ve decided for themselves. “You can’t treat them as incapable of pursuing their own ends,” says Temple. “They are not cavemen; they are just not rich.”40 In other words, informed and voluntary consent, that cornerstone of research ethics, offers sufficient protection, even for the most powerless. To the sick, poor subjects lining up at their clinic doors in Asia and Africa, clinical researchers might now echo used-car salespeople and the like: caveat emptor.