The Body Hunters (21 page)

For Lilly, the important thing wasn't the number of patients that developing country sites such as India might be able to induct into the trial per se. (Along with the eleven North American and Western European countries that had provided subjects for the PROWESS trial, Lilly would enlist ADDRESS subjects from a range of developing countries, including Argentina, Brazil, Chile, Croatia, Egypt, India, Lebanon, Mexico, the Philippines, Romania, Russia, Saudi Arabia, Singapore, Slovak Republic, Slovenia, South Africa, and Thailand.
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) As CROs knew all too well, involving developing countries sped up trials not only because of the ease of rapid recruitment but because their patients provided quick, plentiful clinical “events.” As CRO exec John Wurzlemann plainly noted, “If you don't have events, you're never going to finish your trial.”
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In the ADDRESS trial, the main event researchers would be counting was death within twenty-eight days. Sufficient quantities of patients would have to perish on placebo in order to
demonstrate that Xigris had an effect of some kind. With overall mortality rates for sepsis patients in developing countries running 60 percent higher than those in the United States, even a relative handful of patients could beef up the death count, increasing the odds of speedy, conclusive results.
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While the ADDRESS trial moved ahead Lilly continued its aggressive promotion of Xigris. In March 2004, sepsis experts sponsored by Lilly issued guidelines on the proper treatment of the condition in a prominent journal,
Critical Care Medicine.
Each intervention that might occur to a clinician faced with a septic patient was assigned a grade, with the highest marks awarded to those with the most evidence from the kind of large, multimillion-dollar randomized trials that few other than drug companies can afford. Xigris, not surprisingly, won top marks. Other therapies, including antibiotics and steroids, which were supported by years of widespread use and several independent studies, fared poorly under the grading system because they lacked data from large-scale trials.
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A dozen professional societies signed on to the guidelines, and the PR firm hired by Lilly organized publicity, distributing the guidelines on free posters, pocket guides, and PowerPoint slides.
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That month, a prominent steroid researcher approached Lilly with a proposal for a head-to-head trial pitting Xigris against steroids, a study that could help clinicians finally settle the question as to the relative value of the two therapies. Lilly flatly refused to cooperate. The Xigris marketing was having its effect. Researchers in the field chimed in that such a trial would be unethical, since some patients would be deprived of Xigris.
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A few months later steroid researchers strengthened the evidence in favor of that therapy with a meta analysis of all the available data on the drug. According to their
British Medical Journal
paper, safe, inexpensive steroid therapy had been found to be just as effective as a $7,000 course of Xigris.
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Lilly ignored the results. At its special three-day conference in Hyderabad, India, in July 2004, hosted for Asian critical care
specialists, a Lilly exec extolled Xigris as “the only drug available” to treat patients with sepsis.
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Xigris's momentum burying steroid therapy appeared unstoppable. In September 2004, online medical experts could be found urging clinicians to use Xigris on all patients with severe sepsis. “Should [Xigris] be restricted to patients with severe sepsis with an APACHE II score >25?” the WebMD Web site asked its critical care expert. “I believe the answer is no,” came the prominently posted response.
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Lilly scientists repeatedly re-analyzed the PROWESS data, dreaming up innovative new angles from which to present the positive data again and again. It was cheaper to use it earlier rather than later, Lilly scientists found. It worked even better when used with patients with low protein C levels, they discovered. It even worked with patients who weighed over 300 pounds. Lilly dispatched its scientists to professional meetings to trumpet the news.

At one such gathering in Seattle in October 2004, amid a flurry of Lilly presentations underlining the benefits and cost-effectiveness of Xigris gleaned from re-analyses of the PROWESS trial data, a little noticed session quietly ran its course. There was no written abstract for the paper that Edward Abraham, MD, presented that day, as the session was a late-breaking one. It wouldn't appear on the society's Web site later on, nor did it attract the attention of the various medical publishing outfits, reporters, and industry analysts trolling for material at the conference. They were drawn instead like flies to honey to a different late-breaking session that showed that Viagra might work for pulmonary hypertension.
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To the select few who gathered that day in the misty city Abraham announced that the ADDRESS trial had been terminated eight months before, over a year early. Of the patients who had received placebos, Abraham said, 17 percent had died. Of the group that had received the drug, 18.5 percent had died. There was worse news, too: in patients who had had recent surgery, Xigris had provoked a 20.4 percent death rate, as opposed to just
16.4 percent on placebo. There hadn't been many patients who had high APACHE scores in the trial—just 321 out of 2,613 enrolled subjects. But even among them, 29.5 percent died on the drug, while just 24.7 died on placebo.

India had been the fifth largest contributor of subjects for the trial, after the United States, Germany, France, and Canada. The subjects from developing countries had suffered the highest death rates overall—nearly double that of subjects from North America and Europe.
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In the twelve months following the close of the trial, Lilly did little to publicize the failed ADDRESS trial. The company presented the data only in Seattle and at one other meeting that fall, in Europe. Upon request by the Canadian health authorities, Lilly sent a letter to Canadian hospital administrators, informing them about the trial.
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Buried in the fine print on the
Xigris.com
Web site, a small chart appeared mentioning a subset of the data.
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When the results finally appeared in the
New England Journal of Medicine
in September 2005, the ADDRESS investigators chalked up Xigris's poor showing to the inexperience of many of the local researchers they had had to rely on. “Many of these centers and countries had not previously participated in critical care trials,” they wrote, which “may have affected the patient population included in this study, making it difficult to compare the results of this clinical trial directly with those of other studies . . . such as PROWESS.”
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Nevertheless, word spread in the United States that Xigris was a finicky drug with restricted utility, and by 2004 sales of Xigris amounted to a lackluster $200 million.
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In the developing countries that ran the ADDRESS trial, as many subjects perished on placebo as on Xigris. On this basis, one could argue that the trial neither helped nor harmed them. But this outcome wasn't predictable; on the contrary, before the trial started,
the evidence suggested that patients would, in fact, suffer from the drug. That the FDA and the company moved forward regardless illustrates how detached the for-profit drug development establishment is from the business of protecting public health. After all, precious few patients in India are likely to enjoy the drug's benefits, however slim. At more than $3,000 for a course, the price of Xigris remains prohibitive, despite Lilly's successful lobbying of the government to drop custom duties on the drug.

If Xigris truly were the “only” drug to treat sepsis, as Eli Lilly India chairman Rajiv Gulati frequently tells the press, perhaps such mismatches between public health relevance and drug research might be tolerable. But it isn't. An alternative treatment that is both cheaper and safer exists: low-dose steroids. It languishes in unconfirmed obscurity. How many lives would have been saved had Lilly been compelled to devote some of its ADDRESS trial budget to establish the utility of steroids?

When faced with such questions, Kapadia bristled. “Every trial is always criticized,” he said with frustration. His voice rose a notch and his speech quickened. “There is no trial that is perfect! There is almost no trial that can get every aspect of it right. I wouldn't say this trial would have more than its share of criticisms,” he said. He paused, then added: “I really am unaware of any trial which has no criticism.”
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Peter Lurie's 1997
New England Journal
paper and editor Marcia Angell's editorial decrying researchers' double standards for poor subjects—and likening them to the notorious Tuskegee Syphilis Study—opened years of tortured debate within the biomedical research community. “There have been gazillions of conferences and reports from national commissions and councils,” said Johns Hopkins bioethicist Ruth Faden in 2001. “In the developing world, there's been a tremendous ratcheting up of interest in this question . . . of how to take account of politics and economic questions in research ethics.” While the poles of the debate quickly emerged, with Lurie and Angell on one side and PhRMA spokespeople and FDA regulators on the other, most of the mainstream of the research community remained undecided. “We are struggling,” said Faden. “We are reaching more consensus on conditions under which it is OK” to dole out substandard care in clinical trials, she said, but “increasing lack of consensus on whether it is alright in other circumstances.”
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While the medical and bioethics press continued to appraise the intricate ethical complexities of the issue, a small battalion of researchers, led by FDA regulators and their advisers, attempted to seize the fluidity of the moment to shape ethical guidelines to their advantage. First, in the spring of 1999, Yale University physician Robert Levine, a key adviser in research ethics policymaking circles, circulated some proposed revisions to the Declaration of Helsinki, in advance of an upcoming meeting of the World Medical Association (WMA). How about, instead of insisting that subjects
be assured of the “best proven” methods, Levine suggested, the declaration simply require that they be assured of the best proven methods “that would otherwise be available to him or her”?
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The change would have altered the meaning of the edict entirely. With the addition of nine words, researchers could effectively wash their hands of any obligations to their subjects if they were poor or otherwise deprived.

Levine's proposal faltered at the October 2000 meeting. In light of the still simmering controversies over the mother-to-child HIV prevention trials, the WMA was moved to strengthen protections of research subjects rather than dilute them. They revised the declaration to reiterate that experimental treatments should indeed be tested against the best current treatment and underlined the dictum by pointing out that placebos were only permissible when there was no known effective treatment.
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WMA secretary general Delon Human exulted in the new language. “We say almost explicitly . . . that if there is treatment, then you cannot give a sugar pill to the control group,” he said to a
Washington Post
reporter after the meeting.
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Ethics committees around the world referred to the Declaration of Helsinki when deciding on the ethical permissibility of trials; with the new language, they'd have vital ammunition to shut down placebo-controlled trials.

U.S. officials were irate. But it wasn't the public-health research community that was up in arms this time.

In 1975, the FDA had incorporated the Declaration of Helsinki into its rules for clinical trials conducted outside the United States, refreshing the regulations whenever the declaration was periodically revised.
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Given the precedent, the agency would be expected to adopt this latest version as well. But the drug industry's ability to develop me-too drugs with little if any benefit over existing drugs—by testing them against placebos and conducting trials overseas—could come crashing to a halt if they did. Suddenly, ethics committees might start nixing trials of new allergy
drugs when tested against placebos, or copycat drugs in other noncritical therapeutic areas.

“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.”
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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.
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