The Body Hunters
Page 15
But when the FDA analyzed the PROWESS data, they found that Xigris hadn’t worked for all patients with severe sepsis all the time, as the company’s New England Journal paper had said. It had only worked for half the patients—those who were most sick—and even for them it had worked only after the company revised the protocol midway through the study.
In the trial, in order to ensure that the septic patients who received the drug were roughly similar in age, severity of disease, and other indicators compared to those who received the placebo, Lilly had evaluated them according to a scoring system, the Acute Physiology and Chronic Health Evaluation, or APACHE II. The scoring system runs from 0 to 71, with higher scores signifying greater likelihood of death. When the FDA looked closely at the results it found that patients’ APACHE II scores correlated with their responsiveness to Xigris. For the sickest patients, those with APACHE II scores over 25, the death rate on Xigris had dropped by 12 percent compared to placebo. But for those with scores between 20 and 24 the drug had dropped the death rate by only 4 percent. For patients given Xigris who had APACHE scores under 20, the drug had actually increased the death rate by 3 percent. Worse, these patients suffered from the drug’s side effects—dangerous hemorrhaging—at the same rate.73 The company had also altered the trial protocol midway through the experiment; in the first half Xigris had shown no efficacy whatsoever. Xigris only started to work after Lilly restricted the study to “better quality patients,” as a Lilly researcher explained to a dumbfounded FDA advisory committee.74
The committee was split, ten in favor and ten against, but the FDA approved Xigris in November 2001 anyway.75 The agency added a single caveat: until Lilly provided more data on how the drug worked for patients with low APACHE II scores, the drug’s use would be restricted to patients with APACHE scores over 25. It was a restriction doomed to fail, since the scoring system itself was a “moving window,” as a Lilly researcher admitted. If the patient qualified in the morning, could the drug be given in the afternoon? Who knew? Lilly would be banned from promoting any “off-label” uses, but doctors would be free to use Xigris, as with any other approved drug, however they saw fit. Although ignoring the restrictions could result in “very serious consequences for the patient,” as one FDA adviser acknowledged, many clinicians might sensibly decide to do just that. Besides posting a lengthy transcript of the advisory committee meeting on an obscure section of its Web site, the agency never publicly rebutted the company’s rosy New England Journal of Medicine paper touting Xigris’s efficacy for all sepsis patients.76
With the FDA stamp of approval, the marketing of the drug began in earnest. “New hope for taming deadly shock,” ran the New York Times headline on a long, approving article, featuring quotes from a single sepsis expert—Gordon Bernard.77 Lilly dispatched over two hundred critical care specialists, at $1,000 a pop, to deliver promotional lectures about the new drug. It splurged on a special George Benson concert for docs likely to prescribe the drug.78 In an especially lucrative coup, the company convinced the Centers for Medicare and Medicaid to cover their patients’ hefty Xigris bills.79
In September 2002, alarmed by the FDA’s silence on the potential dangers of Xigris and Lilly’s glowing marketing material on the drug, a clutch of critical care experts who had participated in the advisory committee meeting went public with their concerns in the New England Journal of Medicine. “We believe there is not sufficient evidence at present for it [Xigris] to become standard of care,” Massachusetts General Hospital’s H. Shaw Warren, the National Institutes of Health’s Anthony Suffredini and Peter Q. Eichacker, and University of Texas’s Robert S. Munford wrote.80
Sales of the drug flagged. In order to realize the full sales potential of Xigris, the company would have to overcome the confusing restrictions the FDA had affixed to the label, industry analysts commented. But proving the drug worked in less sick patients could be “impractical and expensive beyond belief,” one sepsis expert said.81 To prove any shred of efficacy, more subjects taking the drug would have to be shown to survive than those taking placebos, but if the FDA analysis of the PROWESS trial were borne out, it was unlikely that there would be much of a contrast between their fates. To show a difference, either huge numbers of patients would have to be enrolled or the trial would have to be conducted in places where such patients generally died faster and more frequently anyway. Then again, if the PROWESS trial results were borne out, the drug could actively kill such patients. Those most vulnerable were those who were the least sick to begin with, to boot. They had the best chances of survival without treatment.
Lilly, like other big drug companies, had decided to use India as a major center for its clinical trials in 2002.82 And so the company looked to India to provide a significant number of subjects for its trial testing Xigris against placebo in sepsis patients with APACHE scores under 25, called the ADDRESS trial (Administration of Drotrecogin Alfa [Activated] in Early Severe Sepsis).83 In India the potential dangers of the drug for less ill patients weren’t widely known, and in 2003 Lilly had even applied to the Indian drug controller’s office, unsuccessfully, for permission to sell the drug for all patients with sepsis, not just those with high APACHE scores. As far as investigators like Kapadia were concerned, the main problem with Xigris wasn’t its safety profile in less sick sepsis patients, but its cost. Kapadia had read the September 2002 critique of the PROWESS trial in the New England Journal of Medicine, but the controversy, according to him, revolved “around the price rather than the drug.”84 In the ADDRESS trial, the drug would be offered for free, a particularly appealing option given that it otherwise cost Indians between 600,000 and 1,000,000 rupees (U.S. $13,000 to $21,000) for a course. Poor Indians had been known to forego lifesaving surgeries on their children for a fraction of that price.85
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.86) 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.”87 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.88
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.89 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.90
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.91
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.92
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.93 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.94
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.95
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.96
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.97 Buried in the fine print on the Xigris.com Web site, a small chart appeared mentioning a subset of the data.98
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.”99 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.100
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.”101
8
Calibrating Ethical Codes
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.”1
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”?2 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.3 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.4 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.5 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.