by Sonia Shah
But according to Indian industry analyst Chandra Gulhati, MD, “even if an erring company is caught red-handed indulging in illegal activities, it is let off, for reasons best known to regulators, with a light warning.”23
Rather than reinforce the sagging regulatory gates, starting in the late 1980s, the government opted to introduce yet another element to the anarchic mix: Western-style, for-profit medical services. During the 1990s Indian leaders shed the nationalistic rules that had protected the nation’s medical market from foreign interests and made way for deep-pocketed investors to march in.
By 2002 it was clear to Indian public health workers that “the provision of medical services” in the country had become “big business.”24 Predictably, the new corporate hospitals did not pick up the slack from overcrowded public ones catering to the 4.5 million Indians infected with HIV—the second-largest population of such patients in the world—the millions of Indians suffering from tuberculosis and chronic hepatitis, or the masses of children dying of diarrhea, measles, pneumonia, and even polio.25 Instead, they sought out elite and upper-middle-class Indians, as well as medical tourists from the UK and the Middle East, providing high-tech specialized care in a business that analysts said could be worth up to $2 billion a year.26
Trailing close behind the new corporate hospitals were the multinational drug companies that would stock their formularies. Anticipating a market for drugs that could reach nearly $10 billion within a few years, Pfizer, Chiron, Merck, and GlaxoSmithKline all announced plans to expand their operations in India between 2000 and 2005. Novartis built a gleaming, marble-white building amid the smog-clogged ruins of Mumbai’s inner city, and ringed it with expansive emerald lawns meticulously groomed by rail-thin locals. Eli Lilly announced plans to triple its R&D in the country.27 Once new patent laws required by the WTO muted the generic drug industry, the multinationals’ market share would balloon from just a quarter to nearly half by 2010, the Daily International Pharma Alert, a trade publication, predicted in January 2005.28 It didn’t bode well for the poor majority. In 2004, Novartis execs had admitted to the World Bank that they viewed India as a market of just 50 million people—that is, the company had no plans to even try to sell its drugs to the other 95 percent of the Indian population.29
Government officials hoped likewise to expand the scale of industry-sponsored clinical trials in the country, from a $70 million business to a $1 billion one. During the early 2000s, they eased the way with a series of exemptions and incentives. Experimental drugs would be exempted from customs duties.30 Companies would no longer have to complete Phase 3 trials in other countries before launching such trials in India. They wouldn’t have to demonstrate their experimental drug’s “special value” to India anymore either. Companies willing to invest in R&D in India would be congratulated with ten-year tax concessions. In 2003, when the director of an American company that tracks the clinical trials business came to India for a conference, government officials feted him as if he were a head of state.31
Over a dozen full-service Western CROs set up shop in the country, all with ambitious plans to expand.32 “The opportunities are huge, the multinationals are eager, the Indian companies are willing,” the Economic Times enthused in 2004. “We have the skills, we have the people and we have an advantage which China doesn’t and probably never will. Best of all, this is one sort of outsourcing which American workers aren’t likely to protest.”33
But would the country’s threadbare ethics infrastructure be up to the task? While in theory clinical sites that conduct trials have to engage the oversight of an ethics committee, in practice such committees are few and far between. Many of those that do meet regularly do so “in order to enable clearance” of proposed trials, not to question their ethics or relevance, Indian health activist Sandhya Srinivasan says.34 “They hardly meet,” agrees Amar Jesani, MD, a Mumbai-based bioethicist who sits on several such committees. “The chairperson will just keep signing. They don’t know how to review a proposal from an ethics point of view,” he says. “To do work as an ethics consultant in India, you must make more and more enemies. . . . There is no ethics culture in the profession.”
Jesani, as one of the founders of the nation’s only medical ethics journal, is one of the most prominent medical ethicists in the country. “I’m not trained in ethics at all,” he says, leaning back in his chair and chuckling. “I have no degree! When I did medicine, there was no class in ethics!” he declares gleefully. “So nobody is trained in ethics, and I am in demand.”
Western drug company executives insist that they can make up for the ethical vacuum. “All global companies follow global protocols when they conduct clinical trials,” Ranjit Shahani, MD, vice chair of Novartis India told Economic Times reporters in 2004.35 True, many of the clinicians in India who might be leading the new trials lack training in good clinical practices, but “this may not necessarily be considered negative,” said Chandrashekhar Potkar, Pfizer’s director of clinical studies in India in 2003.36 Their training could be entirely directed by drug companies.
Plus, the industry funding on offer for trials could provide improbable medical luxuries amid the general scarcity, as the endocrinologist Nadeem Rais knew well. Rais has been conducting clinical trials for major drug companies at his posh south Mumbai clinic, the Chowpatty Medical Centre (CMC), for years. At public clinics examining rooms might come equipped with a metal desk, a few chairs, a dirty ceiling fan, and ragged pieces of paper pinned under a rock for prescriptions.37 At the Chowpatty Medical Centre, patients lounge on plush blue couches while waiters, their uniformed lapels emblazoned with “CMC,” stride by briskly, ferrying trays of lime soda into the consulting rooms. Rais’s air-conditioned office is equipped with two heavy and glistening wooden desks, upholstered seating, and flat-screen computer monitors.
Rais has enrolled thousands of local patients in trials on erectile dysfunction, diabetes, and other conditions for Eli Lilly, GlaxoSmithKline, and others. “We are always overbooked for trials,” he says proudly. On the CenterWatch Web site, which promotes clinical sites around the world for industry trials, Rais boasts that he maintains 90 percent patient “compliance” with trial protocols. “We have electronic medical forms for each patient for the last ten years. We can get any info we want. What do you want to know?” He asks amiably, tossing me one of his patient’s medical records. It neatly lists the patient’s name, address, and medical history: a middle-aged woman with diabetes, as it turns out.38
One subject of a trial at the center, a worker in a shoe store, recalls being “rather awed” by Rais’s clinic. The CMC doctors offered him four different cell phone numbers to call upon, free insulin, and four thousand rupees a month, in exchange for a signature on an informed consent form. “Look, I didn’t have a stable job; insulin costs 1700 rupees a month. I have two daughters. And I weighed 49 kg [108 pounds].” He joined the trial.39
Rais says he doesn’t seek to enroll solely poor and working-class patients, but the fact is that middle-class and wealthy Indians are less interested in participating in the kinds of randomized controlled trials that drug companies looking for FDA approval favor. Less than 1 percent of Indians own health insurance, so most pay upfront for their care, scraping together funds from relatives and friends as necessary to do it.40 While Western hospital wards are studded with Indian physicians, in India itself doctors are at a premium. There is one for every two thousand people.41 Why would well-off Indian patients, accustomed to arranging everything from shoe purchases to marriages through well-oiled personal connections, willingly substitute their own precious doctor’s judgment with that of some randomizing computer?42
Because of Indians’ strong preference for personal connections, only those who “have absolutely no choice” can be expected to agree to the impersonal care doled out in a randomized clinical trial, says clinical researcher Farhad Kapadia of Mumbai’s Hinduja Hospital. And these mostly poor patients who serve as subjects live in a world apart f
rom the socially powerful doctors who experiment upon them.
A 2003 story in a glossy national magazine featured a typical story of the misunderstandings that can result. A woman’s uterus had been removed after the delivery of her first child. According to the doctor, the patient was hemorrhaging after the delivery, so the uterus had to be removed to save her life. The patient’s story was that the delivery had been botched and her uterus removed to destroy the evidence.43 Whether the doctor had failed utterly to secure informed consent from her patient, or whether the doctor was a dangerous fraud, or whether the patient’s account was untrue, was left unexplained. After another such incident, the death of a patient during minor surgery, an angry mob burned down a hospital in Kerala. There is a “tremendous mismatch between patient expectations and services offered by us,” noted the Indian Medical Association’s president, Arul Raj.44
Given all this, the potential for abuse of research subjects in India appears nearly unlimited. But if in the past government officials tolerated ethical lapses because most experimentation was oriented toward public health goals, no such trade-off exists today, for the modern body hunt in India proceeds by the logic not of public health but the profit-driven needs of distant drug companies.
In 2003, Kapadia conducted a trial on behalf of Eli Lilly at Mumbai’s Hinduja Hospital, a large, modern facility in the middle of the steaming city. It was the first “proper randomized trial” he had been involved in, and the ambitious young doctor was enthusiastic about participating in the international study. But his patients “are very reluctant,” Kapadia said. “I’ve had more turn-downs than consents.” Hinduja Hospital is not luxurious by any stretch of the imagination, but it is clean, well lit, and spacious. The elevators work. There are guards at the front entrances. The urban Indians who come to this hospital have high expectations. The problem, Kapadia said, lies in the uncomfortably frank consent form required by the FDA. It didn’t pussyfoot around the risks of the drug or the trial. “It is pretty explicit,” Kapadia said. The drug that Kapadia was testing, Xigris, was not a benign one, nor was the method in which Eli Lilly wanted him to use it.
If Kapadia’s research subjects would suffer the consequences, this had less to do with medical necessity or the lack of safer alternatives than with competitive pressures in a pharmaceutical market across the ocean in the United States. Eli Lilly had a lot at stake with its latest trial on Xigris. The success of the drug was “central” to the company’s “medium-term performance,” the Financial Times noted in 2002. Lilly’s blockbuster drug Prozac had fallen off patent in 2001 and Lilly needed to make up for the lost sales income. If Lilly could prove Xigris safe and effective for use in patients with sepsis, analysts said, the drug could bring in up to $2 billion a year for the company.45
Sepsis felled hundreds of thousands of Americans ever year,46 including 70 percent of those who died in intensive care units.47 It is a mysterious ailment in which the normal inflammation that comes in response to a bout of infection fails to subside.48 The consequences can be dire. Blood coagulates into vessel-blocking clots. Fever, shakes, and vomiting may follow. The organs may fail. (When it gets this bad clinicians call the condition “severe sepsis.”49) One-third with severe cases die within a month.50 Worse, nobody knows for sure why sepsis occurs, or can predict who might fall prey. With the medical establishment shelling out $17 billion every year treating septic patients, interest in developing new treatments runs high.51
But it isn’t easy. In the early 1990s the biotech company Centocor had attempted to launch a sepsis drug called Centoxin. The drug, a genetically engineered version of a human protein thought to be deficient in patients with sepsis, had protected animals from septic shock in some early lab testing, but follow-up studies had failed to replicate the promising results. Centoxin’s performance in the 543 septic patients in the company’s first major human trial was lackluster: as many patients died on the drug as did on placebo. But with $200 million already invested in Centoxin, the company was loath to let go.52 In a 1991 New England Journal of Medicine paper the company re-analyzed its data, separating the gray results into their black and white components. While overall death rates hadn’t changed in the drug and placebo groups, in certain sepsis patients—those with pathogenic bacteria in their blood, a condition known as gram-negative bacteremia—the death rates between the group on the drug and the group on placebo had indeed diverged, from 49 percent on placebo to 30 percent with the aid of the drug, the company explained.53
USA Today enthused that Centoxin could save tens of thousands of patients every year. “The impact of this is like . . . introducing a drug like penicillin,” the paper quoted one awestruck physician.54 Centocor stock soared to nearly $60 a share.55 But if some patients had improved on the drug while overall the fate of the entire group of patients hadn’t changed compared to placebo, critics pointed out, then clearly some patients—those who didn’t have gram-negative bacteremia—had been actively killed by the med. Figuring out which patients would benefit and which might be harmed wasn’t straightforward. The tests that confirmed a case of gram-negative bacteremia could take up to forty-eight hours.56 If docs felt pressured to administer Centoxin before they could figure out whether a patient might benefit from it, sepsis patients who did not have gram-negative bacteremia might start dropping like flies.57
When the FDA found other anomalies in Centocor’s data, they ordered the company to start a new trial. In the new trial the benefits seen in the earlier one vanished: death rates among patients with gram-negative bacteremia were no different in the drug group than among those on placebo.58 What’s more, over three hundred subjects given the drug died, twenty-eight more deaths than would have been expected had they been given no drug at all.59 Stock fell to less than $7 a share and the company laid plans to dump its aging stockpile of Centoxin.60
With Centoxin’s high-profile crash and burn—the New York Times ran a lengthy front-page story on the drug’s spectacular failure in 199361—Eli Lilly would face a skeptical medical elite with its sepsis contender, Xigris. Like Centoxin, Xigris was a biotech version of a naturally occurring molecule, activated protein C, also thought to be deficient in patients with sepsis.62 Like Centocor, Lilly planned to charge an arm and a leg for its drug—$7,000 for a single course of Xigris. After all, unlike most areas of medicine, critical-care medicine hadn’t been subjected to cost-cutting pressures. “The feeling has always been that if you’re sick enough to be in the ICU, you’re sick enough to let the doctors do what they need to do,” Brown University critical care specialist Nicholas Ward said. “In critical-care medicine, we’ve pretty much had a Gold Card to do what we want.”63
Such carte blanche wouldn’t have held had a cheap, effective therapy been available, of course. And a slow trickle of papers had appeared over the course of the 1990s showing that, at least anecdotally, low doses of corticosteroids were highly effective for sepsis. Corticosteroids were old drugs with well-understood properties, and a course of generics might run to about $50 or so.64 But when steroid researchers approached various drug companies to sponsor large-scale controlled trials to prove the drug’s efficacy beyond a shadow of a doubt, they were roundly rebuffed. Patents on steroids had long expired and so the drugs were widely available for a pittance. No jackpot of extra sales income awaited anyone who proved how such drugs worked or whether they saved lives.65
Xigris, on the other hand, had one of the world’s biggest drug companies behind it, and Lilly wouldn’t cut corners. In the company’s first trial of the drug, known as the PROWESS trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), they roped in nearly 1,700 patients at 164 centers in eleven countries for a massive placebo-controlled trial.66 In contrast, the first placebo-controlled study of steroid therapy had enrolled just thirty-one patients.67 The results were impressive—low-dose steroids had saved sixteen septic patients, while more than half of those given placebos had perished—but even wowed critical care expe
rts had to admit that the trial was minuscule. The lead researcher for the PROWESS trial was Vanderbilt University’s Gordon Bernard, MD, a researcher who had debunked high doses of steroids as a treatment for sepsis in 1987. Bernard had precious little truck for its low-dose cousin regimen, calling research supporting it weak and the investigator who led it stupid at a conference in Chicago.68
By June 2000, not even two years into the PROWESS trial, Xigris had proven so effective that the experiment was summarily discontinued. It would have been “unethical” to continue enrolling placebo patients, Lilly officials said, and deny them the lifesaving properties of Xigris. The drug had dropped the mortality rate by six percentage points, from 30 percent on placebo to 24.1 percent on the drug. The company analyzed the data every which way and yet the positive outcomes persisted. The effect was “consistent” across all the various subgroups of patients, whether they were only mildly ill or on death’s door, elderly or youthful. The main adverse effect was serious—sometimes fatal hemorrhaging—but occurring in just 3.5 percent of patients, neatly balanced by the drug’s benefits.69
Eight months later the results appeared in an early release edition of the New England Journal of Medicine, a privilege reserved for papers with urgent public health implications.70 The rapid notice wouldn’t have made much difference to public health—the FDA hadn’t even approved the drug yet so it wasn’t available to physicians—but it was key to Lilly’s efforts to build a buzz about the drug before it hit the market. The same month that the paper appeared the company arranged for Bernard to cohost a thirty-minute Fox cable television special explaining the dangers of sepsis.71 Lilly enlisted leading sepsis experts to start spreading the word about Xigris.72
