by Sonia Shah
Later, data in hand, the company sighed contentedly. “We proved our point,” exulted one Hollis-Eden executive. The Immunitin had indeed slowed the deterioration of some of the patients, although the numbers were small. Whatever happened to the test subjects after the one-year trial, the company didn’t really know. If they had wanted more Immunitin, they would have been out of luck. The company stopped providing the drug after the study ended.32
Finding few Western donors interested in paying for a non-antiretroviral agent for their AIDS programs and governments capable, if they wanted, of overriding the company’s patent on Immunitin, in 2002 Hollis-Eden put its Immunitin development program “temporarily on hold,” according to its 2004 report to investors.33
* * *
Meanwhile, other clinical researchers in South Africa, even those conducting more patient-friendly protocols than Immunitin’s year-long placebo trial, were getting caught coercing and misinforming their research subjects. “Many patients have no idea what their rights are as patients, even in a therapeutic setting,” says University of Stellenbosch bioethicist Keymanthri Moodley. “A lot of people get away with many things in South Africa!”34
In 1999, for example, Quintiles had helped a subsidiary of the $11 billion biotech company Gilead launch a five-hundred-patient trial of its new antiretroviral, Emtriva.35 Some subjects complained about the trial to Costa Gazi who, as the health spokesperson of the dissident Pan Africanist Congress Party, set off to investigate. According to Gazi, one patient was told neither that the drug therapy wasn’t a cure nor that he was allowed to leave the study. Others added that the informed consent process consisted of a few minutes’ long conversation and an instruction to “sign on the line to get a drug that will cure them.” Still others said they were never asked for any written consent at all.36 As for the ethics “committee,” it consisted of a single retired professor.37
When patients in the trial started perishing, mistrust between test subjects and investigators surged. After the sixth patient died the researcher in charge of the study site where the death occurred flatly denied the patient had been enrolled, or had even taken any AIDS drugs, despite the fact that reporters had acquired a copy of her consent form inducting her into the trial.38
But what had killed the test subjects? They were sick with AIDS, after all. And the regimen given to subjects, unlike in the Immunitin trial, was quite involved. Some were given Emtriva along with d4T and nevirapine; others lamivudine along with d4T and nevirapine.
According to Gilead’s consulting scientist, University of the Witwatersrand’s Ian Sanne, the liver failures that had contributed to some of the deaths stemmed from the nevirapine, a conclusion Sanne and other Gilead scientists later published in the Journal of Infectious Diseases.39 That is, the same drug that was just then being recommended, thanks to Jackson’s 012 study, for South African pregnant women and their newborns. True, in the Emtriva study patients sick with AIDS had taken nevirapine for months on end—to prevent infections in babies, only a single dose was necessary. Prescribed in this way, nevirapine had the potential to save thirty thousand South African babies from HIV infection every year.40 But to Mbeki such distinctions hardly impinged upon the facts as he saw them: “Our people are being used as guinea pigs and conned into using dangerous and toxic drugs,” he insisted.41 “It would be immoral and unethical for government, despite the numerous requests we are receiving . . . to attempt to make policy decisions regarding the use of nevirapine in our country,” Mbeki’s health minister declared in 2000.42
A few months later nevirapine’s manufacturer, Boehringer Ingelheim, announced it would give away the drug for free for use in preventing infant infections in developing countries for a period of five years.43 But Mbeki’s government would not be budged. A year after the Emtriva scandal, and two years after the 012 results established the drug’s efficacy, South African regulators reluctantly licensed nevirapine—after countless public articulations of doubt of its efficacy—to prevent mother-to-child transmission of HIV. But the government refused to provide it to clinics and hospitals.44 Was their expressed dissatisfaction with the drug—it was too dangerous and costly, they said—really the motive? Or was it, as some cynical bystanders wondered, “more a question of: what are they going to do with all of these orphans and how are they going to support them when their parents both die?”45
NGOs took the government to court to try to force them to provide the nevirapine. Finally, in March 2002, the health ministry’s final appeal failed and the High Court in Pretoria ordered the government to give nevirapine to all HIV-positive pregnant women at public facilities that were capable of doing so.46
But new developments in the nevirapine saga would stymie the court’s decision even as it was being handed down.
* * *
When Jay Brooks Jackson had first set out to study nevirapine’s use in preventing HIV infections in newborns in 1997, the drug-maker, Boehringer Ingelheim, had professed little interest. They even charged the researchers for the quantity of drug used in the study. “Many of these companies wanted to stay away from this in the sense that if it works then they are under tremendous pressure to give their drug away,” Jackson says. “That was true of Boehringer—they were worried.” The company went so far as to write to Jackson informing him that they would not use his data and had no plans to apply for FDA approval for this use of their drug.47
But sometime in 2002, for reasons it has never made public, Boehringer reversed itself. The company decided to ask the FDA for approval to market nevirapine as an HIV prevention drug for mother-to-child transmission, using the widely heralded HIVNET 012 trial as proof of the drug’s efficacy.
The problem was that that trial had never been conceived to convince FDA officials of anything, but rather as a public-health inquiry. In industry-sponsored trials aimed at FDA approvals drugmakers generally appoint study monitors to help local researchers conform to FDA standards twenty-four hours a day. “I mean, when you are sitting out there in Uganda, nobody comes to help you!” Jackson says, laughing. “The FDA likes documentation, other than the trial data. They want hospital records, to verify adverse events. You know, the FDA has seen a lot of scams, so it is perfectly understandable. But you know, Mulago Hospital! They didn’t have records!” Jackson and his team were swept into a frenzy of checking and rechecking documentation, and the NIH sent a consultant to Uganda to audit the trial site ahead of a planned visit from the FDA.
The consultant didn’t like what he found.
Under FDA regulations subjects must sign a new consent form whenever the trial protocol is changed: the clinicians hadn’t done this after they dropped the placebo arm midway through the trial. They also hadn’t secured new consent forms from the guardians of surviving infants when the mothers who had initially consented had died. They hadn’t reported adverse events as serious if they could be managed without hospitalization, even though the latest FDA rules defines them as serious. On some documents “people who had made a mistake had just crossed it out or whited it out,” says Jackson. “The drug was supposed to be kept at room temperature, and it was, but the temperature wasn’t monitored. Lots of little things like that.” Upon the consultant’s alert the FDA canceled its trip, and Boehringer decided to pull its application.
Although nothing in the consultant’s findings nor in the NIH review of the trial that followed undermined the overall findings of the 012 study,48 the South African government greeted the drug’s withdrawal from FDA consideration as vindication of all their doubts. “We can’t have double standards,” said the health minister in August 2003. “We can’t have something that’s only good for Africa and not good for developed countries.”49 Nevirapine would be deregistered in South Africa, she declared, unless the drug-maker provided new data within a matter of months.50 If it were deregistered, anyone caught providing the drug to a patient to prevent HIV infection could be thrown into prison for up to ten years.51
Outrage over the inve
stigators’ apparent carelessness toward the human rights of research subjects—even in trials designed to promote public health—overflowed into a broader rejection of Western AIDS medicines. “It’s not just antiretrovirals” that can be used for AIDS, the minister said. “We’ve got traditional medicines that we know actually avert AIDS-related diseases. . . . We are busy studying it . . . and we are seeing excellent results.”52 One of the most promising such remedies, according to the minister, combined African potatoes, garlic, lemon, and olive oil. “These things are affordable for South Africans,” she said, “not like things like antiretrovirals.”53
By then, the price of antiretroviral drugs, just five years after the advent of combination therapy, had fallen precipitously. In early 2001, generic drug manufacturers in India had produced a triple antiretroviral drug therapy for $1 a day, or 3 percent of the average cost in the United States.54 Within a few years over three hundred thousand AIDS patients in the developing world—nearly half of all treated AIDS patients in those countries overall—had swallowed the cheap meds.55 The thirty-nine drug companies that had dragged the South African government into court over the policy it designed to bring down drug prices abandoned their reputation-crushing lawsuit that same year.56 By August 2003, when a South African drug company started manufacturing generic antiretroviral drugs, the government’s resistance had finally crumbled. According to a surprise announcement by health officials at an AIDS conference in Durban, the government would commit to providing antiretrovirals “as a matter of urgency” and supported the use of nevirapine to prevent infections in newborns.57
Not only did suspicions about the motives and practices of clinical researchers contribute to delays in AIDS treatment—and to the loss of lives on account of them—but none of the justifications the research establishment had offered earlier to support their lower standards for subjects in poor countries held up in the end.
From Alfred Sommer to Richard Hollis, Western researchers had insisted that the price of AIDS drugs was too high, the drug regimens too complicated, and active-controlled trials too slow. And yet, while they sought affordable but second-rate treatments, the price of antiretroviral therapy had plummeted. Meanwhile, contrary to the assumptions of many Western scientists, studies had revealed that patients in Uganda and Botswana were actually better at taking their antiretroviral drugs than most Americans, and were more honest about it as well.58
Finally, the active-controlled trials derided as disastrous had rendered interpretable results in the same amount of time as the placebo trials. Lallemant’s active-control trial was published in October 2000. It had taken about two years from start to finish—as had the placebo-controlled trials run by the CDC and Jackson.
The results were perfectly interpretable.
7
Outsourcing to India: The One
Billion Body Politic
Over the last five decades a thicket of ethical principles, regulations, and codes has taken root in the United States, governing relations between subjects and investigators as well as patients and clinicians. However uneven or sparse in places, few physicians or scientists involved in human experimentation can avoid navigating it. But the modern hunt for bodies leads drugmakers to places almost entirely shorn of such oversight. Such is the case in India, where a one billion body bounty entices industry investigators.
Ethical transgressions in clinical research in India periodically surface in the nation’s loud and exuberant press. For several decades starting in the 1970s, for example, hundreds of thousands of impoverished Indian women received an unapproved drug, some of them unknowingly, that was distributed by American population control advocates.1 The drug, quinacrine, burns the fallopian tubes, forming scars that sterilize the patient permanently.2 In the mid-1980s government doctors had herded village women into a trial of an injectable contraceptive that had been withdrawn from the market for its association with tumors in rats over a decade previously. The women “had no idea they were participating in a trial,” recalled an activist from Stree Shakti Sanghatana, a Hyderabad-based women’s group. If the women had been informed, paramedics in charge of the trial told Stree activists, no one would have volunteered.3 Between 1991 and 1999 a government-sponsored trial of a leprosy vaccine failed to mention to the rural participants that the trial was double blind and that some would receive a placebo.4 In the late 1990s a Tuskegee-like government trial was exposed, in which researchers purposely withheld treatment from over eleven hundred mostly illiterate women with precancerous lesions on their cervixes in order to study the inevitable progression of the disease. They didn’t inform the patients or ask for their consent, because, they said, such niceties weren’t mandatory when the study began.5 In 2001, a Johns Hopkins researcher was caught testing an experimental cancer drug, which hadn’t been proven safe in animals, on over a dozen patients sick with cancer in the state of Kerala. This researcher had failed to secure adequate informed consent as well.6
In 2003, yet another scandal broke. Clinicians sponsored by an Indian pharmaceutical company had administered an experimental drug to over four hundred women, telling them it would boost their fertility. But according to the FDA, the drug, letrozole, is an anticancer agent toxic to embryos. Worse, letrozole had yet to be approved for medical use.7
None of these transgressions had led to legal protections for research subjects. “In India, there is no law to safeguard the interests of volunteers involved in clinical trials,” Arun Bal, president of the Association for Consumers’ Action on Safety and Health, told the Economic Times in 2004. “Though the Indian Council of Medical Research has laid down guidelines for conducting trials, there is no mechanism in place to ensure that they are being implemented.”8
It isn’t just clinical experimentation that departed from basic ethics, but clinical practice itself. While a labyrinth of ethical, moral, and spiritual conventions governs nearly every aspect of social life in India, from eating to sex to relationships, government regulation of industry and trade remains thin, and medicine is no exception.
The 1990s had seen a massive boom in new medical schools run by private companies and religious groups. Scandals regularly emerged about the new institutions, which critics likened to certificate-churning money machines. Some had been caught selling admission, others even auctioned medical degrees. Medical schools had been caught temporarily hiring fake teachers to fool inspectors that they had sufficient teaching staff. In 2003, there wasn’t a single medical school in the country that taught a course on medical ethics.9
Once physicians garner a license to practice medicine, the government does little to ensure that they demonstrate any ongoing competence.10 Not surprisingly, quackery is widespread. One mid-1990s survey in Mumbai cited in the British Medical Journal found “clinics operating out of residential flats, with kitchens turned into operating theaters.” Naïve, illiterate patients—as of 2001, 44 percent of the nation’s people could not read or write11—keep lining up for these informal clinics regardless, as the waits are still shorter than at the woefully underequipped public clinics.12
Neither the state medical councils nor the Indian Medical Association take it upon themselves to police physicians’ conduct. The Indian Medical Association espouses no code of ethics for its members and has fought off any imposition of minimum standards, whether regarding patient care or licensing. In 1994, when the city of Surat in the northern state of Gujurat suffered an outbreak of plague, three-quarters of the city’s physicians promptly fled. State and national medical authorities said nothing about their negligence.13
In the late 1980s a small group of progressive physicians hoping to strengthen patient rights and regulatory oversight of medical practice launched an effort to revive the moribund state medical council, running nine ambitious new candidates for positions. But other nominees, intent on the prestige of a council position, had hired goons to collect blank ballots from doctors who, for one reason or another, decided not to vote. They inked their own name
s on the ballots and submitted them to the council. On the final day of the vote the council offices were crammed with hired hands dropping off sacks of ballots for their bosses. The slate of progressive physicians lost. In the ensuing scandal, the council was disbanded.14
But perhaps the most chaotic, unregulated aspect of Indian medicine is its vast market in pharmaceuticals. Since a 1972 law had allowed companies to manufacture patented, brand-name compounds so long as they altered the manufacturing process slightly, a flourishing pharmaceutical industry had sprung up. In 2004, there were over twenty thousand licensed drug companies in the country, including most of the major multinational outfits,15 flooding the market with over seventy thousand different brands of medicines.16 (According to the World Health Organization less than three hundred drugs are necessary to control 95 percent of the country’s health problems.17) To regulate this bewildering array of products the government employs just six hundred drug inspectors.18
The illicit marketing of drugs is widespread. In a 2003 raid in Patna, in the eastern state of Bihar, seven out of nine drugstores were found to be operating without licenses.19 Pharmacists routinely sell prescription-only preparations to patients without a prescription, encouraged by drug giants like GlaxoSmithKline, who shower pharmacists with lavish gifts, including free color televisions, for placing large orders.20 Drugs are often repackaged into slick combination pills that make little clinical sense, pharmacologists say. Over seventy combinations are not just ineffective but dangerous, and are sold under more than one thousand different brand names.21 Other drugs are sold for catch-all conditions including “intellectual decay,” “social maladjustment,” and “deterioration in behavior.” Legitimately useful drugs are often sold without any mention of their known adverse effects. According to a 2003 magazine exposé, no less than one in four drugs available on the market is fake or substandard: ground up chalk, sugar, and contaminated tap water masquerading as lifesaving medicines.22
