by Sonia Shah
* * *
In their defense, physician investigators point out that manipulating patients’ beliefs has always been integral to the art of medicine. Doctors can relieve pain in patients, for example, by simply telling them they are receiving an effective painkiller, even while giving them placebos.93 Studies show that when doctors offer a meaningful diagnosis and benign attention, and reassure the patient that healing could occur, they do heal many of their patients, whether or not the therapy they prescribe is effective or not, as determined by randomized controlled trials.94
Because of this, the requirements of informed consent virtually guarantee that doctors’ potency as healers is diminished. The more rigorously patients understand the risks of experimental methods, the less likely they are to benefit from their faith in the doctor or the drug. As Mumbai clinical researcher Farhad Kapadia noted, “You know, you have an international standard [for the] consent form, and it is pretty explicit. When I use a drug in someone who is not in a trial, I don’t go to all these lengths to explain. I say, ‘there are good and bad effects, and generally I think it will help, and if you can afford it we’ll go for it.’ But here, I’ve got to explain everything. I don’t know if they [the patients] feel put off, but they are not so comfortable. If you tell someone there are twenty side effects, they’d be more worried about taking aspirin, rather than if I say, ‘Take this, it is good for your heart.’”95
Not only is informed consent thus an impossible standard, uninformed consent is practically a necessity, some say. “Patients hear what they want to hear and they don’t hear what they don’t want to hear,” commented one surgeon casually at a gathering of CRO executives in 2003. So getting informed consent from a patient is “an exercise in futility.”96 Around the room, heads nodded. Nobody reads the informed consent forms, claimed UCLA meningitis researcher Larry Baraff in an interview. “They look at you, they think you are a decent person, you explain it the best you can, and they just sign the thing.”97
It wouldn’t be difficult for the FDA to require that investigators not only provide written evidence of consent, but actually prove that such consent is truly informed and voluntary. But instead, the agency routinely accepts what amounts to drug companies’ word that their patients have been adequately informed. According to agency whistleblowers, its medical officers are actively discouraged from looking too closely at the consent forms.98
Nobody, it seems, wants to stand in the way of new trials and slow the pace of medical progress by pointing out that informed consent is an emperor with no clothes. “Why do we keep using informed consent despite knowing it doesn’t really work?” asks bioethicist Jonathan Moreno. “We haven’t got an alternative.”99
That may change. In 2001, thirty Nigerian families filed Abdullah v. Pfizer, a class action suit claiming that Pfizer violated the Nuremberg Code in its 1996 Trovan experiment in Nigeria. According to the lawsuit, the company failed to inform the children or their parents that Trovan was experimental and “that they were free to refuse it.” But whether the justice system will be able to correct for regulators’ and researchers’ laxity on informed consent is as yet unclear. The suit, initially dismissed by the U.S. District Court in Manhattan, was remanded back to the court on appeal in October 2003. As of 2005, the case had yet to be heard.100
10
Tipping the Scales
Most of us rarely have a say in how clinical trials are run, or where. And yet we, as members of society, are the ones who collectively bestow upon researchers their conditional privilege to conduct experiments on humans. Without our tacit blessing, the whole business lacks legitimacy.
And so, just as ethics committees evaluate the risks and benefits of individual trials, society must evaluate the risks and benefits of the entire business of human experimentation.
The trouble is, there’s a tendency in the United States to minimize the risks of research while lionizing its benefits, which complicates a fair appraisal of the balance between the two. In popular coverage of research, investigators tend to describe the risks of their work in microscopic detail, constrained by time and place—the test subjects might suffer some skin rash, or some fatigue, or anemia, researchers might allow. Rarely are broader risks—such as the possible undermining of human rights or the hijacking of scarce health care resources—mentioned. That’s fair enough, except that on the topic of benefits, investigators tend to be expansive and speculative, including the experiment’s hypothetical effect on thousands and even millions of other people, not just in the near term, but over years and even decades.1
In a typical formulation, the National Bioethics Advisory Commission wrote that “research has resulted in improvements to health, created valuable new products for everyday living, provided the capacity to sustain cleaner environments in a rapidly industrializing world, and facilitated better personal and family relationships.” An impressive litany, to be sure, and doubtlessly true. But what about all the research that has resulted in less sparkling developments, such as, say, the atom bomb, DDT, and the silicon breast implant?
Faith in the benefits of scientific research remains untarnished despite its failures. The “war on cancer,” launched by President Nixon in 1971, provides an example. While deaths from heart disease and cerebrovascular diseases had already peaked in the United States, cancer’s death toll continued to grow during the 1970s.2 Evidence that curtailing smoking could stanch the unfolding epidemic had emerged by 1956.3 Yet instead of devoting billions to stamping out smoking, or fingering other environmental triggers for cancer, the U.S. government spent $5 billion between 1971 and 1978 to search for new drugs to administer to ailing cancer patients. A flood of new drugs was duly unleashed, but five-year survival rates for cancers of all kinds increased from 39 percent in the 1950s to just 41 percent by the late 1970s. (The war on cancer, FDA commissioner Donald Kennedy said to U.S. News and World Report in 1978, had become the nation’s medical Vietnam.4)
Faith in the benefits of biomedical research is even stronger when it involves problems faced in the developing world. “It takes half a second to see how much more burdened the developing world is with ill health and disability,” says Johns Hopkins bioethicist Ruth Faden. The great need in developing countries, for Faden and others, is not primarily more infrastructure or education but more research. “What we need if anything is more health research in the developing world, not less,” Faden says.5
In January 2003, the Bill and Melinda Gates Foundation, now the world’s leading private funder of international health research, launched an ambitious initiative to tackle the most destructive health problems plaguing the developing world. To wit, Gates funds research into new vaccines that don’t need to be refrigerated, or require multiple visits to scarce health clinics; development of a single plant species that provides multiple micronutrients; and new chemicals that control disease-carrying insects, among other things.
Research into cheap, easy solutions like these, if implemented, would help countless people in poor countries. But vaccines that don’t need refrigeration, shots that only need to be given once, and single plant species that might provide adequate nutrients do little to extract the poor from their health care–deprived environments bereft of clean water and electricity. On the contrary, in effect they engineer ways for people to survive in them indefinitely.6
If money, time, and resources were unlimited, a bit of blind optimism wouldn’t matter much. But in a world of scarcity, exaggerating the benefits of research can be downright dangerous. “There are many millions of people around the world who don’t have access to the scientific advances of the last hundred years,” notes South African bioethicist Solomon Benatar. “In fact, if you go to any developing country and ask the people there, they’d say, ‘Well, we’re not so much interested in doing research. We’re interested in having access to the things that you have already found that work! Why come here to ask research questions when actually what we need is what has already been discovered! Why s
hould we believe that this new research is going to benefit us if the old research doesn’t benefit us?’”7
The scale that Western research advocates often use to weigh risks and benefits of trials is often skewed by a general fuzziness over who takes on the risks and who gets the benefits, too. Such was the case in a series of confrontations during 2004 and 2005 between Cambodian and Thai patient-advocates and Western AIDS researchers and their allies.
In recent years, with HIV vaccine research in the doldrums, AIDS prevention researchers have explored a new approach: the use of antiretroviral pills to ward off infection. Nevirapine and AZT prevent newborns exposed to HIV from getting infected, the thinking goes; what if other antiretroviral drugs, given once a day, could do the same for adults exposed to the bug? People engaged in high-risk activities could pop a pill every day and save themselves from infection, just as Western travelers down antimalarial drugs to ward off malaria before venturing into tropical swamps.
The idea of preventing HIV infections in this way has already been put into practice in a limited fashion. In 1996, the CDC recommended that health care workers exposed to HIV on the job, through inadvertent needle sticks or the like, be given rapid treatment with antiretroviral drugs, even before it was known if they were infected.8
Launched in 2001, Gilead Science’s Viread (tenofovir) seemed a good candidate for this use. Unlike other antiretroviral drugs, tenofovir is effective even when taken just once a day, doesn’t have to be taken with food, and has few toxic side effects.9 By 2004, the CDC, NIH, and the Gates Foundation were planning major new trials testing the new theory. A small Phase 2 trial involving a few hundred subjects would take place in San Francisco and Atlanta. There, researchers would organize subjects into three separate groups; two would get tenofovir or placebo right away, while the other one would simply get counseling, so that researchers could carefully track whether the treated subjects emboldened by hope in the drug grew more lax toward other protective measures, always a risk in trials of new HIV prevention methods. Since these studies weren’t designed to measure how well tenofovir protected subjects from the contagion, it wouldn’t be necessary for researchers to rack up sufficient HIV infections in the placebo group in order to have sensible results.10
Not so in Asian and African countries, where researchers planned to launch straight into large-scale Phase 3 trials without waiting for the Phase 2 results. While the U.S. study was ongoing, the CDC would enroll 1,200 men and women in Botswana and 1,600 intravenous drug users in Thailand.11 The NIH would test the drug on 960 Cambodian sex workers in Phnom Penh.12 The Gates Foundation would sponsor trials of 1,200 high-risk women in Ghana, Cameroon, and Nigeria.13
As in all research into new HIV prevention methods, the subjects would be vulnerable to slacking off on proven effective safeguards such as condoms and clean needles. Around half of all the high-risk subjects in the trials wouldn’t receive the hypothetical protection of tenofovir either, as they’d get placebos. Once again, in the case of the Thai drug users, the CDC wouldn’t provide clean needles. The Thai government condemned such provision. Its reviled 2003 campaign against illegal drug use had resulted in widespread human rights violations, including two thousand extrajudicial murders, according to Human Rights Watch.14
In the summer of 2004, ACT UP Paris and a Cambodian sex workers’ advocacy group decried the trials at an international AIDS conference, spilling fake blood on Gilead’s displays and surrounding the speakers’ podium angrily.15 According to the activists—and hotly denied by researchers—the subjects were being enrolled by blackmail, the counseling offered to them was minimal, and investigators refused to take responsibility for treating any of the subjects who became ill under their watch.16 Such unfortunates would “have to rely on Cambodia’s low standard of healthcare and limited access to antiviral drugs,” as the Wall Street Journal reported.17
Alarmed, the Cambodian prime minister shut down the trial.18 Four months later, Thai AIDS activists starting making noises about the tenofovir trials in Thailand as well. Drug users in Thailand suffered an HIV infection rate of 50 percent and were violently oppressed by the government. How could researchers possibly protect their best interests, as required by the Declaration of Helsinki? They couldn’t even provide clean needles, the single best known measure of HIV prevention for intravenous drug users, a “particularly egregious departure” from Helsinki standards requiring researchers to provide all experimental subjects with the “best current” methods.19 A month later, ACT UP Paris surrounded the Cameroon embassy in France, condemning the Cameroon tenofovir trial as unethical too.20 By February 2005, the Cameroon Ministry of Health had suspended the study.21 In March 2005, researchers themselves canceled the tenofovir trial in Nigeria.22
The AIDS research community was roiling. “It’s a disgraceful day for AIDS activism,” said Mark Harrington, an AIDS activist with the New York–based Treatment Action Group.23 “These forces threaten to derail future trials,” complained two AIDS-vaccine NGOs, Global Campaign for Microbicides and the AIDS Vaccine Advocacy Coalition, in a statement. “The cost is paid in people’s lives—the lives of those who might benefit from new technologies or treatments.”24 Sure the experiments entailed some risk, but look at the benefits, they said. Tenofovir prophylaxis is “perhaps the single greatest near-term hope for the prevention of AIDS,” the Wall Street Journal reported.25 If tenofovir worked, it could “revolutionise AIDS prevention,” echoed the Financial Times.26
But for whom?
Researchers hadn’t determined whether sex workers in Cameroon really would pop a prescription pill every day for the rest of their working lives, or if so, whether they would be able to afford it. “Would it be a sustainable preventive tool? We don’t know enough about that,” allowed Mitchell Warren of the AIDS Vaccine Advocacy Coalition.27 Maybe it would be. Western researchers had thought Africans wouldn’t take ARVs or use condoms, but they did. On the other hand, it wasn’t peevish to suggest that maybe it wouldn’t. Gilead announced that it would sell the drug at cost in poor countries—85¢ compared to $12 per pill in the United States28—but according to Médecins Sans Frontières spokespeople, the company had neglected to apply for marketing approval in poor countries, making the nice-sounding offer “a virtual one.”29 What’s more, the most obvious precedent—antimalarial pills to prevent malaria—had done little to prevent millions of people in developing countries from that scourge. Those drugs are enjoyed almost exclusively by Western travelers, not by people who live in malarial regions.
It isn’t that quantifying the potential benefits lies beyond the ken of science. In fact, researchers had already delved into the questions of how the drug, if proven effective, could be administered and to whom; what clinicians might do if the drug were not fully effective; how subjects might afford to buy sufficient quantities of the drug; whether they were likely to take them faithfully or not; and what would happen to them if they didn’t. The only problem was, that analysis had been conducted for California.30
Meanwhile, the risks of the trial appeared to build. In February 2005, CDC scientists revealed that all the monkeys they had dosed with tenofovir had gotten infected with simian HIV anyway.31 The AIDS Vaccine Advocacy Coalition continued to tout the benefits of the trial to developing countries as an article of faith. “It could be used by millions of people,” the group wrote in defense of the besieged trials. “The world loves biomedical answers.”32
Could activists in developing countries be blamed for wondering: which part of the world?
Fully realizing the promise of medical research, whether inflated or not, requires a gargantuan effort for which researchers can’t, on their own, bear responsibility. They just provide the data. Patients, clinicians, health care companies, and national governments, among other entities, are the ones who have to translate scientific results into action. But there are other benefits of clinical trials—more limited in scope but more tangible—that investigators can easily facilitate, such as making
sure that trial subjects have access to the study drug (if proven effective) after trials end.
And yet, anecdotal evidence suggests that both industry and academic researchers are generally reluctant to take on the responsibility. That’s the government’s job, not theirs, they say. “It is hard to ask the sponsor of the trial to make up for the fact that the country isn’t providing treatment,” says the FDA’s Robert Temple. CROs wash their hands of the entire affair. “It has to do with the commitments the companies can make, which varies from trial to trial,” says Wurzlemann, adding, tepidly, that “it is a matter of concern among everyone.”33
Academic researchers are among the most reluctant to fulfill such obligations. Jay Brooks Jackson is one of the best-funded researchers at Johns Hopkins University. “We ship tons of stuff every week” to clinical sites overseas, he says. “Test kits, reagents, software, I mean it is just endless, it is endless.” But Jackson does not provide antiretroviral drugs to the patients in his prevention studies who become infected with HIV while he is studying them. “We refer them for symptomatic care and that sort of thing; it is sort of like what you would do in 1985 [in the United States]. . . . Over time, when you’ve worked in these countries, you just realize that this is sort of the way it is,” he says.34
Academic researchers worry that if they insist on providing study drugs to the subjects of their trials, their funders will lose interest in footing the bill for the trial. They also contend that promising patients drugs after trials end might be too good of a deal: patients would throw caution to the winds and join the trial regardless of the risks. Better, in that case, not to make any promises. “Only governments can provide long-term care guarantees,” AIDS vaccine researcher and advocate Seth Berkley argued.35
