Exporting Drug Trials to the Developing World
WARNING: Side effects of globalizing human experimentation may include questionable ethics, preventable deaths, and violations of international agreements.
By David Concar
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U.S. drug companies tested Milltown, a tranquilizer, at an insane asylum in Haiti, 1954. © Eve Arnold / Magnum |
When a deadly epidemic of bacterial meningitis swept through northern Nigeria in 1996, Samaila Musa's parents did the obvious thing. They took their stricken 7-year-old to the infectious disease hospital in the nearby city of Kano.
Amidst an anguished dispute over what happened next, one thing is clear: The world's richest pharmaceutical company enrolled Samaila, and hundreds of infected children like him, as test subjects in a now-notorious drug trial.
A team from Pfizer Inc. had learned of the outbreak on the internet and flown to Kano armed with a promising new antibiotic called Trovan (trovafloxacin). With meningitis rare in the West, it was a golden opportunity to put the drug through its paces, compare it to a rival company's approved treatment, and gather the data needed for a license to market the potentially lucrative drug.
Trovan, alas, was no miracle cure. Several (the exact number is disputed) of the sick children given the experimental drug died. Many more suffered lasting injuries from their infections. Samaila, now a teenager, was struck deaf and dumb.
Pfizer says that Trovan worked better than any other treatment administered in Kano. But lawyers representing outraged Nigerian families dispute that view and claim that the trial violated international agreements, including the Nuremberg Code. These international guidelines were drawn up in 1949 to protect human subjects from the kind of appalling experiments Nazi doctors performed on concentration camp inmates.
"The Kano patients didn't know they were being enrolled into a for-profit study. It is absolutely abhorrent that you can use sick children as guinea pigs without informed consent," says Elaine Kusel, the legal partner handling the case at Milberg Weiss in New York.
Pfizer spokesperson Kate Robins disagrees. "The study was conducted in accordance with standard international legislation on clinical trials and the verbal consent of family members of all treated patients," she wrote in a statement sent to Amnesty International Magazine.
Whoever triumphs in the lawsuit, the Trovan affair is just one of several cases from the past decade that have begun to expose the secretive, ethically fraught nature of the pharmaceutical business and the globalization of human experimentation.
Shoe and clothing companies were among the first to seek out the cheap labor, tax breaks, and looser regulations of developing countries in the recent wave of globalization. Pharmaceutical companies discovered that they, too, could save money and time by moving the costliest part of their business — clinical trials — overseas.
It's easy to see why. While pharmaceutical companies face complex regulations and wary patients in the West, the developing world is filled with patients whose only hope of treatment is enrollment in a clinical trial. Add improving infrastructure to the mix and the attraction gets stronger. Chile, Argentina, and Thailand, while poor, have aspiring doctors, hospitals, and health ministers eager for the prestige, money, and access to medicines and equipment that accompany major drugs trials.
The pharmaceutical industry denies using the developing world as the medical equivalent of a sweatshop. "No matter where clinical trials are held, they're held to the same ethical standards," says Mark Grayson of Washington-based Pharmaceutical Research and Manufacturers of America.
Grayson points out that Western-sponsored clinical trials often spur access to better treatments and help countries develop medical expertise and understanding. "A medicine must at some point be tested where a disease exists, and this is why Pfizer sent its doctors to Nigeria," adds Pfizer's Kate Robins in her statement. It is "simply not the case" that the pharmaceutical industry is "conducting more and more trials in less developed countries to avoid regulations."
But that's not the perception of some experts and human rights activists in poorer countries. "The companies don't want to apply the U.S. regulations because they are too tight," says Miguel Kottow Lang, an ethicist at the University of Chile in Santiago. "So they come here and say 'We will use your regulations, or the regulations we are going to teach you.' "
How alarmed should we be? The extent of Western-sponsored experimentation in developing countries is unclear. Commercial confidentiality laws allow companies to keep clinical trials secret. Even the government-approved ethics boards that vet such trials are sworn to regard them as "proprietary" — in both the West and the developing world. Nor must companies notify, much less get approval from, government regulators such as the U.S. Food and Drug Administration before exporting trials. "You don't have to tell the FDA about a clinical trial until after the fact," says Peter Lurie, an expert on trial ethics at the Washington-based campaigning group Public Citizen.
But what patchy data there are point to a sharp increase in experimentation in the developing world. As one indicator of that rise, from 1990 to 1999, the number of foreign clinical scientists seeking FDA approval to market new drugs increased six fold, according to a 2000 report by the U.S. Health and Human Services Department's Inspector General's Office, which raised concerns about "aggressive recruiting" of human subjects.
Research into HIV, malaria, tuberculosis, and the other major infectious disease killers of the developing world explains only part of that surge. Companies specializing in human experimentation are sprouting up across the developing world. Blandly known as "contract research organizations," they provide the big drug firms with local knowledge they need to carry out trials of drugs for heart disease, diabetes, depression and other major illnesses widespread in the West. One such network, LatinTrials, claims on its website to have had "repeat business from 20 of the largest pharma[ceutical] companies. ...Latin American markets," it suggests, "have seen a 1,000 percent increase in clinical trials from 1995 to 2000."
Western pharmaceutical companies are currently testing a pancreatic cancer drug code-named OSI-774 in Argentina, Brazil, and Chile, and a prostate cancer drug code-named YM598 in Argentina, the Czech Republic, and Poland. And in possibly the clearest demonstration yet of the globalized nature of corporate drug trials, Eli-Lilly is putting an experimental drug for severe sepsis, drotrecogin-alfa, through its paces in more than three dozen countries simultaneously. Expensive (up to $10,000 per patient), drotrecogin-alfa is the sort of high-tech drug that used to be tested exclusively in the hospitals of the developed world. Now the test subjects are scattered from Chile to Lebanon, Brazil to India, and the Philippines to Egypt.
There is no suggestion that these particular trials are unethical, and in general, few Western teams blatantly abuse the system. But there is a wider, more insidious problem, say activists: the system itself. The human rights of patients are supposed to be protected by the Declaration of Helsinki, which, in the 1960s supplemented the Nuremberg Code as the main charter at the heart of medical care standards. Although not legally binding, Helsinki sets internationally recognized ethical norms: It forbids coercion, mandates that volunteers fully understand the risks, and states that consent must be in writing or, if verbal, be "formally documented and witnessed." But if the broad principles set out in Helsinki are wholesomely high, critics say that practice is often plagued by poor government oversight, poorly implemented consent procedures, and loopholes that permit second-rate treatment standards in developing countries.
In the Kano meningitis trials not one volunteer signed an informed-consent form, according to the lawyers representing the Kano families. Pfizer's statement explained: "Working in countries where literacy is low and in the middle of a life-threatening epidemic, it is not always possible to gain consent in writing, but the fact that the treatment was experimental was explained to the family of every patient."
The Nigerian families seeking damages say that company doctors never told them that the drug was experimental or that they could have gotten a WHO-approved meningitis treatment from a nearby Doctors Without Borders (MSF) team. And according to Kusel, attorney for the Kano families, there are no witnessed documents attesting to the verbal consent that Pfizer said it obtained and that Helsinki mandates.
Even when researchers are meticulous with consent forms, patients may still not know what they're getting into. The forms, critics say, are designed more to protect doctors and companies from lawsuits than to ensure that patients understand risks. Not even researchers who routinely ask patients to sign consent forms are convinced that the process guarantees patients' rights. In a 2001 survey for the U.S. National Bioethics Advisory Commission, 13 percent of researchers interviewed said they were not sure whether their study participants in developing countries were even aware that they were in a research project. Some experts, including those who carried out this survey, have called for guidelines requiring researchers to assess how much patients understand.
Nor, say critics, is informed consent the only towering safeguard with feet of clay. In clinical trials, patient safety and welfare, as well as scientific rigor, are affected by such methodological variables as severity of illness, drug delivery system, or what treatment the test drug is compared against. In many poor countries, says Public Citizen's Lurie, the government-approved ethics boards that are supposed to assess these variables are non-existent or so poorly resourced that they often rubber stamp the pharmaceutical companies' proposals.
If the Trovan case gets to court, it will do little to ease such concerns. The goal of the experiment was to discover whether oral doses of Pfizer's experimental antibiotic were as effective in combating meningitis as the more painful muscle injections of its competitor Roche's Ceftriaxone. To compare the treatments, Pfizer enrolled 200 sick Nigerian children in a trial that the company says was a success and saved lives. The survival rate of Trovan patients was 90.3 percent versus 89.7 percent for Ceftriaxone, Pfizer says in its statement.
But lawyers for the families claim the company used abnormally low doses of Ceftriaxone to make its own drug look good, and failed to conduct follow-up studies of the surviving children's injuries. They also claim that a local ethics board had not approved the trial in advance: In a 2001 Washington Post article, two Nigerian doctors insisted that the local hospital committee that supposedly signed the paperwork didn't exist in 1996 when the trials took place.
Critics also charge that international documents such as Helsinki legitimate a double standard by allowing ethics boards to apply less stringent rules to developing countries. Feelings run highest over treatment of patients who end up in the "control group." Since no Western ethics board would allow doctors to withhold treatment, researchers must give the control patients the best existing drug. In impoverished African and Asian countries, however, where the control subjects would likely get no treatment outside the trial, researchers can — and sometimes do — test their new treatment against a placebo, i.e., no treatment at all.
For example, as HIV-AIDS tightened its grip on poor countries in the 1990s, infectious disease experts were keen to discover practical ways of slowing its progress. To this end, Western teams, mostly funded by the U.S. government, enrolled thousands of HIV-positive, pregnant women in South Africa and Thailand into clinical trials that became emotional flashpoints in the debate about rights for human subjects.
Despite evidence that the drug AZT could reduce mother-to-baby infection rates by up to two-thirds, researchers took an ethical calculation that would have been extraordinary in developed countries. They gave, or planned to give, more than two-thirds of women an unproven therapy or sham treatment (placebo) and thereby condemned hundreds of infants — who would likely have been saved by an established protocol — to HIV-AIDS and death. The scientists said it was necessary to withhold treatment to find out quickly whether a short course of AZT given at the end of pregnancy would prevent transmission. But then as now, Lurie argues that previous research had in fact already generated evidence that the short course reduced mother-to-infant HIV transmission.
Public Citizen's exposure of the plight of these women and their babies unleashed a wave of protest and anguished editorials in medical journals. Other controversial cases emerged. In a Western-sponsored study in Uganda, led by researchers from Johns Hopkins University, treatments were again withheld from poor patients, this time by a team investigating the impact of antibiotics on the infectiousness of HIV patients. And had activists not raised the alarm over a planned trial of Surfaxin to treat Respiratory Distress Syndrome in neonates two years ago, hundreds of gravely ill, premature babies in Latin America might have received a placebo rather than an effective treatment to help them breathe.
The Surfaxin plan came to light when Pennsylvania-based Discovery Laboratories asked the FDA to endorse its trial protocol. Although giving such sick babies placebos would never have washed in Europe or the U.S., the FDA judged it acceptable in countries whose hospitals were too poor to provide proven treatments.
In the end, the company chose a less contentious trial design that compared Surfaxin with approved treatments. "The FDA had three trial designs to consider," says John Cooper, senior vice president of Discovery Laboratories. "The trial design that dominated the discussions, the clear leader and ultimately agreed on was the trial currently being conducted." Lurie doubts the placebos would have been dropped from the study without outside pressure.
Campaigners including Public Citizen, local AIDS activists, and women's groups are also dismayed by what they see as intransigence in the scientific community. Years after the controversial AZT trials ended, the institutions that funded them and the researchers who carried them out continue to say that no actual harm was done because the patients were so poor that, if the trial hadn't taken place, none would have been treated anyway.
Nonetheless, exposure of research practices in the 1990s has generated some tightening of regulations and guidelines. Researchers in some countries, including the U.S. and Britain, are now supposed to get approval from an ethics committee at home and overseas before they export a drug trial. The government-approved committees, appointed by universities and hospitals, consist of doctors, ethicists, lawyers, and other experts. In the U.S., teams also require a government license to ship any experimental drugs overseas.
On the international front, although reformers strengthened the Declaration of Helsinki in 2001, loopholes persist. Bowing to pressure from industry and some scientists, Helsinki balked at banning placebos where treatments exist. Instead, ethics committees can approve placebo treatments for "compelling and scientifically sound methodological reasons."
And multinationals can still bypass Western ethics committees by organizing trials through foreign subsidiaries. While Lurie and other critics believe that governments and the scientific community should close the loopholes, some ethicists and scientists defend a more flexible approach. They argue that because not all drugs and therapies available in the West are practical or affordable in poor countries, insistence on the very best treatments in every case could make much-needed clinical research impossible. "If you go into this field and you're too dogmatic and you're trying to do global development R&D [research and development], you're going to fail," says John McNeil, an HIV/AIDS vaccine specialist at the Walter Reed Army Institute. "You can have goals, and they can be lofty, but you have to be in a position where you listen to the people you're working with, and you may have to back off a bit."
In developing countries, however, there is resentment from those who feel they are being dictated to by colleagues who do not understand the potential scope for abuse. In Chile, says Miguel Kottow, only public universities and hospitals have ethics committees. Meanwhile, behind the closed doors of private clinics and universities, companies can easily pay local doctors to carry out drug trails without notifying authorities, he says.
And then there is the question of what obligations companies and researchers have to patients and communities after a trial has ended. "If the company is going to get a benefit," Kottow says, "they should share some of it." In other words, the old physician's maxim of "do no harm" is no longer enough. As medical experimentation becomes globalized, says Kottow, doctors and companies need to recognize that test subjects are, in a sense, trading their bodies and deserve a fair deal in return. And the only one way they are going to get it, he insists, is if international agreements spell out obligations to patients and communities and set "just one ethical standard, consistent and the same wherever you do research."
And when patients feel that standard has been abused? Governments should make the companies that export clinical trials accountable back at home, says Milberg Weiss's Elaine Kusel. Last year, an American judge ruled that the Kano compensation suit belongs in a Nigerian rather than a U.S. court. The families' lawyers are now appealing. Trovan was an American drug shipped out to Nigeria to produce data needed for U.S. approval, says Kusel. If it's OK for the profits of far-flung human experimentation to come home, she asks, why not the accountability, too? 
