by Sonia Shah
Anyway, FDA officials, CRO execs, and industry researchers who run trials abroad argue, just looking at the potential benefits of the drug in a trial is too simplistic a way to evaluate all the benefits that might accrue to the participants and their society from taking on a clinical trial. Even when experimental subjects don’t benefit from the study drug, they likely benefit from the extra medical attention they’d be bound to receive in a trial aimed at getting a drug approved by the FDA. “You see, patients are very cared for in trials,” said Nadeem Rais, a diabetes specialist who conducts industry trials in Mumbai, India. And these medical services are not only free; in many trials, subjects are even paid to participate.36
A 1999 study, for instance, found that patients enrolled in randomized controlled clinical trials survive better and with fewer complications than those getting care outside research protocols.37 “Companies need to do clinical trials in developing countries, because the trials bring benefits to the patients,” says HIV researcher Arthur Ammann, who has tried to convince companies to do more trials in developing countries. “They get special attention. . . . And they provide potential therapy for those patients.”38
“Patients who go into these trials are getting really, really good care,” said Macé Schuurmans, a lung specialist who has conducted industry trials in Switzerland and at South Africa’s Stellenbosch University. He says his South African patients are very grateful to him for conducting these trials on them. “In an affluent country, you give the patient the best treatment you know of, and it is usually available. Here, [in South Africa], you have to decide if you can do five chemotherapies, and you’ve got twenty patients. Which five will get that chemotherapy? . . . If you see the queues in hospitals . . . they’ll wait the whole day. People go there, they cough, and maybe cross-infect themselves. They have to wait to see the doctor, they have to queue to get the medicines. [But if they get into an industry trial], if they wait for the doctor at all, they get tea, they get to look at television and it is quite nice. . . . The patient is really very happy. They say, ‘Gosh, I’m really happy this happened to me.’”39
There are intangible benefits that accrue to the facility running the trial, too, which may eventually help local patients in other ways, Schuurmans and others say. Sometimes poorly equipped clinics will get a new machine or two for use during the trial and to keep afterward. Clinicians might get specialized training that they can later use to treat patients. During its Trovan test, Pfizer upgraded facilities at Kano Infectious Disease Hospital with high-tech equipment.40 The company even doubled one lab technician’s salary for helping with the trial, the Washington Post reported.41
“It generates quite a lot of hard-earned money,” says Schuurmans, money that can be used to treat patients or conduct public health–oriented research.42 “We got some equipment, and they didn’t ask for it back,” after an industry-sponsored trial ended, says Mumbai-based cardiologist Yash Lokhandwala. “Per patient recruited for the trial, they give a sum that goes to the hospital; it is, like, 15,000 rupees per patient, so if you get one hundred patients, that comes to fifteen lakhs of rupees [around $33,000] for the hospital.”43
Doctors and nurses might learn about cutting-edge new drugs and the latest techniques. After all, “distribution of wealth and knowledge is unequal,” Wurzlemann, the CRO doc, said. “Sharing that knowledge helps make the world more fair.” It is unlikely that American doctors and patients would tolerate such trade-offs, but elsewhere clinicians profess gratitude. The placebo-controlled trial of nitazoxanide, which resulted in thirteen deaths in Lusaka’s University Teaching Hospital in 2000–2001 and failed to ensure a later supply of an approved drug, “was a good experience for Zambia,” affirmed University Teaching Hospital clinician Mary Ngoma.44
For others, a few token machines and payments do not always compensate for the diversion of precious health care resources away from treating patients. Lokhandwala conducted clinical trials for multinational drug companies while working at an over-burdened public hospital in Mumbai. He recalls: “For these trials, everything has to be maintained, documented, kept in the cupboard for three years. The fridge has to be maintained at the same temperature. If the temperature goes a little bit more or less, you have to immediately alert them, and you have to stop the trials until the repairman comes, and so on. Suppose you break an ampule, you have to keep that broken part, to make sure you keep it for the study monitors to show that you had two or three. Who is going to do all this? I had my usual duties and, in addition, this trial was a big headache for me. . . . Here in clinical work everyone is overworked, and then you tell someone to spend their time on paperwork!”45
Clearly, reading the scale on risks and benefits is no straightforward task. It depends on whom you ask, when, and in what context. “The idea that one can pronounce on the ethics of something today and that will be correct forever,” says Benatar, “would seem to suggest that ethics is like a cookery book. If you want to make cookies, you can make them with a recipe and they will always look and taste the same. The ethics of international research are infinitely more complicated than that.”46
The clinical research establishment manages the complexity by essentially leaving it to the experts. “There is sensitivity in some parts around who can speak on ethical issues,” affirms South African human rights activist and physician Leslie London. The general idea is that the appropriate venue for discussing risks and benefits of clinical trials is not the front page but cloistered ethics-committee meeting rooms and the pages of academic journals, where bioethicists and researchers delve into the complexities of a single trial at a time. It’s a piecemeal, microscopic approach that isn’t particularly well-equipped to grapple with how trials, in the aggregate, may exploit subjects’ poverty, undermine human rights, or misallocate resources. “You get sort of ‘well you balance this and you balance that and this is important,’” says London.
“And you never get a straight answer.”47
Conclusion
Listen long enough to biomedical researchers, as I recently did at a multidisciplinary scientific conference, and you will doubtless hear admiring commentary about human experiments of days past, when daring trials free of onerous regulation produced spectacular results. Such experimentation, the research scientist will say, is unfortunately no longer possible “due to ethical concerns.”
Due to ethical concerns. I heard the phrase at least a few times over the course of a single week-long conference. It is an interesting construction, which seems to be almost exclusively reserved for biomedical transgressions. It’s hard to imagine anyone talking about indentured labor, or oil spills, or corporate embezzlement as not being possible “due to ethical concerns.” Those things are simply considered morally wrong and socially illegitimate, and are punishable by law. But when clinical researchers deceive patients, exploit their poverty, or divert scarce resources away from their care, it isn’t considered an unalloyed bad. The main business of medical research—improving health, saving lives—overshadows it. The exploitation and human rights violations are just side effects.
Subduing these “side effects” requires mothballing the mythology around medical research that sets them up as “side effects” in the first place. As bioethicist Solomon Benatar explains, “Research being done in developing countries . . . is not really for the benefit of those people [the subjects]. It may happen to be, for the few people lucky enough to get into the trial. But the reason the researcher is coming to that country is more often than not because somebody is willing to pay for the study. Somebody wants an answer to a question. The data is valuable either academically or commercially.”1
In other words, the main business of clinical research is not enhancing or saving lives but acquiring stuff: data. It is an industry, not a social service. The people who sponsor and direct clinical trials do it for the data, not to please patients or to help bolster ailing health facilities, although they may point to these side effects to justify their activi
ties. Their motives don’t make them corrupt or mercenary, either, just regular, self-protective humans like the rest of us.
But if clinical research is a self-serving industry, then there’s no reason to allow it special leeway, to look the other way when it bends and even breaks the rules. If we think that trial subjects should be informed and their participation should be consensual, we should require that informed consent gets checked and confirmed. If it’s impossible, then we should require the research be stopped. We should require that the deals for subjects—access to study drugs after the trial ends, for example—be fair and good right here and now, not in some speculative future when prices fall, or poverty ends, and other people apply better solutions.
Such requirements, which could be incorporated into FDA rules, would be logical correctives to the profit-driven, competitive industry that clinical research has now become. But that begs the question as to whether we really want to accommodate this model in the first place.
Rather than simply dispelling the myths, we could start to demand that drug companies and medical researchers actually live up to them. The promise of medical research is that it will alleviate ill health and save lives, but clinical researchers only take on a tiny slice of that job: getting the data. When it comes to implementation, shoulders are shrugged: that’s someone else’s job. The disconnect might be acceptable for basic science, but if we want medical research to truly alleviate ill health and save lives, then we have to hold it accountable when it renders little more than interesting papers and “me-too” drugs, whether it does so ethically or not.
Achieving this kind of accountability is no easy task. The public has no mechanism for setting priorities in research in the first place, no way to articulate what it is that we most want from medical research, and how we would use it if we had it. Aside from a few targeted programs, either the market decides and research goes into whatever drug companies think will sell, or sponsors decide on a case-by-case basis and whichever grant applications look most interesting get funded. Imagine instead a systematic review and a robust, independent, open public debate on where medical research has gotten us thus far and where it is that we want it to take us, not just among specialists and advocates, but all of us. It is hard to say where such an exercise might lead. Perhaps we’d see that research on the shelf has little meaning. Poor countries may well prioritize the implementation of old research over the pursuit of new experimentation.
Opportunities to exploit the gap between the haves and have-nots would shrivel.
There are obvious pitfalls in these suggestions. Drug companies can easily find loopholes in stricter informed consent and other rules. Researchers can easily mount convincing arguments that millions will die if research is delayed or burdened with greater accountability. But there is one suggestion for slowing the body hunt that is fairly airtight, and that is to require that new drugs prove themselves better than already available ones, not just better than nothing.
This would trigger a profound shift in drug development and the clinical research it entails. Not only would it maximize the potential for drug trials to render public health benefits, but such trials would prove less risky for subjects, too. Investigators would, by necessity, provide all of them with active treatments. More important, higher FDA standards for new drugs would cut much of the fat out of the drug industry, favoring companies that produced useful new drugs rather than hypermarketed copycats. The pace of new drug development would inevitably slow, as would the concomitant hunt for bodies. The competitive urgency that leads researchers to dilute ethical standards or transgress them entirely might start to abate.
Of course such a change would likely require an act of Congress and the drug industry would fight it tooth and nail, enlisting sympathetic patient groups to support them. We’re not nearly there yet. But to get us on the road, we can start supporting drug developers that are already doing something similar: nonprofit outfits that develop drugs aimed at public health. If public and nonprofit drug companies can show they can develop worthwhile drugs efficiently, public confidence in the idea of making medicines not as a business but as a public health effort might grow. It may not seem so radical, then, to raise the bar on FDA rules, too.
It used to bother me that people could be so squeamish about human experimentation but yet have no problem capitalizing on the products it renders. It is the same kind of “not in my backyard” attitude that sends toxic waste and open-pit mining to Asia and Africa while Americans enjoy disposable plastics and aluminum foil. But I’ve come to believe it signifies something deeper: an understanding that there is something unsettling about using people for their tissues, blood, and metabolism. Turning the body into a thing rightly offends our sensibilities about what it means to be human. Experimentation depersonalizes us: trial subjects no longer have humor, style, habit, ideas. And we like to think of ourselves as more than just mushy machines.
But medicines are not just commodities, they are social goods, and their development requires experimentation on humans. So long as that remains true, we need to find ways to do it right, and to do it fairly.
Notes
Preface
1. Daniel Callahan, What Price Better Health? Hazards of the Research Imperative (Los Angeles: University of California Press, 2003), 3.
2. Jon Cohen, Shots in the Dark: The Wayward Search for an AIDS Vaccine (New York: W.W. Norton, 2001), 100.
3. Ibid., 251.
4. Julie Schmit, “Costs, Regulations Move More Drug Tests Outside USA,” USA Today, May 16, 2005; Marc Kaufman, “Clinical Trials of Drugs Fewer, Study Says: Report Also Notes Decline in Number of Principal Investigators in U.S.,” Washington Post, May 4, 2005, A2.
1: Clinical Trials Go Global
1. See “Drop in Death Rates for Diseases Treated with Pharmaceuticals, 1965–1996,” available at www.quintiles.com, citing U.S. National Center for Health Statistics 1998.
2. John Wurzlemann, “Presentation on Eastern Europe,” in Globalization of Clinical Trials panel, Maximizing Clinical Efficiency Phases conference (Washington, DC, October 9, 2003).
3. Mark McLellan, “The Current Status of Clinical Trials,” in Maximizing Clinical Efficiency Phases conference (Washington, DC, October 9, 2003).
4. Andrew Pollack, “Three Universities Join Researcher to Develop Drugs,” New York Times, July 31, 2003.
5. David Horrobin, “Are Large Clinical Trials in Rapidly Lethal Diseases Usually Ethical?” The Lancet, February 22, 2003, 695–97.
6. Stan Bernard, “The Drug Drought: Primary Causes, Promising Solutions,” Pharmaceutical Executive, November 2002, 7.
7. Bonnie Brescia, “Better Budgeting for Patient Recruitment,” Pharmaceutical Executive, May 2002, 86; Andrew Pollack, “In Drug Research, the Guinea Pigs of Choice Are, Well, Human,” New York Times, August 4, 2004.
8. The bubble of goodwill burst within weeks, when a faulty batch of vaccine was released, infecting 220 children with polio. Laurie Garrett, Betrayal of Trust: The Collapse of Global Public Health (New York: Hyperion, 2000), 330. The public recoiled in horror. Salk’s vaccine, it was later revealed, also contained monkey tissue, a potential source of other pathogenic viruses, some of which could have triggered certain cancers. Anita Guerrini, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: Johns Hopkins University Press, 2003), 129.
9. Garrett, Betrayal of Trust, 330; Sarah Marie Lambert and Howard Markel, “Making History: Thomas Francis, Jr., MD, and the 1954 Salk Poliomyelitis Vaccine Field Trial,” Archives of Pediatrics and Adolescent Medicine, May 2000, 512; Marcia Meldrum, “‘A Calculated Risk’: The Salk Polio Vaccine Field Trials of 1954,” BMJ, October 31, 1998, 1233–36.
10. Kathleen B. Drennan, “Pharma Wants You: Clinical Trials Are Agencies’ New Proving Ground,” Pharmaceutical Executive, April 2003, 83–84.
11. Dan Moskowitz, “What Stops Cancer Patients Enrolling?” Scrip, November 2002, 13.
12. In the original random
ized, double-blind, placebo-controlled trial some subjects with metastatic breast cancer would get ninety minutes of infusion with Herceptin. Other, equally ill women would get ninety minutes of infusion with some inert substance. Then the researchers would watch to see which group got sicker faster. Patients couldn’t have been less interested in participating. A year later the trial was still underenrolled. To entice more patients into the trial the CRO running the Herceptin trial dropped the placebo group. Despite the fact that for all anyone knew Herceptin could have been worse than a placebo, enrollment skyrocketed 500 percent over the original lethargic rate. “Patients were also much more willing to travel to the clinic each week to receive treatment,” the CRO exulted on its Web site. See www.covance.com/clinical/content/pg_clin_case-onc.html. Interview with Dennis DeRosia, 2001.
13. Horrobin, “Are Large Clinical Trials in Rapidly Lethal Diseases Usually Ethical?”
14. Harsha Murthy, “The Use of Innovative Strategies in Patient Recruitment: Best Practices and Success Stories from Pharma and Biotech,” Maximizing Clinical Efficiency Phases conference, (Washington, DC, October 10, 2003).
15. Horrobin, “Are Large Clinical Trials in Rapidly Lethal Diseases Usually Ethical?”
16. Bernard, “The Drug Drought.”
17. Roy Porter, The Greatest Benefit to Mankind: A Medical History of Humanity (New York: W.W. Norton, 1997), 67.
18. Thomas Bodenheimer, “Uneasy Alliance—Clinical Investigators and the Pharmaceutical Industry,” New England Journal of Medicine, May 18, 2000, 1539–44.
19. Ibid.
20. See Quintiles Web site at www.quintiles.com.
21. Sonia Shah, “The Globalization of Clinical Research,” The Nation, July 1, 2002.
22. Public Citizen, “Comments on the Draft Health and Human Services Inspector General’s Report,” Washington, DC, July 5, 2001.
