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BOOK REVIEW

Help, Harm and Human Subjects

Sheldon Krimsky

WHEN EXPERIMENTS TRAVEL: Clinical Trials and the Global Search for Human Subjects. Adriana Petryna. xii + 258 pp. Princeton University Press, 2009. $65 cloth, $24.95 paper.

EXPLOITATION AND DEVELOPING COUNTRIES: The Ethics of Clinical Research. Edited by Jennifer S. Hawkins and Ezekiel J. Emanuel. viii + 327 pp. Princeton University Press, 2008. $65 cloth, $24.95 paper.

CHASING MEDICAL MIRACLES: The Promise and Perils of Clinical Trials. Alex O’Meara. viii + 263 pp. Walker and Company, 2009. $25.

Those of you who browse bulletin boards or ride in buses or subway cars have undoubtedly come across posters bearing messages like this: “If you are between the ages of 18 and 35 and have difficulty sleeping, you may qualify to participate in a new study that could help your condition.” Such solicitations are now nearly ubiquitous. That’s because the clinical trial business has grown significantly over the past several decades, largely in response to the growth of drug development and of global markets in pharmaceuticals. To get new drugs into the marketplace, companies must deliver safety and efficacy data from clinical trials to the U.S. Food and Drug Administration (FDA). It is estimated that every year about 2.3 million people take part in clinical trials held in the United States; in 2008, more than 65,000 such trials, sponsored by federal agencies and private industry, were listed in a National Institutes of Health (NIH) database for those trying to locate clinical trials.

Investment in drug development has grown steadily since the 1980s as a result of biomedical advances relating to stem cell research, pharmacogenetics, proteomics and the mapping of the human genome. Recently the drug industry has been spending the money it budgets for research and development on a new generation of cancer drugs. As Big Pharma has investigated these oncologic agents, more volunteers have been needed in clinical trials to evaluate the prospects of various compounds.

Many trials have had difficulty recruiting subjects. According to a 2006 article by Judith M. Watson and David J. Torgerson, “Increasing Recruitment to Randomized Trials” (BMC Medical Research Methodology 6:34), a survey of the corresponding authors of articles published in 2000 or 2001 reporting the results of randomized trials revealed that nearly 60 percent of the trials had either proceeded with fewer subjects than initially planned or found it necessary to extend the recruitment period.

And more recently Sarah Kliff, in an article published online in Newsweek on March 10, 2009, has reported that 80 percent of clinical trials are delayed at least a month because of low enrollment.

When people cannot be recruited for trials in the United States, the world marketplace becomes the stage for medical outsourcing. Eastern Europe, Africa, Asia and South America have helped fill the demand for human trial subjects, usually with indigent people who have little or no access to health care. According to a report from Visiongain (a company that provides business information to the pharmaceutical industry), in 2008 the global clinical trial business was worth about $50 billion and was growing at a rate of 10 percent a year.

Three recently published books address the subject of clinical trials from different vantage points. When Experiments Travel, by Adriana Petryna, is an ethnographic analysis of leaders in the new growth industry of Contract Research Organizations (CROs), which provide clinical-trial services to drug developers. Exploitation and Developing Countries, edited by Jennifer S. Hawkins and Ezekiel J. Emanuel, is a volume of essays by bioethicists focusing on issues of global equity and justice in clinical trials that enroll impoverished groups in developing nations. And Chasing Medical Miracles is journalist Alex O’Meara’s memoir of his experiences jumping through hoops to gain access to a clinical trial that gave hope of a cure for his diabetes.

In When Experiments Travel, Petryna, an anthropologist at the University of Pennsylvania, explores this question: Why are so many of the clinical trials sponsored by companies in the United States being held in developing nations? To explain the phenomenon known as “offshoring of trials,” Petryna analyzes information gleaned from government sources, the Web sites of nonprofit organizations, and interviews with leading scientists and entrepreneurs who have founded CROs. She learns that, as is true of many trends in globalization, government policies play a central role. “In the early 1990s,” she notes, “the FDA began to actively promote the globalization of clinical trials, declaring that the search for sites and sources of data is part of its mandate.”

After examining the global marketplace for human subjects, Petryna concludes that the norms of protection vary significantly among countries. The book is built primarily on her scholarly, detached presentation of qualitative interview data and an analysis of published statistics. However, she periodically expresses moral judgments such as the following: “The benefits deriving from globalized research are arguably uncertain, and its risks are unevenly distributed and its costs, unjust.”

Petryna condemns First World companies and complicit governments for exploiting vulnerable, impoverished patients as experimental subjects. However, many of the complex ethical issues of transnational human trials are left unexplored in her book. Among those are whether desperate people can be both exploited and helped, and what set of humane principles should guide outsourced clinical trials. These are the subjects of the volume edited by Hawkins and Emanuel, Exploitation and Developing Countries.

The essays in this collection are organized primarily around two cases, which serve as the grist for ethical analysis. In the Havrix case, 40,000 school children in Thailand received either an inactivated hepatitis A vaccine or a hepatitis B vaccine in a randomized controlled trial sponsored by the U.S. Army in conjunction with SmithKline Beecham Biologicals and Thailand’s Ministry of Public Health. In the Surfaxin case, 650 premature infants in Bolivia who had respiratory distress syndrome (RDS), for which the standard treatment was lung surfactant replacement therapy with one of four approved surfactant drugs, were subjects in a placebo-controlled trial of a new surfactant made by Discovery Labs. In addition, in the introduction to Exploitation and Developing Countries, there is a discussion of trials in sub-Saharan Africa in which women were treated with antiviral agents to reduce maternal-fetal transmission of HIV.

The essayists reflect on a series of moral dilemmas. Can there be informed voluntary consent when the clinical trials are conducted in countries in which people face extreme poverty, illness and desperation? Is it ethical to use placebo controls against a new drug in clinical trials when some form of effective therapy exists for a medical condition and is the standard of care? When is a clinical trial protocol exploitative of desperate human subjects? Should U.S. companies engaged in overseas trials be required to follow ethical and medical standards that are no less stringent than those they would be required to follow in the United States? Or should the moral acceptability of a trial be based on whether the company’s actions will improve the lives of the population of the country where the trial will be conducted?

A number of the essays address the complex issue of placebos. Thomas Pogge (“Testing Our Drugs on the Poor Abroad”) explores the question of whether it is “wrong to test a new medicine (Surfaxin) for some life-threatening medical condition (RDS) with a placebo-control design when there already exists an effective medicine for this condition against which the new drug could be tested.” Pogge points out that if the Surfaxin trial had had an active control design, the lives of more than 280 infants might have been saved; nevertheless, with the placebo-control design, the trial saved the lives of 140 infants who probably would have died if the trial had not been conducted in Bolivia.

The book’s contributors examine responses to ethical questions through the lens of a variety of ethical theories: utilitarianism (greatest good for the greatest number), deontology (respect for persons), virtue ethics (accepted standards and norms), Rawlsian justice (the most vulnerable must not be made worse off), situation ethics (contextualized to local conditions) and intuitionism (what feels fundamentally fair and just). The meaning of exploitationin the circumstances discussed remains elusive; nevertheless, the volume’s artful philosophical analyses illuminate the issues. Andrew Siegel, in “Kantian Ethics, Exploitation and Multinational Clinical Trials,” expresses the paradoxical dialectic:

We must also exercise caution when legislating against exploitation, for the perverse reality is that the best prospect some persons currently have for improving their lives is to submit to exploitative exchanges.

In “Exploitation and Placebo Controls,” Jennifer Hawkins proffers a set of conditions that she believes are jointly sufficient to morally justify the use of placebo controls even when participants fail to receive the best care available.

The last chapter consists of a consensus statement obtained from participants at an international conference on research in developing countries. It addresses the question of whether it is unethical to recruit persons in a poor country to be clinical-trial subjects when neither they nor their country will benefit from the medical advance being investigated.

Overall, these are essays of high quality. However, the anthology is limited in one obvious respect: It has no contributions (with the exception of the consensus statement) from ethicists in those parts of the world most adversely affected by clinical-trial outsourcing.

The two books already discussed, which are soberly academic in tone, were written by scholars pursuing broad explanatory themes and universal ethical principles. Alex O’Meara’s Chasing Medical Miracles, the first-person account of a clinical-trial subject, is almost breezy in comparison—the book is a page-turner.

O’Meara, a journalist, has type I diabetes complicated by hypoglycemic unawareness that has repeatedly landed him in emergency rooms. He describes the lengths to which he goes to be included in a somatic gene therapy trial that would afford him some hope that his body would begin producing its own insulin. What makes his memoir unique and captivating is that he steeped himself in the culture of clinical trials, entering not as a naive and ill-informed subject but as a fully informed and tenacious advocate of the trial, which he hoped would liberate him from having to wear an insulin pump. His personal story is so compelling that the intervening background chapters feel like an unwelcome intrusion.

The trial involved transplanting pancreatic islet cells from matched donors into the livers of patients with diabetes. To be cleared for participation, O’Meara had to overcome a number of obstacles. To take just one example, an x-ray of his lung revealed a nodule. He volunteered to undergo surgical removal of the nodule, hoping that it would turn out to be fungal, since in that case he would still be eligible for the trial. The surgeon needed 98 titanium staples to close his lung after the surgery. “I saw the little rivets on my x-ray,” O’Meara writes. “They were looking great, the surgeon said. And no, he told me, the staples wouldn’t set off metal detectors at airports.”

If the book has a weakness, it is that the author makes it appear that, to qualify for a trial, a candidate must be in tip-top physical shape (O’Meara was a marathon runner). His case is hardly representative of the way people actually get recruited for trials or of the type of medical screening that usually takes place to ensure that the trial candidate meets the letter of the protocol.

O’Meara’s trial was fraught with risks, and things did not go smoothly for him: He experienced multiple complications and got mixed results. Thus his experience left him well qualified to write the book’s useful afterword, in which he presents a set of soul-searching questions that anyone who is considering enrolling in a clinical trial would do well to consider.

Chasing Medical Miracles provides a useful counterpoint to the detached, scholarly approach of social scientists and ethicists featured in the other two books. It reminds us that people in desperation over their illnesses seek hope, and that many of them grasp that hope in a clinical trial that offers them an experimental treatment. Taken together, these three books reveal the profound complexity of the task of meeting the needs of vulnerable populations while advancing medical science for the benefit of future generations.

Sheldon Krimsky is a professor in the Department of Urban and Environmental Policy and Planning at Tufts University and an adjunct professor in the Department of Public Health and Community Medicine at Tufts University School of Medicine. He is the author of, among other books, Science in the Private Interest (Rowman and Littlefield, 2004) and is coauthor with Tania Simoncelli of Genetic Justice (forthcoming from Columbia University Press).

OPINION

JULY 10, 2009

Bookshelf

Helping Science, Making Money

Drug trials involving 20,000 people or more are now fairly common.

BY SCOTT GOTTLIEB

When I was a medical student, a pulmonary professor of mine cajoled me into joining a clinical trial that she was running. The general aim of the tests was to determine whether prolonged periods of short and shallow breathing would cause a person’s lungs to go into spasm. It turns out, as I can attest, that they do. After essentially panting for one hour, I became so acutely short of breath that I needed an albuterol inhaler to stop me from fainting. That was enough for me — I quit. But my professor called several times, pleading for me to reconsider. She didn’t want to lose me, she said, because I was a “perfect control subject.”

What she didn’t do was offer money as an enticement — a strategy that has become commonplace in recent years as clinical trials increasingly shift from academic settings and into the commercial realm, with companies recruiting and paying tens of thousands of people to participate in tests.

Clinical trials cover a broad range of medical matters, including the testing of new devices, theories (like prolonged shallow breathing leads to lung spasm) and approaches to care. But the most extensive clinical-trial testing is done on new drugs. That has always been the case, but nowadays meeting the ever more daunting requirements of the Food and Drug Administration has become such a logistical burden for pharmaceutical companies that they turn to businesses that specialize in administering clinical trials. These highly profitable companies, and the self-described human “guinea pigs” they hire, are the central focus of Alex O’Meara’s “Chasing Medical Miracles,” his investigation of “the promise and perils” of a $24 billion industry.

Mr. O’Meara himself has served as a clinical-trial guinea pig, and he writes with authority about the growing ranks of people who make something of a living from taking not-yet-FDA-approved drugs. If participants sign up for a long-term study, they’re said to be in “lockdown” until it’s over. Before they can take part in another clinical trial, the guinea pigs must observe a month-long “washout” period “to get all the drugs they ingested from the previous testing out of their systems.”

The author describes a world of clinical trials dominated by secretive companies, working on behalf of big drug makers, that are known (if at all) to trial participants by acronyms such as PPD (Pharmaceutical Product Development) and MDS Pharma Services (the company’s own Web site doesn’t say what the MDS stands for). The clinical-trial business itself is known by the acronym CRO, but Mr. O’Meara notes that even CRO doesn’t have a standard definition — some say it stands for “clinical research organizations” others say “contract research organizations” — which only adds to the industry’s reputation for stealthiness.

Mr. O’Meara worries about the portents of a large business sector’s maintaining such a low profile, but “Chasing Medical Miracles” is not so much an exposé as a worried portrait. The book is framed by the author’s account of his own guinea-pig experience. A lifelong diabetic with “brittle” disease, he has had to endure frequent finger pricks to obtain blood samples that can be checked for sugar levels. He enrolls in a clinical study that will try to stimulate the insulin-secreting activity of the pancreas by transplanting cells from cadaver pancreases.

His clinical-trial experience is the jumping off place for Mr. O’Meara — a freelance journalist who has worked for the Baltimore Sun and Newsday — to apply his reportorial skills to studying the CRO industry. He bunks with guinea pigs during lockdowns, talks to the heads of clinical-trial companies and meets the lawyers developing novel legal theories to sue them when something goes wrong, even though participants sign exhaustive waivers acknowledging the dangers inherent in testing new drugs and innovative medical procedures.

The guinea pigs that Mr. O’Meara trails are mostly in it for the money. Many are students or the marginally employed; not long ago, he says, the ranks of clinical-trial participants were often made up mostly of drying-out drunks and the homeless, but the burgeoning of the CRO business and the need for ever more patients has resulted in sweetened compensation. He’s sketchy on industry-wide rates, but does visit the sign-in for a clinical trail that pays participants $830 in exchange for a three-day confinement and two return visits.

Mr. O’Meara is adept at portraying clinical trials and in discussing ethical concerns — about CROs possibly skewing results to favor the interests of the drug companies that hire them, and about the financial incentive for clinical-trial applicants to lie about their medical history. But he gives too short shrift to the legal and regulatory forces that have prompted the rise of the CRO.

With the FDA increasingly concerned about ensuring drug safety, new layers of rules and requirements — including much wider and more extensive testing — have been added to an already complex approval system. A decade ago, a trial for a new blood-pressure pill might have enrolled a few thousand participants. Now late-stage trials on 20,000 people or more are fairly standard for these kinds of primary-care drugs. It is often simply beyond the capacity of an academic medical center or even a big pharmaceutical company to recruit and monitor the highly specific and often “treatment naïve” patients that the FDA typically requires.

As for the clinical-trial patient Alex O’Meara, the experimental cell-transplant diabetes treatment works for a time. He’s able to go off insulin and reduce the frequency of blood-sampling finger pricks. But eventually the transplanted cells start to fail. At the book’s close, he is clinically better off but not cured, satisfied just to have taken a shot — and content in the knowledge that he might have helped, in some small way, the advance of medicine.

Dr. Gottlieb, a practicing physician and resident fellow at the American Enterprise Institute, was a deputy commissioner of the Food and Drug Administration from 2005 to 2007. He is on the boards of two health-care companies that do business with CROs.

Copyright 2009 Dow Jones & Company, Inc. All Rights Reserved

Review: Chasing Medical Miracles by Alex O’Meara

“Enjoy this bracing tour through “the history, horror, and headaches” of clinical trials, described by a guide with both a detached delivery and knowledgeable perspective. Former Newsday and Baltimore Sun reporter O’Meara, a Type I diabetic, signed up for a trial offering a possible cure, so he may be more than a little invested in how trials work. But his self-interest is a compelling element as he surveys a $24-billion-a-year industry that affects the lives of 20 million Americans. His investigation briskly sails through the interests that spark clinical trials, the money that pays for them and the “bonanza of cash and/or equipment and medications” for developing countries where researchers find it cheaper to recruit trial subjects. Best and most sweetly, however, the book delves into the human guinea pigs, such as gene therapy trial participant whose death raised questions about government oversight and the self-interest of the lead researcher. O’Meara presents lessons from a medical front that offers something more important than success or failure—hope. “I’m still able to say, ’At least I tried.’” O’Meara notes. (June)”