When Experiments Travel

Clinical Trials and the Global Search for Human Subjects

Adriana Petryna

• Publisher: Princeton University Press
• Year: 2009
• ISBN:
  9781400830824
• Topic: Social Sciences
• Subtopic: Cultural & Social Anthropology
• Index: Social Sciences

The phenomenal growth of global pharmaceutical sales and the quest for innovation are driving an unprecedented search for human test subjects, particularly in middle- and low-income countries. Our hope for medical progress increasingly depends on the willingness of the world's poor to participate in clinical drug trials. While these experiments often provide those in need with vital and previously unattainable medical resources, the outsourcing and offshoring of trials also create new problems. In this groundbreaking book, anthropologist Adriana Petryna takes us deep into the clinical trials industry as it brings together players separated by vast economic and cultural differences. Moving between corporate and scientific offices in the United States and research and public health sites in Poland and Brazil, When Experiments Travel documents the complex ways that commercial medical science, with all its benefits and risks, is being integrated into local health systems and emerging drug markets.
Providing a unique perspective on globalized clinical trials, When Experiments Travel raises central questions: Are such trials exploitative or are they social goods? How are experiments controlled and how is drug safety ensured? And do these experiments help or harm public health in the countries where they are conducted? Empirically rich and theoretically innovative, the book shows that neither the language of coercion nor that of rational choice fully captures the range of situations and value systems at work in medical experiments today. When Experiments Travel challenges conventional understandings of the ethics and politics of transnational science and changes the way we think about global medicine and the new infrastructures of our lives.

CHAPTER ONE

ETHICAL VARIABILITY

Why Are Clinical Trials Globalizing?

In the view of Dr. Lee, a company scientist who coordinates clinical trials in Eastern Europe, public distrust of the clinical trials process is rampant in the United States and in Western Europe, and “it is becoming a major barrier to our work.” For him, the growth of clinical research offshore expresses a straightforward yet unsettling value system: “If a doctor or nurse asked you if you were willing to put a family member in a clinical trial, and if it was not a life-or-death issue, would you do it? The answer would most likely be no. The fact is that all of us, drug researchers and consumers, are economically dependent on other people’s willingness to say yes.” This expert knows that landscapes of experimentation evolve in a kind of give-and-take where people with unmet medical needs are willing to say yes to the movement of global capital and scientific and medical commodities.

Consider Poland. The country had one of the highest rates of cardiovascular-disease-related deaths in the world, and it has recently developed impressive preventive apparatuses to reverse this trend. Poland’s leading heart institutes and public hospitals have become preferred destinations for trials of therapies ranging from hypertension treatments to invasive surgical procedures. Hospital administrators so welcomed these trials that by the late 1990s a prestigious cardiology institute in Warsaw was “awash in throm-bolytics,” or clot-busting drugs, according to one businessman and former physician coordinating trials in Poland. He suggested to me in 2005 that clinical trials were a social good, an integral part of health-care delivery. “Not a single ampule in the institute was purchased. Each patient who needed treatment got it from a clinical trial.”¹ Here underserved patients are experimental subjects whose added value lies in the fact that they have not previously been treated with the particular drug or class of drugs under study. As a clinical research expert told me, untreated patients of this sort minimize the chance of specific drug-drug interactions and “offer a more likely prospect of minimizing the number of variables affecting results and a better chance of showing drug effectiveness.” That people in lower-income countries (just like people in affluent ones) might be consuming several drugs or self-medicating, often unsystematically, has not deterred companies from pursuing particular sites in which they imagine the “naive” (i.e., those who have not been diagnosed or treated for the condition under study) might be found—in a poorer region or hospital, for example.²

Certainly, the human research enterprise is about obtaining valuable data that can get drugs approved. But it is also about creating new experimental infrastructures, remediating old ones, and expanding market frontiers.³ “Pharmaceuticals are the new gold,” as Dr. Paulo Picon, a southern Brazilian cardiologist and public health expert, told me skeptically. He is a staunch critic of the increasing use of clinical trials as a means of introducing high-cost medicines in Brazil’s ailing public health-care system. “After a trial ends, the industry enlists doctors to prescribe and patients to demand drugs from the state.” Pharmaceutical costs overburden the system, and “often these new drugs have not even been approved here and their benefits are not yet clearly established.”

Whether they work in the United States, Poland, or Brazil, my informants raise crucial issues that go to the heart of the globalized clinical trial. Are clinical trials exploitative or are they social goods or some combination of both? How are research protocols designed and data produced? How do the results of clinical trials strengthen or undermine the delivery of affordable and effective interventions? Who is ultimately responsible for the experimental subject’s immediate and long-term well-being?

Pharmaceutical research and development (R&D) includes laboratory and animal studies and clinical testing in humans—in the United States both are subject to federal regulation.⁴ R&D spending has soared over the past three decades, from $1.1 billion in 1975 to $44.5 billion in 2007. For the top ten pharmaceutical firms—more than half of which are based in the United States—approximately 40 percent of this amount is spent on clinical trials.⁵ Clinical trials involving new drugs are generally divided into four phases. In Phase 1 trials, researchers determine the safety and safe dose range of experimental drugs and detect their toxicological side effects in a small group (20–80) of healthy volunteers. In Phase 2 trials, 100 to 300 people are recruited for assessment of the drug’s efficacy and further evaluation of its safety. In Phase 3 trials, investigators administer the study drug to larger groups (1,000–3,000) of people to confirm its effectiveness, scrutinize side effects, compare it to other treatments, and collect information on optimal use. These trials are frequently coordinated across multiple centers, which, increasingly, are located worldwide. Phase 4 trials, also known as postmarketing surveillance, are primarily observational and nonexperimental studies in which companies and regulators collate data on the drug’s risks and benefits once it enters the market. Postmarketing surveillance involves millions of people but in practice remains vastly underdeveloped.⁶

In 2000, representatives from diverse interest groups met to reflect on the state of clinical research in the United States, which, they said, was contributing to an overall decline in drug innovation. They agreed that, in spite of greater research funding from the National Institutes of Health (NIH) and revolutions in basic biomedical science, clinical research is “increasingly encumbered by high costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants” (Sung et al. 2003:1278). Moreover, the U.S. clinical research environment limits the translation of basic scientific concepts into human studies and medical practice. The environment must be improved, and the president and U.S. Congress must enact bold new approaches. If not, they claimed, the “data and information produced by the basic science enterprise will not result in a tangible public benefit” (ibid.:1279; see also Rosenberg 2003).⁷

The clinical trials industry promises to address and overcome such technical and regulatory barriers. Since the 1980s, pharmaceutical companies have increasingly outsourced clinical research.⁸ As the CEO of one contract research organization told me, “About 60 percent of all clinical development costs are spent on Phase 2 and Phase 3 trials. So the big money is there.” He stated that drug firms outsource “about half of their initial toxicological or Phase 1 studies,” and that CROs like his are also engaged in postapproval marketing studies to promote new products. The CRO market size is estimated at $10 billion and growing. Hundreds of CROs operate worldwide, employing nearly one hundred thousand professionals who implement clinical trials protocols for the pharmaceutical industry.⁹

The geography of clinical testing is changing dramatically. In 2005, 40 percent of all trials were carried out in emerging markets, up from 10 percent in 1991 (Lustgarden 2005:68). Figures are available for some firms. GlaxoSmithKline ran 29 percent of its trials outside the United States and Western Europe in 2004; by 2007, that figure grew to 50 percent. Wyeth Pharmaceuticals conducted half of its trials outside the United States in 2004; that figure rose to 70 percent in 2006. Merck conducted half of its clinical trials outside the United States in 2004, an increase of 45 percent since 1999 (Schmit 2005). According to recent industry statistics, Central-Eastern Europe has the highest volume of patients (6.27) enrolled per investigative site, followed by the Asia-Pacific region (5.78), South-Central America (4.56), Western Europe (3.08), and the United States (1.92) (Parexel 2008: 135). Between 1995 and 2006, the highest annual growth in active investigators occurred in Russia, Argentina, India, Poland, Brazil, and China. Of these select countries, as of 2006, Russia had the highest number of investigators enrolled with the FDA (623), followed by India (464), Argentina (462), Poland (322), China (307), and Brazil (292).¹⁰

As the clinical trials enterprise becomes ever more outsourced and off-shored, it also becomes increasingly decentralized and more difficult to track. While we have estimates of numbers of investigators involved, estimates for the number of clinical trials actually being initiated worldwide vary considerably. In March 2006, a member of a World Health Organization initiative to create a global registry of clinical trials told me, “Our best guess is that 20,000 new trials are initiated worldwide annually. But take this ‘guesstimate’ with a grain of salt.” A global field of experimental activity is booming and experts struggle to simply keep count.¹¹

Companies are free to move medical research to cost-effective sites around the globe. Meanwhile, the subjects of research depend upon local and national communities to mediate their participation in clinical trials and to protect them from harms that may be associated with such participation. An international trial registry could help us to better account for this corporate–human subjects disjuncture and to gauge the relevance of international ethical guidelines and capacities of local and national institutions to protect patient-citizens in an era of global experimentality.

The decision regarding whether to carry out clinical trials, where, and how is as much a scientific as it is an economic and political one.¹² This political economy bears the stamp of a set of practices inherent in the pharmaceutical industry as it has evolved in North America in the twentieth century. Specifically, I have in mind the history of research among minorities and so-called cooperative patients and professional guinea pigs. I also have in mind the power the industry exerts over evidence making and drug regulatory policy.¹³ Some of these operations are empirically accessible, while others are proprietary and part of the pharmaceutical black box. The anthropological challenge is to engage the transparent and public ways in which private-sector research undergoes global restructuring today.¹⁴

Anthropologist Carol Greenhouse urges those studying “closed institutions” to move beyond an analytics of “hidden transcripts” and to chart transcripts “that surface in plain sight” (2005:364). In her analysis of legal responses to the 9/11 tragedy, particularly the establishment of closed military tribunals, Greenhouse focuses on what she calls the “visible junctures” and “discursive trails” of state and legal institutions—less emphasis on the elusive black box and more attention on the sites where the demands for “invisibility and visibility confront each other” (Sivaramakrishnan 2005: 326). In this way, the anthropologist finds the means of objectifying “emergent lines of political restructuring,” and thus interpreting them and, hopefully, identifying alternative possibilities of action.

In this book, I take the operations of the clinical trials industry as a window into global drug development and the ways experimental subjects and therapeutic evidence are constituted. I collected the professional histories of leading scientists and entrepreneurs who founded the industry in the 1970s and 1980s. In doing so, I produced a recent history of outsourced clinical research, tracing it back to the postwar boom in pharmaceutical production and to regulatory and health-care system changes in the United States.

In 2001, I began to engage U.S.-based contract researchers and clinical trials professionals—scientists, former physicians, M.D./Ph.D.’s, businesspeople and marketers—who spoke openly and plainly about all aspects, both good and bad, of the science of drug development. In reflecting on their craft, they gave me deeper insights into recent media coverage of the hazards of drugs and how they might have been created. Executives also allowed me to follow the activities of some of their affiliates overseas. The men and women I spoke with saw themselves as innovators operating at the productive margins of very large and powerful institutions—academia and multinational pharmaceutical companies—for which many of them had previously worked. In their self-presentation, these professionals objected to the occasional media vilification of their work as a corruption of the scientific method and a breach of ethics.¹⁵ They are largely drawn from the same labor pool as pharmaceutical and biotech employees, but questions are periodically raised about their “degree of independence from their pharmaceutical-industry clients” (Shuchman 2007:1365). The industry’s main trade group suggests that the scrutiny is misplaced, as “[s]ponsors call the shots. Sponsors shoulder final responsibility for the trials they design” (ClinPage 2007). One CRO professional told me that sponsors exhibit an unrealistic “bravado” in their demands, and that he and his colleagues were engaged in a “less delusional” form of work. He believed that most pharmaceutical clients were largely “out of touch” with the realities and exigencies of on-the-ground research.

These physicians and scientists, “purely operational,” on the one hand, were also troubleshooters and fastidious with detail. They conveyed a heightened sense of the risks of the competitive world they labored in, of its responsibilities, rules, and penalties. They deployed informal moralities and sometimes had to choose between alternatives that were not obviously right or wrong. In this sense, my anthropological work differs from that of a journalist; it is not exposé-oriented and I do not have the entry points to undertake such work. Rather, these subcontracted actors offer a crash course on the integrity and weaknesses of global expert systems, forms of science, capitalism, and law—and in how these translate into social practices that can be considered, contested, or debated. In taking them on their own terms, I ask: What ethical deliberations and actions are possible in arenas fraught with high financial and political stakes? What is transparency and what are the risks of distortion? How are those risks distributed, deferred, or mitigated, and what spaces of negotiation open in their wake?

Their critiques, however, should not be taken at face value; they must be understood in the context of a mutable research ecology that is fraught with competition. Two executives from another company referred to their business sector as an “opportunistic” by-product of “an overinflated industry” that needed to be “downsized.”

When I asked a researcher about risks in drug testing, he expressed frustration with the clinical trials operational model, specifically with regard to “how dumb the drug-testing process is with respect to detecting harms.” Trial sponsors exercise significant control over the definition of a reportable adverse event; it seemed that exercising critical independence allowed him and his colleagues to identify new areas of expertise and needs in drug development that would, in turn, lead to the expansion of their outsourced enterprise. After 2004, and in the wake of the FDA’s issuance of safety warnings for several approved drugs, this scientist’s company (like others) attempted to differentiate itself from competitors by promoting its own drug safety–enhancing niche, promoting technological strategies aimed at lowering risk and improving the “robustness” (i.e., reliability) of scientific results.

Contract research organizations are thriving businesses at home and abroad. As a former CEO, whom I will call Rob, told me during a conversation in 2004, “There has been a big evolution from the 1980s until now, from simple capabilities to our being able to run entire global programs. By the mid-1990s, companies like ours were planting flags all over the globe.” Members of this subcontracted community gave me insights, drawn from their own experiences, into cultures of drug development and the technical and political challenges they face. As they invent the means to make drugs approvable and marketable, they claim to be the creators of a “translational science” in their own right. By and large, they stressed lawfulness and technical competence. Their narratives also conformed to business models, and as such they were strategies for creating value. Juxtaposing what these actors told me with the accounts of other actors in the clinical trials “food chain” helped me see the remedial kind of work the clinical trials industry, and specifically CROs, perform. The professionals’ narratives attest to concrete problems and unknowns that are only part...