ETHICS AND COMMUNITIES OF FATE
Duke University Press
Copyright © 2010 Duke University Press
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Chapter One KAUSHIK SUNDER RAJAN
The Experimental Machinery of Global Clinical Trials | CASE STUDIES FROM INDIA
In earlier work, I have written about emergent systems of technoscientific production, value generation, and commodity circulation that concern the life sciences under the rubric of what might be called "biocapital," focusing on the sequencing of the human genome and the science of genomics that was emerging around this venture. The study of clinical trials is a necessary follow-up to the study of genomics in a project on biocapital.
This is because, first, within the biomedical process itself, clinical trials are often consequent to technologies such as genomics. Genomics is important to the drug discovery process-it potentially allows for the rational screening and identification of promising lead molecules that could conceivably have a therapeutic effect. This is the "upstream" or early-stage component of therapeutic development, but it is only distantly related, epistemologically and temporally, to the production of a therapeutic molecule. Clinical trials, on the other hand, constitute the "downstream" or drug development component of the process of therapeutic development. There is no way that any new drug molecule can come to market without a series of trials for safety and efficacy in animals and humans. Clinical trials therefore constitute the experimental machinery of biocapital: they are necessary to conduct before a drug comes to market, are particularly elaborate in the context of the U.S. regulatory framework, and are in themselves cost-intensive and high-risk with no guarantee of success.
Clinical trials constitute the set of practices required to certify a new drug molecule as safe and efficacious for the market. This set of practices serves in its rationale as a regulatory watchdog to prevent the market from being flooded with unsafe or spurious medication. In the United States, the clinical trials procedure is an elaborate one, occurring in four stages and contributing to the immense time, risk, and expense of the drug development process.
The stages of clinical trials are as follows: First, there is preclinical toxicological testing of a potential new drug molecule. This is usually performed on animals, in order to determine whether the molecule being tested is safe enough to put into a living system. This is followed by dosage studies, in order to come up with a metric that relates the dose of the drug being administered to safety and efficacy. Predictably, the efficacy of a drug increases with its dose, but so too does its toxicity, so the attempt is to find an optimum range of doses within which efficacy is maximized without compromising safety too much. If the drug is found too toxic to animals, the trial will not proceed any further, but if acceptable dose ranges can be determined within animals, then it proceeds to a three-phase trial in humans. Phase 1 trials are conducted on a small number of healthy volunteers to test the basic safety of the drug (since drugs that seem safe in animals may yet show adverse effects in humans). Phase ii involves scaled-up, larger, efficacy and safety trials on one hundred to three hundred patients. Phase iii trials are large-scale, randomized trials that may be conducted on a few thousand people, usually patients suffering from the ailment for which the therapy has been developed. These trials are usually coordinated across multiple centers, often (increasingly) globally.
Most trial sponsors are biotechnology or pharmaceutical companies because drug development in the United States (and in most parts of the world) is largely undertaken by the private sector. Universities and publicly funded laboratories in the States do play an enormous role in early-stage drug discovery-the identification of potential lead molecules and the conduct of early preclinical tests, but the institutional structure of drug development is such that they invariably license promising molecules to corporations in order to take them through clinical trials. This means that the biomedical and experimental rationales for clinical trials are completely entwined with the market value that these companies see from the drugs that eventually get developed, and with the market risk that attends the drug development process. Parenthetically, there is no epistemic reason why the drug development process should be so completely in the private sector, though this has become a naturalized facet of the biomedical economy, and is one of the factors that has allowed the seamless appropriation of health as an index whose value can be purely evaluated in terms set by the market. According to the Healthcare Financial Management Association's newsletter, "Twenty years ago, 80 percent of clinical research trials were conducted through academic medical centers. In 1998, estimates indicated the number of academic medical centers as investigator sites had dropped to less than half." Health research and production is thus progressively captured by capital, and now needs to be seen as a semiautonomous sector of capital. This is an example of what Balibar and Wallerstein have described as the continual expansion of the value form and infinite process of accumulation. The organizational complexity of clinical trials has however meant that it has been difficult for pharmaceutical companies to manage them, leading to the emergence of an entirely new industry segment devoted to the management and administration of clinical trials. These companies, called clinical research organizations (CROS), are now an integral part of the overall biomedical economy.
Clinical trials provide comparative insights into the study of biocapital across multiple sites globally. My own work focuses on India and the United States, two countries that are interconnected through flows of capital, infrastructure, and expertise, especially through the investment of nonresident Indian entrepreneurs repatriating a "culture of innovation" back to India. In this context, a host of CROS are emerging in India to conduct these trials, thereby providing a contracted service for (largely Western) biotech and pharmaceutical companies. If clinical trials are the experimental machinery of biocapital, then India, in this story, envisages itself as a major experimental site. Clinical trials, therefore, provide a lens through which to study the globalizing dynamics of biocapital in terms of the cost and biomedical rationales for outsourcing trials to developing country sites like India.
The Indian Clinical Trials Landscape
In this essay, I outline some of the dynamics of clinical trials in India, especially in terms of the huge amounts of capacity building taking place in anticipation of the movement of global trials there. I am interested in briefly mapping the various institutional actors and political economic dynamics at play in this arena. But I am particularly interested in showing how ethics is fundamental to the experimental machinery of global clinical trials as it touches down in India. It provides an engine to create ethical subjects involved in conducting clinical trials (CRO managers, employees, and researchers), but also allows the seamless creation of, and expropriation of, Third World experimental subjects, who are, I argue, "merely risked." Capacity building is certainly technological and institutional; but I want to focus on the various human capacities that are generated and/or taken advantage of as part of this experimental machinery. Ethics in the globalizing world of biotechnology is, as Aihwa Ong points out in the introduction to this volume, situated; and my interest lies in understanding the ways in which these situated ethics both structure and respond to pharmaceutical logics of value generation.
The movement of clinical trials to international (non-U.S.) locations started in earnest in the mid-1990s. Adriana Petryna cites figures that point to a dramatic growth in the number of international human subjects recruited into these trials, from 4,000 in 1995 to 400,000 in 1999. A recent study by the consulting firm A. T. Kearney shows that roughly half of the 1,200 clinical trials conducted in 2005 in the United States had an international trial site. In the 1990s, most of this international growth occurred, as Petryna notes, in countries that had agreed to harmonize standards in commercial drug testing with those set by the International Conference on Harmonization (ICH) guidelines. These included primarily Latin American and Eastern European countries, but interestingly not India. Over the past four years, however, India has been one of the most aggressive sites of clinical research infrastructure establishment and growth.
Indian actors currently see the country as providing an extremely attractive destination for outsourced clinical trials from the West. Contract research in the Indian pharmaceutical industry is already robust, and was estimated by the Chemical Pharmaceutical Generic Association to be worth between $100 and 120 million in 2005, while growing at 20-25 percent per year. Indian actors are eagerly anticipating the further influx of global clinical trials into the country. Who are these actors, and what are their anticipations based upon?
The most central, perhaps, are members of the burgeoning CRO industry. These are the most immediate beneficiaries in terms of revenues and profits of trials coming to India, and are therefore keen to create conditions whereby the influx of these trials can grow in a sustained and streamlined fashion. CROs are the major drivers of the ramp-up in clinical research infrastructure, and are particularly influential in building a regulatory framework for the conduct of trials. It is estimated that there are approximately one hundred CROs of reasonable size operating in the country at the moment. Some of these are fairly well established, with a couple being fifteen to twenty years old. A number of the better known CROs were seeded in the late 1990s, but many of these CROs have emerged since 2005.
The Indian pharmaceutical industry is another interested party. It is in the process of retooling its business model in the wake of India becoming a signatory to patent regimes imposed by the World Trade Organization (WTO). Indian patent laws prior to WTO allowed only process and not product patents on therapeutic molecules. This meant that one could not patent a drug itself, only the specific manufacturing process that produced it. This allowed Indian pharmaceutical companies to reverse-engineer generic versions of drugs that had product patent protection in the West. Such reverse engineering is now not possible under a WTO regime for the duration of a drug's patent (twenty years). This has forced a number of leading Indian drug companies into a business model driven by research and development, whereby they, like their Western counterparts, engage in the much riskier process of novel drug discovery and development. Clinical trials become constitutive of this business model, because one cannot develop novel drugs without subjecting them to this elaborate regime of safety and efficacy testing. In other words, the Indian pharmaceutical industry has itself served as a spur to the CRO industry. Becoming signatory to the WTO has also potentially made India a more attractive clinical research destination from the perspective of Western trial sponsors seeking to outsource global trials, since their intellectual property is better protected under such a regime.
What is surprising, however, is the immediacy with which clinical trial activity has sprung into life in India post-WTO. In many ways, the real spurt in business, regulatory, and training activity around clinical trials in India started around the same time that India started implementing a WTO-based patent regime (January 1, 2005). This suggests that the elements of a robust CRO industry were already in place in anticipation of WTO compliance, and that the initial spur to this industry was perhaps not just an anticipation of Western trials post-WTO, but was more complicated and homegrown.
That initial spur did in fact come from the Indian pharmaceutical industry as it started retooling its business models in anticipation of a WTO regime. While most Indian pharmaceutical companies retain robust generic divisions even after WTO (enabling them to compete with off-patent generics in Indian and increasingly also in Western markets), a few entrepreneurial ones such as Ranbaxy and Dr. Reddy's Laboratories have moved aggressively towards an R & D-based infrastructure. Even within generics divisions, bioequivalence studies are an important subset of clinical trials, and one that Indian companies, because of their traditional expertise in generic markets, are well positioned to conduct.
Ranbaxy has been responsible for the growth of the Indian clinical research industry in more ways than one. Its business model is currently twofold-first, to aggressively increase its presence in global generics markets (including the United States), and second, to try and discover its own therapeutic molecules that it might license to multinational pharmaceutical companies in exchange for the payment of various milestone-related royalties. In both cases, developing clinical testing facilities became very important for the company, and Ranbaxy was one of the first Indian pharmaceutical companies to develop an in-house CRO. It also started outsourcing trials, thereby spurring the development of a CRO industry. In addition, Ranbaxy also ended up being a source of much clinical research expertise. Three of Ranbaxy's main clinical researchers left the company in 2000 to create Wellquest in Bombay (itself a CRO seeded by another major Indian pharmaceutical company, Nicholas Piramal), while two other scientists from Ranbaxy were the cofounders of another major CRO, Lambda, in 1999. In this way, certain sections of the Indian pharmaceutical industry have generated clinical research work themselves, and have provided the capital and expertise required for the industry to take off. These events again make it too simple to suggest that clinical research capacity is purely being built as a consequence of the desire of "the West" to outsource trials to cheap Indian locations, though Indian actors are certainly betting on such a desire materializing in more research contracts.
A third actor consists of the regulatory agents and agents of the state. The immediate regulatory agency in India is the Drug Controller General of India (DCGI), a nominal equivalent of the U.S. Food and Drug Administration (FDA). The DCGI was, until a few years ago, indeed a fairly peripheral presence on the Indian regulatory landscape, but is now in the process of recreating itself as a serious regulatory agenda-setting organization.
Yet another actor consists of educational and training institutes for clinical research. Building the human resource capability to conduct and monitor trials in India is a key challenge, and a number of entrepreneurial ventures are engaged purely in training the labor force required to undertake this work. Finally, there are the physicians who actually conduct the trials, who in the Indian context have a relatively marginal presence compared to the CRO industry in setting the infrastructural and regulatory agenda for the conduct of such research.
There is a striking and universal interest among these actors (though not to the same extent as among physicians) not just in building clinical research infrastructure in India but also in promoting India as a clinical trial destination globally. The experimental potential of Indian populations as trial subjects melds seamlessly into the market potential that CROs perceive from an influx of these trials into India, and this convergence is facilitated by a larger historical moment that sees the Indian state branding and marketing itself to investors at global forums. Investments in the nation-state articulate with investments in biomedicine to result in capacity building for clinical trials.
Some of the enthusiasm around clinical trials within India is mirrored in the West by agents who might outsource clinical trials to the country. However, for the most part, the surge in clinical trials contracts to India is still in the realm of anticipation and potential. The infrastructure building occurring in India is very real; but it is a bet on future outcomes that, like any other speculation, may or may not pay off. Understanding the clinical trial situation in India involves understanding both the enthusiasms and the reservations that exist on the part of Western agents who may wish to contract trials out to India.
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