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04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 188 Justice in Health Research what is the role of evidence-based medicine? Wendy Rogers * and Angela Ballantyne † ABSTRACT Evidence-based medicine (EBM) aims to facilitate access to up-todate, accurate information about the effectiveness of medical interventions, in order to improve human health.The quality of the research results available for EBM processes of synthesis and meta-analysis is critical to this process. If there are distortions or corruptions in the research process, EBM becomes a false prophet, collecting and propagating unreliable results.This article examines flaws in the current processes of research production and the implications of these for justice and for vulnerable patients, and explores possible solutions. evidence-based medicine (EBM) occurred in 1992, with the publication in the Journal of the American Medical Association of the paper by the McMaster Evidence-Based Medicine Working Group (EBMWG 1992). In the years since then, EBM has attracted its fair share of controversy (Jenicek 2006).At its best, EBM seems to offer a vision of clarity in medical practice based upon the ideal of practitioners using the best available evidence as the T HE OFFICIAL BIRTH OF * Department of Philosophy, Macquarie University, Sydney, Australia. † Institution for Social and Policy Studies, Interdisciplinary Center for Bioethics,Yale University. Correspondence: Wendy Rogers, Department of Philosophy, Macquarie University, NSW 2109, Australia. E-mail: wendy.rogers@mq.edu.au. The authors would like to thank Olga Anikeeva for research assistance, Jenny Doust and Ryan Orange for helpful comments on earlier drafts of this paper, and the reviewers for their insights. Perspectives in Biology and Medicine, volume 52, number 2 (spring 2009):188–202 © 2009 by The Johns Hopkins University Press 188 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 189 Justice in Health Research foundation for informed decision making with patients (Strauss and Jones 2004). At its worst, EBM may represent a return to medical paternalism, with experts prescribing algorithms for care in the form of clinical guidelines and taking little account of the many factors likely to render the guidelines unreliable, biased, or irrelevant to the specific patient needing care (Brase 2005). Between these two extremes lies a spectrum of views about EBM, together with ongoing debates about just what the contribution of EBM is, or has been, to improved patient outcomes (Buetow et al. 2006). More recently, the activities of EBM have engaged the interest of ethicists, who have raised issues ranging from patient and clinician autonomy to use or misuse of evidence in allocation decisions about health-care resources (Goodman 2003; ter Muelen et al. 2005). The main focus of EBM has been to find and use evidence from clinical trials to guide clinical practice. Around the world, clinicians have struggled to master the techniques of searching literature and performing meta-analyses, and then struggled more with making sense of their results in terms of individual patient care. Partly in response to this, a whole industry of reviewers and guideline developers has sprung up, with academics and clinicians donating often astonishing amounts of time and energy to reviewing research for groups like the Cochrane Collaboration. Research is the lifeblood of EBM, making it therefore important to consider the ethical issues that arise in the production of research. Here we turn our attention to issues of justice arising from the research that underpins the reviews and the search for the best available evidence. We examine two aspects of medical research: its production, including the constituents of research populations and the structure of the research agenda, and its results, including access, publication, and analysis by such agencies as the Food and Drug Administration (FDA) and by reviewers. Within each subsection, we investigate the impact of research distortions on the systematic reviews and clinical guidelines that are the practical outputs of EBM. Flawed research undermines the whole raison d’être of EBM, which is founded, more or less explicitly, on a widely shared vision of medical research aimed at creating safe and effective therapeutic agents for the good of all. The key elements of this model are ethical research, integrity in research methods, and publication of peer-reviewed results in the public domain. This process allows grouping and meta-analysis of multiple trial results, leading to stronger evidence about the safety and efficacy of treatments. Without good-quality research, EBM becomes a false prophet, collecting and propagating unreliable results. Worse still, these distortions can perpetuate and exacerbate injustices in research and further marginalize vulnerable patients. Throughout this critique we focus on research-related justice in EBM, in particular, justice in relation to the role of industry, and research on vulnerable populations. Before proceeding with our analysis, we should therefore explain what we mean by justice in health research and the role of EBM. In terms of medical practice, EBM is grounded in notions of non-maleficence and beneficence—in spring 2009 • volume 52, number 2 189 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 190 Wendy Rogers and Angela Ballantyne other words, providing safe and efficacious treatments that avoid harms and provide benefits to patients.The contribution of EBM to patient autonomy is more contentious and lies outside our present scope (see, for example, Hope 1996; Rogers 2002). As part of its role to inform practice, EBM aims to ensure that medical research is translated efficiently and accurately into clinical guidelines, thereby improving clinical care and health outcomes.The EBM project has not been directly concerned with how these improved health outcomes are distributed among the population, and it therefore has not focused on justice in terms of equity of access to treatments or of health outcomes. Because EBM act as a clearing house for research, however, issues of justice arising from the research that informs EBM can legitimately be considered among the ethical issues raised by EBM itself. For the purposes of the current analysis, we take justice in research to include at least these three components: 1. Fair access to research participation, with no exploitation of vulnerable groups or unjustified exclusions of potential participants. 2. A just global research agenda that distributes health research resources fairly in relation to disease burdens. Developed countries have a justice obligation to spend some of their health research budgets on conditions affecting poor populations (London 2005). 3. Fair processes, such that research is designed and performed in ways that derive maximum utility from results that are then presented in an unbiased and publicly accessible format, and that those who review research are not subject to financial conflicts of interest. In summary, just research is research that contributes to identifying safe and effective treatments that reduce the global burden of disease. There is not space here to argue for these claims, which we take to be widely shared; rather, we present them as background premises to the ensuing analysis. The Production of Research There have been significant changes in the structure of research over the past 20 years, relating to funding, location, and the ways in which it is organized.These changes have put increasing power and control into industry hands, with adverse consequences for the welfare of research participants and the integrity of the research itself. Given the importance of high-quality research to EBM, these are serious issues. The pharmaceutical industry is the greatest source of research funds on a global scale. The Global Forum in Health Research estimates that the private forprofit sector funds 51% of global research annually, investing approximately $80. billion (Burke and Matlin 2008). Their funding is increasingly channeled through contract research organizations (CROs), rather than academic institutions. Estimates suggest that, between 1992 and 2001, CROs increased their 190 Perspectives in Biology and Medicine 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 191 Justice in Health Research numbers of enrolled research participants from seven to 20 million, with a commensurate increase in income from $1 billion to $7.9 billion (Mirowski and Van Horne 2005; cited in Sismondo 2008).The market imperative requires CROs to be competitive, with pressures to contain costs and produce results. Greater commercial control over research funding allows industry to play a larger role in research design and conduct. Industry has an obligation to its shareholders to make a profit, which creates significant incentives for introducing bias into the research process. There are a number of ways that bias may be introduced into research. First, the design of the study may be manipulated to produce positive results.The choice of comparator (for example, placebo or suboptimal dose of competitor drug) can make a positive finding more likely, as can the selection of participants who may have characteristics that favor the drug under investigation. Second, outcomes may be selected to favor the trial drug, or the statistical methods used may minimize or mask adverse events. Recent investigations have demonstrated a clear association between funding source and trial outcome, with commercially funded research three to four times more likely to have findings favorable to the sponsor than non–industry-funded research (De Vries and Lemmens 2006). The structure of research has profound implications for the quality and integrity of the evidence base that underpins EBM. In the next sections, we discuss in more depth the selection of participants in research and setting the research agenda. Participants in Research The question of whom to involve in research is a vexed one. On the one hand, the more specific the question and the more homogenous the research population, the more likely a trial is to produce a definitive answer.This leads to a search for research participants with single conditions and minimal variables. On the other hand, the results of trials have to be “applied” to diverse populations, comprising women and men of multiple ethnicities and with variable comorbidities. Research with representative populations is necessary to develop medical and clinical knowledge about the etiology of disease and about the safety and efficacy of medical interventions in diverse populations (Rogers 2004a, 2004b). Commercial pressures lead to demands for fast answers, making the narrowly focused trial with homogenous participants appealing. However, this strategy can lead to a number of injustices. Certain populations may be overburdened with research because they are accessible, compliant, or financially needy. Elliott (2008) has described vividly the lives of those who “guinea pig” for CROs in the United States, and it is a far cry from the ethical ideal of research participation as detailed in the Nuremberg code or the Declaration of Helsinki. Given the sometimes appalling conditions in which U.S. citizens contribute to the research endeavor, it is unlikely that conditions are better for people in Eastern Europe spring 2009 • volume 52, number 2 191 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 192 Wendy Rogers and Angela Ballantyne and Asia, who are becoming the participants of choice for commercial medical research (Petryna 2007). Questions of justice also arise when potentially vulnerable populations are excluded from research. The systematic exclusion of women and minority groups from clinical research in the 1970s to the 1990s has been well documented (Dresser 1992).The exclusion of women from landmark research studies such as the Multiple Risk Factor Intervention Trials (MRFIT) and the Physicians’ Health Study generated significant concern and international debate (GAO 1990). In response, many countries introduced guidelines, regulation, and in the case of the U.S. National Institutes of Health, legislation requiring researchers to include both women and ethnic minorities in research. Three related factors were responsible for the under-representation in clinical research of women, ethnic minorities, and other groups perceived to be “vulnerable,” such as children and prisoners: explicit protectionist policies of exclusion; practical considerations of research efficiency and cost; and false assumptions about the relevance of sex, gender, and racial differences. The protectionist policies of the 1970s were in fact a backlash against previous exploitation of vulnerable populations in research. The 20th century saw a number of examples of blatantly unethical research with vulnerable populations, including the Nazi World War II medical experiments conducted on concentration camp prisoners and the Japanese biological warfare experiments in Manchuria (Harris 2002). Public protest led to the development of medical research guidelines such as the Nuremburg Code of medical research (1949) and the U.S. Belmont Report (1979). These, along with guidelines in other jurisdictions, focused on informed consent, preventing exploitation, and just subject selection. They ushered in a protectionist research paradigm, in which researchers conservatively sought to avoid exploitation by recruiting non-vulnerable research populations—adult, white males. For example, from 1977 to 1993 the Federal Drug Administration (FDA) in the United States prohibited research including women of childbearing potential in early-phase drugs trials to avoid potential harm to reproductive capacity or to any fetuses if the women became pregnant (Merkatz et al. 1993). In addition to protectionist concerns, there were purported practical reasons for the exclusion of women and minorities from research. Commonly cited were the alleged need for homogenous populations, the cost of including minorities and women, and the difficulty of recruiting these populations (Dresser 1992; Ferguson 2002). These justifications reflect what we call the “distortion paradigm,” which defines the white adult male body as normal and considers female biological processes as distortions of this norm. Interestingly and paradoxically, biological processes were thought to interfere with research to a sufficient degree to justify the exclusion of women, minorities, and children, and yet these groups were thought to be similar enough that studies of predominantly white adult 192 Perspectives in Biology and Medicine 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 193 Justice in Health Research male subjects could be used as the basis for treatment guidelines for the general population. Despite regulatory efforts to encourage the inclusion of women and minorities as participants in research, some distortions still exist. Unfortunately, recent evidence demonstrates the persistent under-representation of women over the age of 65 in research and the over-representation of men in studies of heart disease and colorectal and lung cancer trials (Hutchins et al. 1999; Murthy, Krumholz, and Gross 2004). The overall effect of these practices is research results that are unable to answer questions about safety and efficacy for many of the end users of the research. Given that EBM is built on meta-analysis and reviews of the best available research, the resulting guidelines will only be as good as the quality of research from which they are derived.Yet despite increasing recognition of sex and gender differences in coronary heart disease (CHD), for example, a recent review has demonstrated that most contemporary guidelines for prevention, diagnostic testing, and medical and surgical treatments for CHD are still based on studies conducted predominately on middle-aged men (Wenger 2006). In the absence of research including women, minorities, and children, clinical treatment is based on studies with adult male research populations, despite important physiological differences between ethnicities, between men and women, and between adults and children.This extrapolation can lead to both the undertreatment of such populations as pregnant women and children, because there is a lack of clinical data demonstrating safe and effective treatment options, and exposure to harm from unknown risks of drugs in these populations (Rogers 2004b). Although the ethical issues associated with the inclusion of children and pregnant women in research are particularly vexed, pregnant women and children nevertheless require medical treatment. The choice is thus between exposing them to potential harm in a regulated and monitored research setting, or exposing them to potential harm in unmonitored clinical settings, through either withholding treatment or providing treatment that is untested in these populations. Groups traditionally excluded from research, such as women and some ethnic groups, continue to receive suboptimal clinical care.Women have not, for example, achieved the same gains in relation to CHD as men: despite significant improvements for men, mortality from CHD in women has not declined in the past 20 years (AHA 2006). The relationship between historical exclusion from research and current under-treatment represents a correlation rather than a demonstrable causal link. Nevertheless, it seems clear that EBM cannot deliver safe and efficacious treatments for women, minorities, and other disadvantaged groups without appropriate research evidence that includes fair representation of these groups. spring 2009 • volume 52, number 2 193 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 194 Wendy Rogers and Angela Ballantyne Improving Participation in Research Effectively regulating the participation in research of previously excluded or vulnerable groups is a challenging problem.To date, the American regulation of the inclusion of women and minorities in NIH-funded research represents the most sophisticated international model (National Institutes of Health Revitalization Act of 1993, Public Law 103-43). The NIH Inclusion Policy is backed by strong financial incentives, as the success of NIH grant applications depends on satisfactory targets for the recruitment of women and minorities, with targets reviewed by specialist scientific peer-review committees. Funding can be withdrawn from a project if recruitment does not match agreed inclusion targets. There is some evidence that the NIH guidelines have an indirect impact on research outside of America, with chairs of Human Research Ethics Committees in Australia commenting that Australian research projects receiving NIH funding or involving American collaborators are more likely explicitly to disclose the numbers of women recruited for the research (Ballantyne and Rogers 2008); countries such as Canada and Australia may well need more robust regulation of research to ensure that women and diverse ethnic groups are appropriately represented. While inclusion guidelines should be tied to public research funding and suitably qualified scientific peer review, such regulations cannot easily be extended to apply to privately sponsored research. Other universal mechanisms— such as institutional review boards (IRBs) and FDA approval of trials—apply to commercial research sponsors, but the effectiveness of these instruments has also been criticized. Now that many drug studies occur outside of academia, sponsors can shop around for a favorable for-profit IRB who will promise fast approval (Elliot 2004).We discuss concerns about conflict of interest amongst FDA reviewers below. Improved participation of traditionally excluded groups in research does not always entail “equal” participation. Research protocols must be informed by an investigation of the theoretical likelihood of differences between subgroups, be designed to detect any differences between subgroups, and include appropriate statistical subgroup analyses to look specifically for the effects of such factors as sex, gender, age, and race. The Research Agenda The research agenda determines what research is conducted and what results will therefore be available to inform EBM. With global health research funding fairly evenly split between private-for-profit sector sponsors (51%) and public sector sponsors (49%), the research agenda reflects a mix of the interests of industry and the governments of predominantly high-income countries. The role played by commercial research sponsors has increased over recent decades, leading to a stronger focus on patentable treatments that address the needs of affluent markets. As a result, research into diseases of poverty, epidemiological 194 Perspectives in Biology and Medicine 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 195 Justice in Health Research research, and research into non-patentable behavioral and environmental solutions to ill health are currently underfunded (Trouiller et al. 2002).The problem here is twofold: an emphasis on patentable treatments (for example, drugs) at the expense of other potentially effective but less-profitable interventions; and a focus on conditions prevalent in rich populations.We deal with each of these in turn. The focus on drug research is compounded by the dominance of the randomized control trial (RCT) in EBM. In a “happy accident,” the interests of industry in developing patentable treatments align well with the reliance of EBM upon the RCT, because drugs happen to be especially suited to testing in an RCT.The goals of commercial research sponsors, combined with the methodological standards of EBM, create an increasing emphasis on pharmaceutical solutions to disease. The clinical evidence base is dominated by RCTs of drug treatments. This in turn impacts medical practice as a whole. When a clinician asks, “What is the best treatment for raised cholesterol?” the answer will come back loud and clear that published studies support the effectiveness of statins.We do not know what other effective interventions might have been identified if the research agenda (with funding to match) had had less of a focus upon RCTs of potentially profitable drugs. Furthermore, in many countries, it is the public purse that supports purchase of medications. By providing the evidence that EBM requires—in other words, results from RCTs—industry can influence not only clinicians but also government purchasing authorities. Given that environmental and behavioral factors are estimated to cause up to 70% of premature death in the United States (Lee and Paxman 1997), a narrow focus on drug development can never maximize population health outcomes. Expanded research in social and environmental health innovation is needed to balance out the research agenda. Patents provide financial incentives that direct research towards drugs with a profitable market, regardless of whether the drugs address significant disease burdens. As we know, the private for-profit sector is the largest investor in health research globally. Predictably, the majority of global expenditure on health research is directed towards conditions of the wealthy, which account for only a small percentage of global morbidity and mortality; conditions afflicting the majority of the world’s poor remain under-researched (Trouiller et al. 2002). Industry will continue to invest in drugs likeViagra rather than vaccines, ifViagra promises a greater return on investment (Johnston and Wasunna 2007). This approach to research fails to meet the requirements of justice in research as we have framed them. A just research agenda would address the health needs of all populations and work to minimize the global burden of disease. National funding bodies have the capacity to set national research priorities and allocate funding for projects addressing these questions, but in free-market democracies, governments cannot dictate where private industry should invest its research dollars. As governments around the world recognize, however, health care is a spring 2009 • volume 52, number 2 195 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 196 Wendy Rogers and Angela Ballantyne special good because of the strategic importance of health to individuals’ range of opportunities and ability to fulfill their life goals (Daniels 1985).The current reliance on commercial sponsorship of research cannot fulfill the requirements of a just research agenda because it does not support the distribution of safe and effective medical interventions for the global poor. Changing the Direction of the Research Agenda In addition to the patent system, alternative mechanisms are required to enhance innovation, research, and development for diseases predominantly affecting poor populations, thereby moving towards justice in the research agenda. Numerous models have been suggested and are currently being debated. Philosopher Thomas Pogge (2009) has, for example, suggested a parallel patent system, where inventors could opt to apply for a “health impact” patent where their financial return is calculated according to the impact of their intervention on global morbidity and mortality. An alternative approach is that of the proposed Medical Research and Development Treaty, which would determine global research priority areas (Ashiya and Jindal 2007). Signatories would agree to invest a set proportion of their GDP in funding priority research projects.These strategies are ambitious and promising, but they are unlikely to be implemented in the near future. Other more limited but also more immediate approaches to setting the research agenda include community-based participatory research (CBPR) that aims to improve the correlation between health research and community health needs. This approach ensures that the target consumers of research knowledge are actively involved in setting the research agenda and designing research protocols. Models of effective CBPR have been demonstrated in research with traditionally underserved groups, such as indigenous populations and drug users. Ownership, Publication, and Review of Research Results We have already commented on some of the effects of the commercialization of research and the increasing use of CROs to perform research for pharmaceutical companies. There is one final consequence flowing from the emergence of CROs that we need to consider, and that relates to ownership and control of the results of research. In academic settings, there is an imperative to publish. Ideally, the motive for this is to make results public, in order to advance knowledge and ultimately to benefit patients.There are ancillary benefits for academics, as publications are widely recognized as a sign of success and are increasingly a requirement for career progression. CROs, however, are free to protect the interests of their funders by engaging in a number of publication practices that subvert the ideal of honest or unbiased communication for the public good.These practices have been described by others, most comprehensively Healy and Cattell (2003) 196 Perspectives in Biology and Medicine 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 197 Justice in Health Research and Elliott (2004).The process of publication planning in CROs involves hiring authors to ghostwrite manuscripts based on trial results, and offering these to established academics. In an apparent win-win situation, the academics secure a gift publication, while the addition of their names helps to secure publication in a prestigious journal (De Vries and Lemmens 2006). The links are not overt: a careful reading of the published paper may fail to reveal any ties with the pharmaceutical company or the CRO. But this is only the beginning. The publication campaign may be closely choreographed to flood the literature with accounts of trials favorable to the company’s interests. For example, Healy and Cattell (2003) have documented the sertraline campaign. A commercial agency organized 55 papers that were published between 1998 and 2001, and these became a significant part of the evidence base about sertraline, drowning out other more critical results published in less prestigious journals or by lesserknown authors. Once the over-publication of positive results is coupled with suppression of unfavorable results, the literature, and thus the evidence base, reflects a very partial and biased picture of the benefits and harms of particular drugs. Obtaining the unadorned results (both positive and negative) of trials held by commercial companies can be a difficult if not impossible task. Manipulation of results in the public record skews the evidence, making the systematic reviews upon which EBM depends unreliable. The whole thrust of commercially funded research is to get new treatments to market as soon as possible. Regulatory bodies such as the FDA are charged with approving new drugs, thus opening the gateway to the market. The FDA relies upon advisory committees to examine the research evidence provided by sponsors in order to determine whether the drug is safe and effective, where “safe” is understood to involve a balance between benefits and risks. Ideally, this process should involve only those people who are free from conflicts of interest caused by industry links. The reach of industry sponsorship means that it is increasingly difficult for the FDA to find experts without industry ties, and hence without a conflict of interest. In their study of FDA decisions, Lurie et al. (2006) found that there was at least one advisory committee member with at least one financial conflict at 73% of meetings.Traditional approaches to conflicts of interest in this situation require disclosure or recusal, but disclosure of even quite substantial financial ties rarely led to recusal from specific meetings.The bias caused by conflicts of interest can be unpredictable: a biased decision maker may over or under-compensate for their bias. In the case of the FDA however, the bias seems to have worked in favor of industry.The authors calculated that for every one committee member with a conflict, there was a 10% greater likelihood that the meeting would favor the drug under review. Quantifying the effects of conflicts of interest is a challenging task; nevertheless, it seems reasonable to assume that if this level of bias exists at the FDA, despite its formal procedures for disclosure, the biases are likely to be equal or greater in researchers performing and reviewing research of commercial funders. spring 2009 • volume 52, number 2 197 04_52.2rogers 188–202:02_51.3schwartz 320– 4/3/09 3:36 PM Page 198 Wendy Rogers and Angela Ballantyne One solution would be to use only those academics and specialists without conflicts of interest, but this is problematic given the widespread involvement of academics and specialists in clinical research. The situation has become sufficiently challenging that, in a 2002 editorial, Drazen and Curfman of the New England Journal of Medicine announced a change in their conflict-of-interest policy for authors of review articles and editorials. For these types of articles, the journal would now exclude only authors with a “significant financial conflict of interest,” whereas prior to 2002 it had excluded any author with a financial conflict of interest.The journal justified its change in policy by citing the difficulty they had had in finding authoritative specialists without a conflict of interest. The end result of all of these factors is the creation of a research literature base that is very much shaped by the interests of industry. Concern for patient welfare, health outcomes, or the global disease burden run a distant second, while independent academic activity has been compromised by conflicts of interest. Improving Access to Research Results There are various mechanisms for improving the transparency of clinical research, publication of results, and the accountability of researchers. For example, in 2005 the International Committee of Medical Journal Editors (ICMJE) circulated a policy requiring researchers to register their trial design in an approved and publicly accessible clinical trials registry (CTR) before the onset of patient enrollment, as a condition of publication of trial results in the world’s leading medical journals. CTRs are designed to combat selective reporting of trials, a practice that distorts the body of evidence available for clinical decision making. Despite initial resistance from the research community, CTRs have been an overwhelming success. Five CTRs meet the ICMJE criteria, and the largest— clinicaltrials.gov in the United States—had over 54,036 trials registered in April 2008 and receives 40 million viewers per month (ICMJE 2005). Advocates are now calling for basic results reporting to be included in the CTRs. Because the ICMJE will not count brief (
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