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9 Toward a Patient-Centered Strategy for Clinical Trials THE CHANGING POLITICS OF CLINICAL TRIAL ENGAGEMENT1 Many people, perhaps especially those in the medical profession, think of the term “health politics” as an oxymoron, said Larry Brown, Professor of Health Policy and Management, Mailman School of Public Health at Columbia University, and that the one should have nothing to do with the other. However, the challenges and strategies involved in “politics” are those of managing deep conflicts in values and interests. Such issues are intrinsic to the clinical trial enterprise, which must ask itself questions like: • hat kinds of trials are worth doing, or more worth doing than others? W • hat kinds of patients and what categories of diseases should be W addressed in trials? • ho ought to pay for them? And from whose budget should the W funds come? Thus, the goals of clinical trials have important and inescapable political dimensions because of the choices that will be made about which trials will be done and the parameters under which they will be carried out. 1 This section is based on the presentation made by Larry Brown, Professor of Health Policy and Management, Mailman School of Public Health at Columbia University. 75

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76 PUBLIC ENGAGEMENT AND CLINICAL TRIALS Goals of Clinical Trials Society wants trials that will advance the cause of evidence-based medicine, improve the quality and effectiveness of care, and correct errors in past practice. Desired trial goals are to save money for the health care system, to identify what does not work, and to be a force for cost con - tainment. While clinical trials should be robust and efficient and timely and accessible, they should also honor a lengthening list of social criteria and priorities: diversity of the study populations, meticulous patient safety, strict informed consent, rigorous institutional review, and, not least important, accountability with respect to investigators’ conflicts of interest and the role of industry and private interests in sponsoring and shaping the trials. Although it obviously would require heavier investment in clinical trials in order to achieve all these goals, Brown said, it is not so clear where that money should come from. Should it derive from new public money at a time when government budgets are under intense pressure? Should it be public money rechanneled from basic research to clinical evaluations? Should it be private money? Should institutions bear more of the costs of running trials? Should it come from a combination of these sources? In part because of multiple goals, competing internal priorities, and funding uncertainties, over time researchers have not only increased the number of trials but also asked more of them, by making them more com- plex, and, in some ways, more internally conflicting. Researchers have complicated the design and execution of trials—essentially for political reasons—because trials stand at the center of converging, yet often incom- patible, public and professional priorities and expectations. The NIH Example Managing the kinds of conflicts and tensions faced by trial researchers ought to be possible. Indeed, the lustrous history of biomedical research in the United States since the end of the Second World War, primarily under the auspices of NIH, suggests that is so. NIH has developed an impressive list of political resources and strat- egies that might offer clues and cues for managing the current clinical trials enterprise. Brown provided a checklist of these NIH resources and strategies, along with some of the notable individuals involved, including the following: • trong entrepreneurial energies by citizen advocates of great S skill and tenacity, such as Mary Lasker, known for her unflag- ging support of biomedical research, especially cancer research,

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77 TOWARD A PATIENT-CENTERED STRATEGY and Florence Mahoney, a colleague of Lasker’s in the support of research, who developed a keen interest in aging and mental health. They and many other advocates put enormous skill and energy into supporting research over the long haul. • S killful advocacy for more research money by disease groups, which prompted growth in the number of NIH Institutes and Centers that focus on specific diseases, conditions, and treatment approaches, as well as increases in the total NIH budget over time. • edical leaders in specialty associations, faculty of academic med- M ical centers, and academic medical center deans who have been dependable research champions when the need arose to discuss research needs with members of Congress, testify at congressional hearings, and make the case to the news media. • C ultivation of congressional champions, for example, the late Senator Lister Hill (D-AL) and Representative John E. Fogarty (D-RI),2 as well as numerous successors, rewarded for their efforts by public recognition and good press. • E ngagement of prominent public figures and celebrities in research advocacy. Recent examples include Elizabeth Taylor in HIV/AIDS research and Michael J. Fox in Parkinson’s disease research. • N IH’s skillful use of the news and information media. A principal touch point with advocates and the news media has been NIH’s insistence on the integrity of the research funding process, which employs peer review to award federal funding to leading scientific researchers. • F inally, NIH responsiveness to emerging groups and movements. For example, when it became clear there was strong interest among Americans and important members of Congress in complementary and alternative medicine, NIH launched a small investigational program that now has grown to a Center with almost $1.3 billion in the President’s fiscal year 2012 budget request. Despite (or perhaps because of) these impressive efforts, expecta- tions of how quickly biomedical science can “solve” major health issues have been unrealistic. In 1965, when President Lyndon Johnson launched the quest for a fully implantable artificial heart (which he wanted to have signed, sealed, and delivered by Valentine’s Day, 1970), he said 2 For whom were named, respectively, the Lister Hill National Center for Biomedical Communications (est. 1968), an intramural research division of the National Library of Medicine, and the John E. Fogarty International Center for Advanced Study in the Health Sciences (est. 1968), at the NIH.

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78 PUBLIC ENGAGEMENT AND CLINICAL TRIALS what he wanted was results, not research, Brown noted. Other bumps in the road have appeared as well: ongoing disputes about the rela- tive balance between basic and applied research, the best management and organization of NIH, the famous battle over an independent cancer institute, and the relationship between burden of disease and priorities for research funding. Nevertheless, over the years, the nation’s federally funded research establishment has weathered such political challenges successfully. Are these precedents transferable, translatable, and adaptable to new challenges? Clearly, the clinical trials enterprise faces some different, more complicated problems than does basic research, which, Brown remarked, is in some ways the easy case. For basic research, Congress appropriates money, the money goes to NIH, and it is allocated to leading research scientists who carry out studies in their laboratories. Research results are the ends of this process, and research is the clearly understood means to those ends. The importance of clinical studies is somewhat more difficult to communicate; it is harder to explain their rationale, legitimate their activities, and justify spending money on them. Reasons for this difficulty include the culture of academic medical centers, which are more attuned to basic research than to clinical trials and less inclined to reward those who commit the enormous amounts of time and labor that trials require. Other reasons involve the challenges of site selection and management and the need for identification of local cham- pions who will be effective politically, organizationally, and scientifically. But one of the biggest difficulties is recruiting and retaining people in tri - als, and whether the supply of participants is, or can be made, adequate to the demands of the increasing number of complex trials. Challenges for Consumer Organizations Brown put forth a number of factors that contribute to this recruit- ment and retention problem, including when people • istrust the research enterprise, out of a generalized concern that d researchers (or research sponsors) do not have patients’ best inter- ests at heart; • ear that if they participate in a trial, something bad might happen f to them, or they will not obtain beneficial treatment because they are in the wrong arm of the trial; • elieve it is advantageous, or at least not harmful, to wait and b obtain the benefit of new treatments without going through the inconvenience of trial participation (free-rider problems); • ack information about trials for which they might be eligible; l

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79 TOWARD A PATIENT-CENTERED STRATEGY • ave clinicians who do not know about relevant trials or do not h encourage (or even discourage) their patients’ participation; • ill incur costs for the treatments that insurance may not cover; w • re daunted by the complexity of enrollment and continued com- a pliance and participation; • xperience burnout, fatigue, or boredom with the trial; e • ack either general literacy (including non-native speakers of Eng- l lish) or health literacy (affecting foreign-born and native speakers alike); and • ome from cultures within the United States that might be impor- c tant to a trial for diversity reasons, but that have either no tradition of trial participation, or a negative experience with trials (see, e.g., Washington, 2006). These dilemmas have no single response, and there is no obvious formula for moving forward in resolving them, Brown said. What may be needed is a concerted effort by a range of organizations acting as net - works with carefully coordinated strategies to raise the prominence and secure the legitimacy of the clinical trials enterprise. Following the suc - cessful example of patient organizations, such as those for CF, Alzheim - er’s disease, and breast cancer, these crucial groups need to take on the challenge of forging links with medical specialty associations, academic medical centers, community physicians, and other relevant community organizations and leaders. This will help them present a united front of support for research to their patient and family constituents. At the same time, consumer-oriented organizations must cultivate congressional and state-level champions. Attention at the state level is crucial, since roughly half the states mandate at least some insurance coverage for the cost of “routine care” received in clinical trials. 3 Such state-level opportunities should not be overlooked in a narrow focus on the federal government. Finally, consumers and researchers must ally and make a clear case for clinical trials with the news and information media. It is a formidable translational challenge, Brown said, but one that might draw on the NIH political playbook. 3 The Patient Protection and Affordable Care Act enacted in March 2010 requires health insurers to pay the cost of routine care delivered in phase I-IV clinical trials. The require- ment will take effect in 2014 and will offer a baseline of insurance coverage for clinical trial participants in all 50 states and the District of Columbia (NCI, 2010).

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80 PUBLIC ENGAGEMENT AND CLINICAL TRIALS Challenges for the Research Community Clearly, clinical trials need a large number of effective champions. More and more strategic coordination among important organizations and the application of their collective leverage would support public- sector research efforts at the federal and state levels and foster robust public-private partnerships. Brown offered some cautions. Because of the extraordinary demands of clinical trials, researchers must resist the temptation to overload trial protocols with multiple questions, variables, and population groups. If there are opportunities to use other kinds of research, including obser- vational research, that will answer a research question just as well, those alternatives should be sought so as not to drive the clinical trials enter- prise into the ground. Trials should be saved for when they truly offer a comparative advantage. Given that the promotion of clinical trials is highly labor-, time-, and capital-intensive, is it worth the effort? Or a lost cause? A very good case, he said, can be made that it is indeed worth the effort, perhaps now more than ever. In the nearly 7 decades since World War II, which encompass the major expansion of NIH, the United States has energetically pursued the technological imperative—striving to conquer numerous diseases—and has fairly consistently accepted the notion that “more is better.” Remark - able results have accrued, except in the realm of health care costs. This nation now spends more than 17 percent of its gross domestic product on health care. With the country in the midst of an economic crisis, the implications of this current rate of health spending are disconcerting. Economists increasingly talk about the unsustainability of Medicare, Med- icaid, and private health care spending, and Congress is at loggerheads over the way forward. In all domains of health care, cost concerns make this a serious and difficult time. Research simply must figure out which treatments work (and work better) and which do not, and for whom. The country no longer has the luxury of assuming that more is truly better or taking a cavalier attitude toward evaluation, Brown said. That imperative is not solely because of cost containment, although reining in costs is a strong driver. It is also motivated by questions of quality. Increasingly, surveys show Americans realize that more health care does not necessarily mean better health. They recognize there are negative health consequences of overuse and over- exposure to the system, that treatments have risks, medical errors occur alarmingly frequently, and imperfectly understood drugs may interact in dangerous ways or cause negative side effects.

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81 TOWARD A PATIENT-CENTERED STRATEGY People—often armed with Internet search results—increasingly ask their doctors for evidence. “You’re recommending this treatment; what is the evidence it works and that it will work for me? Compared to what?” What these trends imply is that, in the overall portfolio of NIH and other research funders, both public and private, it only makes sense to expand investments in evaluative clinical studies that can answer such questions. Concluding Remarks In his concluding observations, Brown remarked that the nation has not moved faster in solving problems with clinical trials for a number of reasons, including, perhaps, because “clinical trials are means to the means to the end—that is, cures and solving medical problems.” Meanwhile, many more immediate items crowd the agendas of patient groups, payers, academic medical centers, NIH, and others. Clinical trials simply have not risen high enough to motivate the investment of political and budgetary capital that would bring the supply of resources for trials into line with the growing demand for trial results. It takes time and effort to elevate an issue on any organization’s agenda. It involves tradeoffs, he said, and it requires an organizational decision to expend the political capital, use the leverage, and deploy scarce human and monetary resources. In the strategic portfolios that reflect the roles and missions of the key organizations to which NIH and other policy makers respond, it is simple common sense to raise the priority of clinical trials—to find out “what works” in health care. In the last analysis, the choices we make about clinical trials speak to how we as a society are willing to expend our political capital and what we really care about, Brown said. CLOSING PANEL4 The workshop’s final panel began with an overarching note by Jeffrey Drazen, New England Journal of Medicine, that this workshop was concerned with how to enhance the process for developing and testing clinical inter- vention strategies. Human capital is needed in order to translate ideas about strategy into treatments that can actually be used in clinical practice. New treatments may be readily integrated into clinical care, or they may require a reengineering of the whole process of care delivery, or they may land any- where between these two poles. 4 Participants in the summary panel were Jeffrey Drazen, Editor-in-Chief, New England Journal of Medicine; Juan Lertora, Director, Clinical Pharmacology, NIH Clinical Center; Greg Simon, Senior Vice President, Patient Engagement, Pfizer Inc.; and Nancy Sung, Senior Program Officer, Burroughs Wellcome Fund.

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82 PUBLIC ENGAGEMENT AND CLINICAL TRIALS There is a fundamental misunderstanding of what constitutes scien- tific objectivity, said Greg Simon, Pfizer, Inc., that began when the inves- tigator—“the man in the white coat”—was deemed the most important person in the room, that is, the objective observer. Unfortunately, there is no such thing. Objectivity is a social phenomenon. Bringing the patient experience into research as a valued component is not “an act of charity,” Simon said, it actually improves the social objectivity of the research. When patients are constantly an afterthought, researchers miss the substantial contribution that patients could make. As one example, involving patients would mean that the mind-body relation- ship, which is responsible for much of the confounding nature of placebos (a rock on which many costly trials have foundered), finally would have to be unraveled. Additional principles of public engagement in clinical trials discussed during the workshop are listed in Box 9-1. The “learn-and-confirm” paradigm used in clinical trials—learning in the early stages and confirming in the later ones—could be aptly applied to the history of clinical trials itself, said Juan Lertora, NIH Clinical Cen - ter. At present, the research enterprise probably does not learn enough from trials that have failed. Was failure caused by questions posed incor- rectly? he asked. Was implementation flawed? Did it result from lack of communication with and engagement of the community? Or, from the need for more financial or logistical help from the sponsor? Researchers can learn from failures as well as successes, said Lertora. Experiences such as those of 23andMe and the other consumer- oriented websites described at the workshop suggest the depth of public interest in participating in clinical trials. Use of a web interface to pro- vide registrants with instant feedback on survey questions is in strik- ing contrast to the lack of information that participants in conventional trials—and their physicians—receive, according to Nancy Sung, Senior Program Officer, Burroughs Wellcome Fund. It helps explain why these customer-oriented sites have achieved the continued participation and active engagement of so many of their registrants. Working to ensure patient satisfaction for those participating in clinical trials is an indepen - dent goal that could also improve patient recruitment and retention. People may be more willing to participate in trials when they see individuals who they believe will understand their culture and concerns. A long-term strategy to increase participation of minorities in clinical trials, said Sung, would be to continue efforts to increase preparation of underrepresented groups to be faculty and investigators. Meanwhile, many patient groups have established research founda- tions that support targeted clinical research and encourage participation

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83 TOWARD A PATIENT-CENTERED STRATEGY BOX 9-1a Principles of Public Engagement Discussed During the Workshop • Even a relatively small patient group can ally itself with strong and visible partners. The CF community in the United States is small—only about 30,000 patients—but has teamed up with more than 110 clinical centers around the country to encourage CF research. These relationships also give the disease—and the people affected—greater visibility, attention, and influence. • Highly visible events, such as the Alzheimer’s Association’s national Walk to End Alzheimer’s, raises awareness of Alzheimer’s disease (as well as funds) among large numbers of the public. • Increasingly, websites offer numerous ways for families and volunteers not just to passively learn about health conditions, but also to actively participate in research. • Voluntary health organizations can work with a resource people trust—their doctors—who can act as information conduits and legitimate participation in trials and other disease advocacy activities. • Multicenter clinical research projects find that different trial sites enroll pa- tients at markedly different rates, indicating that concerted efforts to reach out to the community and to persuade referring doctors to enroll their pa- tients in a trial could make a difference. • It is important that researchers be clear with both patients and doctors about the state of the science and the purpose of the trial, bearing in mind the vast differences in health and science literacy that impede effective communication. • A more effective communication will present trial information within the framework of the patient’s motivation to participate in research, not in terms of the researcher’s goals. • It takes time and energy to gain community input and forge communication links. • Partnership with community representatives in the trial planning permits addressing of the issues they want to know more about and helps ensure the community will benefit from the research effort. a Based on workshop panel discussions and presentations. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not neces- sarily endorsed or verified by the Forum or the National Academies, and they should not be construed as reflecting any group consensus.

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84 PUBLIC ENGAGEMENT AND CLINICAL TRIALS in it. The Health Research Alliance (HRA) is a consortium of nearly 50 nonprofit, nongovernmental funders of biomedical research and includes numerous patient groups.5 5 The HRA fosters open communication and collaboration among its members; provides data and analysis about the funding of biomedical research and training by HRA member organizations; identifies gaps in funding and facilitates innovative grant making; and ad - dresses key issues in accelerating research discovery and its translation. For more informa - tion, see http://www.healthra.org/pdfs/HRA_fact_sheet_6_17_2011.pdf (accessed October 10, 2011).