Appendix D
Background Papers

APPENDIX D1. PORT RESEARCH COMPARED WITH CLINICAL RESEARCH: CONFLICTS OF INTEREST IN PATIENT OUTCOMES RESEARCH

David Asch, M.D.1

Introduction

Several forces in the last two decades have worked to increase the collaboration of industry, government, and academic biomedical research centers.1 First is the increasing scope and expense of medical research programs. Second is the threat of a simultaneous contraction of federal research support for these projects. Third is the competitive pressure to facilitate efficient translation of the products of academic research into marketable goods and services. The resulting growth of different collaborative agreements among universities, industries, and government-supported researchers has highlighted concerns about the kinds of conflicts of interest that can result from these complex arrangements.

An enlarging literature addresses these concerns. It is a given that even the most conscientious investigators cannot eliminate the subtlest biases that affect their work. But when researchers receive support from the companies that produce the products or services they are investigating, when they enter into consulting arrangements with them, or when they share in the ownership of these products, their commitment to upholding professional norms may be or appear compromised. Such personal economic interests increase the likelihood that researchers will lose their

1  

Dr. Asch is Assistant Professor of Medicine at the University of Pennsylvania.



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Patient Outcomes Research Teams: Managing Conflict of Interest Appendix D Background Papers APPENDIX D1. PORT RESEARCH COMPARED WITH CLINICAL RESEARCH: CONFLICTS OF INTEREST IN PATIENT OUTCOMES RESEARCH David Asch, M.D.1 Introduction Several forces in the last two decades have worked to increase the collaboration of industry, government, and academic biomedical research centers.1 First is the increasing scope and expense of medical research programs. Second is the threat of a simultaneous contraction of federal research support for these projects. Third is the competitive pressure to facilitate efficient translation of the products of academic research into marketable goods and services. The resulting growth of different collaborative agreements among universities, industries, and government-supported researchers has highlighted concerns about the kinds of conflicts of interest that can result from these complex arrangements. An enlarging literature addresses these concerns. It is a given that even the most conscientious investigators cannot eliminate the subtlest biases that affect their work. But when researchers receive support from the companies that produce the products or services they are investigating, when they enter into consulting arrangements with them, or when they share in the ownership of these products, their commitment to upholding professional norms may be or appear compromised. Such personal economic interests increase the likelihood that researchers will lose their 1   Dr. Asch is Assistant Professor of Medicine at the University of Pennsylvania.

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Patient Outcomes Research Teams: Managing Conflict of Interest objectivity—consciously or unconsciously—and so widen the opportunities for misleading research results. And even when objectivity is preserved, the public recognition of such potential conflicts of interest may erode confidence in biomedical research.2 The substance of these concerns is illustrated in the recent controversy surrounding several investigators who conducted research supporting the wide indications for an ophthalmic ointment while owning large amounts of the manufacturer's stock.3, 4, 5 Later research by different investigators challenged the original findings.6, 7 Attempts to address these problems have recognized the need to balance the potential for misguided research with the legitimate social goals underlying economic incentives. The many advantages to these economic incentives have been extensively discussed elsewhere. Links between investigators and for-profit concerns create efficiencies not only in the conduct of research, but also in the commercialization and distribution of the products of research. In part because of this continuum between efficiency and conflict, conflict of interest in this setting has defied simple definition.8 There is, nevertheless, widespread consensus that conflicts of interest by any definition need attention from within the biomedical research community. The past few years have seen statements by federal funding agencies,9 universities,10 scientific journals,11 professional organizations,8 , 12 , 13, 14 and individual research teams.15 None of these statements, however, distinguishes among various types of biomedical research or among the differences in research goals or methods that may encourage or deter conflicts of interest for investigators. One relatively new form of medical research uses somewhat nontraditional research methods to compare and evaluate the effectiveness of different medical practices in achieving desired patient outcomes. These projects are supported by the Agency for Health Care Policy and Research (formerly the National Center for Health Services Research) under their Medical Treatment Effectiveness Program. Research is conducted by multidisciplinary Patient Outcomes Research Teams (PORTs) using novel methodologies that span a wide area of expertise. The methodologies employed by PORTs are novel enough, and the intensity of their projects are deep enough, to raise concerns that the existing guidelines on conflicts of interest need to be expanded. This paper introduces principles of outcomes research and examines ways in which members of PORTs may be at risk for conflicts of interest different from those faced by more traditional clinical researchers.

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Patient Outcomes Research Teams: Managing Conflict of Interest Patient Outcomes Research Teams The goal of PORTs is to foster effective medical approaches to specific clinical problems. They seek to achieve this goal by evaluating and comparing the outcomes of existing variations in medical practice, and disseminating that information in the form of practice guidelines. The principle underlying outcomes research is that medical practices—for example the use of particular surgical techniques or diagnostic tests—ought to be subject to the same standards of safety and efficacy as are pharmaceutical agents. The measured outcomes themselves ought to be robust enough to include most of the parameters patients typically value: survival, health status, functional capacity, and quality of life. Medical practices will be more effectively and appropriately utilized if their existing variation is perceived as an observational forum for natural selection. Through the Medical Treatment Effectiveness Program those practices that achieve expressed goals will be identified and will continue, while those that fail to achieve these goals will fall into disuse. The hope is that medical practices will evolve in the right direction with this kind of cherry-picking. These natural evolutionary forces may substitute for the expensive, time consuming, and cumbersome randomized clinical trials that have been the traditional way to evaluate alternative treatment strategies.19 Each PORT focuses on a specific clinical problem, for example benign prostatic hyperplasia or gallstones, with the aim of evaluating the medical alternatives to this problem and identifying those that best achieve desired patient goals. While each PORT may be narrowly focused on only one clinical problem, it approaches that problem in an extremely comprehensive way. This depth requires that PORT research be divided into a sequence of interrelated subtasks. The model for PORT research is to: (1) review and synthesize existing published evidence regarding treatment alternatives in order to identify current practices and controversies, to obtain first estimates for decision outcomes, and to identify gaps in the scientific knowledge base; (2) analyze insurance claims databases to estimate the probabilities of relevant outcomes, for example mortality, reoperation, and other complications; (3) interview patients and practitioners to obtain primary data regarding preferences, decision making, and outcome measures not available from insurance databases; (4) develop decision analytic models to provide a rational framework for understanding the tradeoffs in probability and outcome involved in the examined treatment alternatives, and to help explain observed variations in medical practices; (5) formulate practice guidelines based on the findings in the earlier steps; (6) disseminate these guidelines, and examine their effects on service utilization and appropriateness, practice variation, and patient outcome.

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Patient Outcomes Research Teams: Managing Conflict of Interest The diversity of these subtasks requires that PORTs be complex multidisciplinary teams with expertise in epidemiology and biostatistics, clinical decision and utility analysis, claims data analysis, psychometrics and survey research, medical education, and the relevant clinical disciplines. While these teams may focus narrowly on a single clinical problem, they approach those problems with great depth. Although PORTs are designed to evaluate existing alternatives in the management of common clinical syndromes, they serve a related goal of linking medical management decisions with specific patient outcomes. Patient preferences for these outcomes are diverse. The better able physicians are to predict the various outcomes of treatment alternatives, the better equipped they will be to tailor their medical management to the individual goals and risk preferences of their patients. Because the personal goals of many patients may be best achieved by medical strategies of ''watchful waiting,''20 resource utilization and the intensity of medical service delivery may actually decrease as physicians learn to better tailor their decisions to reflect patient preferences. On a case by case basis, outcomes research helps not only to define the best treatment alternatives, but also to define how much is too much. The emphasis that PORTs have placed on individual patient preferences has important societal consequences. Evidence from the studies of benign prostatic hyperplasia suggest that the individual interests of many patients may be best served by less costly medical strategies. 20 It is certainly no coincidence that the opportunity to articulate convincingly that less may be better arrives in the setting of deafening societal cries for reduced health care expenditures. At the same time, the emphasis PORTs place on individual patient preferences, on the understanding of practice variation, and on the development and dissemination of practice guidelines, dovetails neatly with rising patient consumerism, the perception of health care as a commodity, and the recognition of the health care system within an industrial model. Patients and payers have become more influential stakeholders in the medical enterprise, and PORTs evaluate medical treatment alternatives in a format that is particularly well adapted to the interests of those stakeholders. Understanding the effects of power shifts among stakeholders may help us predict the different kinds of conflicts of interest to which PORTs may become susceptible. Conflicts of Interest in Patient Outcomes Research Teams Like the outcome research supported by PORTs, randomized clinical trials also are designed to compare and evaluate treatment alternatives

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Patient Outcomes Research Teams: Managing Conflict of Interest according to predetermined outcome measures. While the outcomes evaluated in clinical trials may be more narrowly defined—survival alone, for example—there is nothing intrinsically different between the goals of the Medical Treatment Effectiveness Program, and the goals of more traditional randomized clinical trials. PORTs rely on insurance claims data systems for their analyses, and so must focus their efforts on existing medical products and services. Only these treatment alternatives have the track record necessary for the kinds of analyses that PORTs do. Prospective clinical trials are not limited in the same way. Aside from this difference in potential subjects for study, however, PORTs and more traditional investigators involved in clinical trials differ only in their methods. By and large they share common goals. PORTs are likely to find themselves susceptible to qualitatively the same kinds of conflicts of interest as more traditional investigators. Opportunity and Motive Vulnerability to conflicts of interest is a story of opportunity and motive. Although investigators' personal interests may conflict with their professional responsibilities, they will not really be at risk for betraying those trusts if they have no opportunity for infecting their research with bias. Investigators engaged in clinical research can be influenced, consciously or unconsciously, in their research design, in their interpretation of findings, and in the timing and forum they choose to report their results.11 Peer review does much to reduce these opportunities for bias, but does not eliminate them. Moreover, the peer review system requires that investigators act responsibly in revealing all aspects of their study design so that referees can knowledgeably review the findings. There are abundant opportunities for conflicts of interest in traditional clinical research. PORTs also are vulnerable to infecting their methods, consciously or not, with interests that conflict with professional research goals. Some might argue that compared with investigators involved in randomized clinical trials, PORTs are less vulnerable because they rely so heavily on secondary data sources that are, by and large, out of their control. Insurance claims data, for example, exist already on computer tapes waiting to be analyzed.21 But within the complex research design and multiple subtasks necessary for outcome research are many areas of vulnerability. The techniques of meta-analysis of the existing literature are highly subjective: some published studies (and, in general, most unpublished studies) will be excluded because they fail to meet criteria for rigor established by the investigators. While insurance claims data tapes already

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Patient Outcomes Research Teams: Managing Conflict of Interest exist, the data must be "cleaned" and transformed to make it suitable for the kinds of analyses PORTs do. It may be difficult for publication referees to review these transformations. When primary data must be collected about functional status, for example to assess outcomes with greater resolution than mortality or reoperation rates, biases and subjectivity can as easily be introduced as in any other primary research. The development of practice guidelines, although based on the initial subtasks of outcome research, is highly subject to personal interpretation. These are not necessarily weaknesses of the PORT methodology, but they represent PORTs' vulnerabilities. While PORTs rely heavily on secondary data sources, they do not remain at arm's length from those data. Numerous opportunities exist for conflicts of interest to bias the methodologies of these teams. These opportunities are multiplied by the large numbers of diverse team members required to complete these complex projects. At the same time, pluralistic teams may introduce checks and balances that limit opportunities for bias. PORTs are at least as vulnerable to conflicts of interest as are investigators involved in more traditional clinical research. These vulnerabilities represent the opportunity for personal interests to alter the direction of research so that it satisfies different goals. What might those interests be? Given the opportunity to redirect research findings, what might be the motives? Traditional Conflicts of Interest: Funding, Consulting, and Equity Investigators in PORTs might be subject to the same kinds of conflicting interests as investigators in clinical research. It is not uncommon for investigators involved in clinical research, particularly pharmaceutical research, to have all or part of their research supported by the industries whose products they are evaluating. While outcome research in general is less likely to receive direct funding from industries, industries may understandably look upon PORTs as centers of excellence in their clinical areas and so choose to support related research by members of the team. This is especially likely to occur in PORTs because they are designed to approach narrow clinical problems with depth. Moreover, because of the expense of these large scale research programs, and the incentives to limit unnecessary duplication of research efforts, PORTs may have near research monopolies on their clinical problems. This concentration focuses industry interests on a smaller group. For the same reason, members of PORTs are especially likely to be offered and enter into consulting arrangements with industries that produce related products and services. If PORTs really have their clinical playing fields all

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Patient Outcomes Research Teams: Managing Conflict of Interest to themselves, the absence of competing and confirming research teams will make the potential end results of conflicts less easily or less quickly detected. Nevertheless, there are obvious social advantages to such academic and industry collaboration, because it embodies the kind of information and technology transfer that makes for the efficient commercialization of academic findings. Industries often are able to support such research efforts with products, services, and information that would otherwise be unavailable. Both industry and agency funds, for example, may support the staff that is in effect the machinery of the PORTs. While this overlap represents an efficiency, it highlights the difficulty researchers may have in keeping their interests separate. Conflicts may arise because the findings of PORTs in their outcomes research may have profound effects on the industries that support their other research. PORTs are particularly vulnerable to this kind of conflict because they focus on existing services and, among these, the big ticket items. Besides receiving industry support for related research, and the possibility of having conflictual consulting arrangements, members of PORTs are at risk for conflicts if they have equity interests in related companies. The conflict created when an investigator has a direct financial stake in the results of his research is not fundamentally different between investigators in outcome research and in other kinds of research, but members of PORTs may be particularly susceptible. Like investigators involved in pharmaceutical research, PORTs focus on existing products and services. The end results of their research may have clearer market implications than the results of investigations undertaken at a more basic level. At the same time, industries providing established products and services are more likely to be publicly traded and so offer better defined avenues for exploiting the inside information available to PORTs. Spinoff Ventures and Intellectual Property Rights Although PORTs focus on existing medical practices, there are nevertheless opportunities for entrepreneurialism that may conflict with the goals of academic research or may represent the diversion of federal funds for private gain. One not so surprising finding of the PORT investigating benign prostatic hyperplasia, for example, is that the subjective importance of various symptoms and outcomes varies greatly among patients with prostatism.22 If patients knew more about these outcomes and the probabilities of achieving them, they would be better equipped to make informed choices to reflect their personal preferences and goals. For this reason the PORT is developing an interactive

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Patient Outcomes Research Teams: Managing Conflict of Interest computer video disk to help inform patients of various options and outcomes. The video disk can be perceived as a diagnostic test to determine true patient preferences.16 Such video disks have obvious commercial potential, not only for prostatism, but also for innumerable other common conditions for which patients and practitioners want educational tools. Although the commercial development of such products will serve many social goals, members of PORTs will be uniquely positioned to benefit from these commercial applications because they have investigated precisely those issues necessary for such educational tools. Moreover, their primary data collection on patient preferences for outcomes can be seen as an extensive predevelopment marketing survey that will convey additional advantages in bringing such a product to its commercial potential. Small publication delays will enhance these competitive advantages. PORTs with different kinds of expertise might be able to commercialize other talents as well. Insurance companies are potentially hungry audiences for information about the appropriateness of various medical practices in different clinical situations, and members of PORTs may be particularly qualified to provide this information. Sideline consulting firms with competitive advantages sustained by PORT research represent, in part, the harnessing of the federally funded PORT machinery for private gain. Even though PORTs are not specifically involved in new product development, they are nevertheless vulnerable to conflicts of intellectual property rights. Changing Stakeholders Investigators in any kind of research are vulnerable to conflicts that arise because of funding or consulting arrangements with industry, owning equity in evaluated products, or participating in spinoff ventures. PORTs and their members may be vulnerable, in addition, to pressures from stakeholders typically unrepresented in more traditional research. Because PORTs may be perceived as influential evaluators of existing medical practices, for example, they represent a potential challenge to the providers of those services. Such perceptions may play out in different ways. The fundamental justification for the PORT methodologies is to hasten and improve the evaluation of medical practices. Practitioners heavily invested in existing technologies may feel vulnerable when those practices come under evaluation.23 PORTs rely on such practitioners in their primary data collection about preferences for risks and outcomes. In 1986, 32 percent of urologists' Medicare revenue came from transurethral prostate

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Patient Outcomes Research Teams: Managing Conflict of Interest resections.24 Can a practicing urologist, who might receive most of his income from transurethral prostate resections, objectively contribute to a study that may suggest that this procedure does not yield the most desired outcomes?25 By the nature of research priorities, PORTs focus on the "cash cows" of clinical services, and physicians may feel that these practices are on trial. It is not only individual physicians who may introduce these conflicts. While investigators in more traditional clinical trials may develop conflicts through the participation of industry collaborators, PORTs may develop conflicts because of the participation of professional societies. These societies may offer consulting arrangements to PORTs or support them in related research to confirm or refute findings or test new technologies that might increase the portfolio of skills that their members share.26 PORTs may be especially vulnerable to such arrangements because of their relative exposure on their clinical playing fields and the influence they therefore may carry. It is unusual to be concerned about the direct effects of conflicts introduced by clinician stakeholders or their professional societies. Health insurers are another group of stakeholders likely to be drawn to outcome research. Practice guidelines represent one promising arm in a general strategy to reduce health care costs. The ability to compare the health outcomes of high intensity and low intensity geographic areas introduces the appealing possibility that cost and quality may not always be in conflict. While there are already societal pressures on PORTs to support findings of this sort, insurance companies may intensify these pressures, as well as bring them within arm's length. Like other industries, insurance companies may introduce conflicts through consulting arrangements, or by funding related research. Even without these arrangements, however, PORTs must collaborate with insurers for access to claims data. Even the nonprofit insurance systems cannot be perceived as disinterested in the findings. These potential conflicts are not fundamentally new, but they are pressures from stakeholders not generally represented in more traditional clinical research. Conclusions: What's Different about Outcomes Research? If there is really something that distinguishes outcome research from more traditional types of clinical research it is that it was born in a period when power in the medical enterprise was shifting among the various interest groups. PORTs have available to them powerful tools for evaluating the medical profession from the outside. For this reason, they are well positioned to meet the awakening interests of patients and payers,

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Patient Outcomes Research Teams: Managing Conflict of Interest and they also pose a substantial potential threat to the autonomy of existing practitioners and the integrity of the medical profession. 27 It is difficult to speculate how influential PORTs may become, but their emphasis on evaluation and the development of practice guidelines is consistent with broad trends in health care. Through their efforts, PORTs may facilitate access to information about medical treatment decisionmaking and so increase the chance that market forces of supply and demand— rather than medical professionalism—will determine the efficient delivery of health care. These are distant goals, but the direction is clear and the first steps are taken. Because the PORT methodology is so well adapted to these social agendas, members of PORTs are vulnerable to the conflicts of interest introduced by those interested in cost containment. At the same time, members of PORTs are likely to feel reactive pressures from clinicians and professional societies struggling to defend their professional and monetary interests from previously silent stakeholders. These are pressures investigators involved in more traditional clinical research are not likely to feel. The products of outcome research are of concern to more interest groups than are the products of more traditional clinical research. But is outcome research sufficiently different that separate guidelines need to be constructed to prevent the socially undesirable consequences of industry links? The stakes may be higher, and there may be a few extra players, but the object of the game is fundamentally the same. Separate guidelines constructed for different types of medical research establish multiple standards. If certain collaborative arrangements are tolerated in clinical research but not in outcome research, which standard is right? The tendency to gravitate toward the strictest standards can de facto impede future social progress. Complex interrelationships among governmental, academic, and industrial institutions create opportunities for social progress while creating opportunities for potentially destructive conflicts of interest. Restrictive guidelines that eliminate the possibility of conflict will also eliminate opportunities for the efficient translation of research findings into marketable goods and services. The best institutional guidelines will not eliminate industry collaboration, but will help investigators navigate toward its socially desirable products and away from its socially undesirable products. Those who write guidelines must fight the urge to increase restrictions and instead work for specificity in their applications. What is needed is clarity, not increased strigency.

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Patient Outcomes Research Teams: Managing Conflict of Interest References 1. Hanna KE. Collaborative research in biomedicine: resolving conflicts. In: Institute of Medicine. Government and Industry Collaboration in Biomedical Research and Education. Washington: National Academy Press. 1989. 2. Relman AS. Economic incentives in clinical investigation. New Eng J Med 1989;320:933–4. 3. Booth W. Conflict of interest eyed at Harvard. Science 1988;242:1497–9. 4. Lichter PR. Biomedical research, conflict of interest, and the public trust. Ophthalmology 1989;96:575–8. 5. Tseng SCG, Maumenee AE, Stark WJ, Maumenee IH, Jensen AD, Green WR , Kenyon KR. Topical retinoid treatment for various dry-eye disorders. Ophthalmology 1985;92:717–27. 6. Soong HK, Martin NF, Wagoner MD, et al. Topical retinoid therapy for squamous metaplasia of various ocular surface disorders: a multicenter, placebo-controlled double-masked study. Ophthalmology 1988;95:1442–6. 7. Gilbard JP, Huang AJW, Belldegrun R, Lee JS, Rossi SR, Gray KL. Open-label crossover study of vitamin A ointment as a treatment for keratoconjunctivitis sicca. Ophthalmology 1989;96:244–6. 8. Council on Scientific Affairs and Council on Ethical and Judicial Affairs. Conflicts of interest in medical center/industry research relationships. JAMA 1990;263:2790–3. 9. U.S. Department of Health and Human Services. Request for comment on proposed guidelines for policies on conflict of interest. NIH Guide for Grants and Contracts 1989;18(32):1–5. 10. Harvard University Faculty of Medicine. Policy on Conflicts of Interest and Commitment. March 22, 1990. 11. Relman AS. Dealing with conflicts of interest. N Engl J Med 1984;310:1182–3. 12. American Thoracic Society. The potential for conflict of interest of members of the American Thoracic Society. Am Rev Respir Dis 1988;137:489–90. 13. Association of Academic Health Centers Task Force on Science Policy. Conflicts of Interest in Academic Health Centers. 1990. 14. Association of American Medical Colleges. Guidelines For Dealing With Faculty Conflicts of Commitment and Conflicts of Research. February 22, 1990. 15. Healy B, Campeau L, Gray R, et al. Conflict of interest guidelines for a multicenter clinical trial of treatment after coronary-artery bypass-graft surgery. N Engl J Med 1989;320:949–51. 16. Wennberg JE, Mulley AG, Hanley D, et al. An assessment of prostatectomy for benign urinary tract obstruction. JAMA 1988;259:3027–30. 17. Stewart AL, Hays RD, Ware JE. The MOS short-form general health survey. Reliability and validity in a patient population. Med Care 1988;26:724–35. 18. Stewart AL, Greenfield S, Hays RD, Well K, Rogers WH, Berry SD, McGlynn EA, Ware JE. Functional status and well-being of patients with chronic conditions: results from the medical outcomes study. JAMA 1989;262:907–13. 19. Greenfield S. The state of outcome research: are we on target? N Engl J Med 1989;320:1142–3. 20. Barry MJ, Mulley AG, Fowler FJ, Wennberg JW. Watchful waiting vs immediate transurethral resection for symptomatic prostatism: the importance of patients' preferences. JAMA 1988;259:3010–17. 21. Wennberg JE, Roos N, Sola L, Schori A, Jaffe R. Use of claims data systems to evaluate health care outcomes: mortality and reoperation following prostatectomy. JAMA 1987;257:933–6. 22. Fowler FJ, Wennberg JE, Timothy RP, Barry MJ, Mulley AG, Hanley D. Symptom status and quality of life following prostatectomy. JAMA 1988;259:3018–22.

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Patient Outcomes Research Teams: Managing Conflict of Interest mittee on Human Resources and Intergovernmental Operations, 101st Congress, 1st Session June 13, 1989. 4. "On Preventing Conflicts of Interest In Government-Sponsored Research at Universities: A Joint Statement of The Council of the American Association of University Professors and The American Council on Education," American Council on Education, December 1964. 5. See, e.g., D. Blumenthal, M. Gluck, K.S. Louis, M.A. Stoto, and D. Wise, "University-Industry Research Relationships in Biotechnology: Implications for the University," Science, Vol. 232, 13 June 1986, pp. 1361–1366. 6. The Patents and Trademark Amendments of 1980, Pub. L. 96–517, 94 Stat. 3019 et seq. and Government Research and Development Patent Policy, Pub. L. 98–620, Title V, November 8, 1984, 98 Stat. 3364 et seq., amending 35 U.S.C. Sections 200–211. 7. Letter to Thomas A. Bartlett, President of the Association of American Universities from Representatives Gore and Fuqua, House Committee on Science and Technology, United States House of Representatives, November 18, 1981, p. 1; quoted in A. Burke, "University Policies on Conflict of Interest and Delay of Publication: Report of the Clearinghouse on University-Industry Relations of the Association of American Universities," Journal of College and University Law, Vol. 12, No. 2, February 1985, p. 178 (hereinafter cited as "Clearinghouse Report"). 8. Clearinghouse Report, p. 178. 9. See A. Bartlett Giamatti, "The University, Industry, and Cooperative Research," Science, Vol. 218, 24 December 1982, pp. 1278–1280. 10. Statement of Policy on Conflicts of Interest, as voted by the President and Fellows of Harvard College, March 1, 1982, and Guidelines for Research Projects Undertaken in Cooperation with Industry, as voted by the President and Fellows of Harvard College, October 3, 1983. 11. See, e.g., Utah Code Ann., Sec. 67-16-1, et seq. (1986 and 1989 Supp.), quoted in Clearinghouse Report, p. 181. 12. See, e.g., "In Re Executive Commission and Ethical Standards Re: Appearance of Rutgers Attorneys," 537 A.2d 713 (N.J. Super. 1988). 13. See, e.g., Agency for International Development Acquisition Regulation, Sec. 752.7020 (March 1985, AIDS Handbook 14), March 21, 1990, pp. 14–140, 14–141). 14. Id. 15. "Medical School Dean Writes to Faculty About Tseng Matter," Harvard University Gazette, November 18, 1988, p. 8. 16. Id. 17. See, e.g., M. Chase, "Mixing Science, Stocks Raises Question of Bias in the Testing of Drugs," Wall Street Journal (January 26, 1989); P.G. Gosselin, "Doubts Grow over Doctor's Flawed Cancer Test," Boston

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Patient Outcomes Research Teams: Managing Conflict of Interest Globe (June 9, 1989); and W.E. Leary, ''Business and Scholarship: A New Ethical Quandry," New York Times (June 12, 1989). 18. "Federal Response to Misconduct in Science: Are Conflicts of Interest Hazardous to Our Health?" Hearings to the House Committee on Government Operations, Subcommittee on Human Resources and Intergovernmental Relations, 100th Congress, 2d Session, September 29, 1988, pp. 56 et seq. (statement of Victor J. Marder, M.D., University of Rochester Medical Center, followed by George Bernier, Dean of University of Pittsburgh Medical School). 19. See, e.g., Rep. Ted Weiss, "Research That the U.S. Government Is Paying For Should Not Be Tainted by Any Possibility of Bias," Chronicle of Higher Education, October 4, 1989. 20. "PHS Grants Policy Statement," U.S. Department of Health and Human Services, DHHS Publication No. (GASH) 82–50,000, January 1, 1987, p. 55. 21. Notice, "Extramural Researchers' Financial Conflicts of Interest," NIH Guide for Grants and Contracts, Vol. 18, No. 2, January 20, 1989, p. 1. 22. See J. Palca, "NIH Grapples With Conflict of Interest," Science , Vol. 245, 7 July 1989, p. 23. 23. "Request for Comment on Proposed Guidelines for Policies on Conflict of Interest," National Institutes of Health and the Alcohol, Drug Abuse and Mental Health Administration, NIH Guide for Grants and Contracts, Vol. 18, No. 32, September 15, 1989. 24. See J. Palca, "NIH Conflict of Interest Guidelines Shot Down," Science, Vol. 247, 12 January 1990, p. 154. 25. Id. 26. E. Marshall, "When Commerce and Academe Collide," Science, Vol. 248, 13 April 1990, 152. 27. See B. Healey, et al., "Conflict Of Interest Guidelines for A Multicenter Clinical Trial of Treatment After Coronary-Artery Bypass--Graft Surgery," The New England Journal of Medicine, Vol. 320, No. 14, April 6, 1989, pp. 949–951. 28. See C. Holden, "Research Group Forswears Financial Ties to Firms Whose Drugs It Tests," Science, Vol. 244, 21 April 1989, p. 282. 29. A.S. Relman, M.D., "Economic Incentives in Clinical Investigation," The New England Journal of Medicine, Vol. 320, No. 14, April 6, 1989, pp. 933–934. 30. "Business and Scholarship: A New Ethical Quandary," New York Times (June 12, 1989). 31. Op. cit., footnote 1, pp. 9–12.

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Patient Outcomes Research Teams: Managing Conflict of Interest 32. "Conflicts of Interest in Academic Health Centers; A Report by the AHC Task Force on Science Policy," Association of Academic Health Centers, 1990, p. 48. 33. Id., p. 50. 34. Op cit., footnote 26, p. 155. 35. Id. 36. Harvard University Faculty of Medicine Policy on Conflicts of Interest and Commitment, March 22, 1990. APPENDIX D4. THE STRUCTURE AND METHODS OF PORTS: SOURCES OF BIAS John Wennberg, M.D.1 I want to thank the Institute of Medicine for hosting this Workshop on Potential Conflicts of Interest in Patient Outcomes Research Teams. Some five years ago, the John A. Hartford Foundation provided our research group with the support to undertake an evaluation of the practice-style related reasons for variations in treatment rates for benign prostatic hypertrophy or BPH, a common condition that affects most men after age 65. We knew from previous research that the rates for one BPH treatment, namely prostate surgery, varied such that in some communities in Maine over 50% of men received a prostatectomy by age 80, while in others the rate was as low as 15%. We undertook a series of research studies to identify the causes of variation, focusing on the discovery and testing of the different treatment theories that might explain the large differences in practice patterns. It is in the evolution of our experience with the evaluation of alternative treatments of BPH we learned one version of the PORT mission. Recognizing that at least some of our concerns over conflict of interest are idiosyncratic to the mission as we have discovered it and that they may seem foreign or remote to those who have different versions in mind—I want to raise them for your consideration, to show how important the interpretation of the mission is to understanding of the potentials for conflict of interest. 1   Dr. Wennberg is Professor of Epidemiology in the Department of Community and Family Medicine, Dartmouth Medical School. He is also principal investigator of the Dartmouth PORT.

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Patient Outcomes Research Teams: Managing Conflict of Interest PORT Mission In my opinion, the PORT mission is to achieve a non-regulatory solution to the failure in the past to undertake the systematic evaluation of all treatment options available to treat a particular condition such as BPH, cataracts, stable angina or a heart attack. The Food and Drug Administration (FDA) has provided a strong regulatory focus for causing new drugs to be evaluated before they reach the medical market. But the FDA evaluation paradigm has been narrowly conceived—restricted in the theories it causes to be evaluated, in the outcomes it considers relevant, and in the pressures it places on the profession and industry to evaluate. The treatment theories actively evaluated involve only drugs versus placebos, even though in most clinical situations the options for treatment are much broader. For example, in the case of stable angina the options include use of surgery (coronary artery bypass), a device (coronary artery angioplasty), diet (low fat diets) and other life-style modifications. The FDA approach is further limited in that it is not concerned with new uses made of drugs once they are on the market. For example, physicians have learned to use certain anti-hypertensive drugs to treat the symptoms of BPH, even though these drugs have not been evaluated for this purpose. The outcomes considered relevant by the FDA are often changes in biochemical or physiologic parameters, and they do not necessarily include those outcomes that are relevant to patients such as relief of pain, improvement in functional status, and avoidance of complications. (For example, they may include improved coronary artery blood flow or improvement in the flow of urine, but not changes in symptoms, the occurrence of side effects or changes in functional status.) The failure to systematically evaluate all treatment theories relevant to a particular condition, to use outcome measures that capture the events that are relevant to patients and to make the results of assessments available to physicians and patients in ways useful in choosing treatment options results in systematic flaws in the scientific and ethical basis for clinical decisionmaking. The flaw in federal science policy that irrationally restricts evaluations is not likely to be repaired, however, by extending regulatory mandates. I say this not simply to echo a disfavorable attitude toward regulation, but for structural reasons. The required focus is on the evaluation of all relevant treatment theories. Much of medical theory emerges from the exigencies of clinical problem solving, as part of the ongoing practice of medicine. For example, much of surgical innovation is really a modification of traditional treatment strategies which do not involve novel equipment or new drugs that could be easily withheld from practice until evaluations have been made.

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Patient Outcomes Research Teams: Managing Conflict of Interest Some of the most expensive ''medical theories" emerge in the building of hospitals or other facilities. One of the major theories of interest to outcome research is whether the availability of hospital beds at the rate of 4.5 beds per 1,000 produces better outcomes to the population served than availability at a rate of 2.9 per 1,000. The mission of the PORTs, then, is to become the focus for extending the mandate to evaluate to all relevant treatment theories for a particular condition or problem. It must do this without regulatory gate-keeping authority and without the firm (and confining) bases in administrative law that protect its members from corruption through the elaborate client-judge protocols that routinize the relationships of the FDA. PORT members must actively engage in the give and take of the marketplace of ideas. They must become known to and directly engage the originators of ideas and the innovators of new technologies. Ultimately, they must set the rules that cause ideas to be evaluated. I use the phrase "set the rules" in the sense of pointing to the examples for good research based on appropriate methods, identifying the relevant outcomes, establishing processes for evaluating and synthesizing research and reaching conclusions on the status of specific treatment theories. I also use the word "cause to be evaluated" to make clear that the PORT's mission is not to do all of the evaluation itself, but rather to move the profession (and patients) to accept the ethic of evaluation on the basis of good science. PORTs follow a professional, not a regulatory model. I want to give you some examples of what they do based on our own experiences with the evaluation of alternative treatments for BPH, so you may see the nature of some of the interactions between PORTs, physicians and patients as well as industry. I will then turn to consider some features that could lead to conflict of interest or corruption of the process. Experiences of the Dartmouth Assessment Team As I mentioned, the entry into the problem of alternative treatments for BPH was the discovery and follow-up of the variations in rates of prostatectomy among communities in Maine. We met with physicians from high and low rate communities across the state of Maine. Initially, the arguments were between our group and the clinicians; very soon, however, the debate was among the clinicians in Maine, as they began to discuss their opinions on the treatment of BPH. It soon became apparent that the clinicians divided roughly into two camps, one camp subscribing to the preventive theory, the other to the quality of life theory of surgery. Under the preventive theory, surgery early in the course of BPH is called for, because for most people the disease will progress to the point

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Patient Outcomes Research Teams: Managing Conflict of Interest where surgery is required to save patients from the serious complications of bladder or kidney failure. If surgery is delayed, patients will be older and sicker when they require it; overall, life expectancy was thought to be higher if one operates early. Physicians who subscribed to the quality of life theory were much less pessimistic about the natural history of the disease, believing that in most people it does not progress to the point where life is threatened. For most people, surgery is of value because it reduces symptoms and improves the quality of life. The decision to undergo surgery should therefore be based on symptoms, their anticipated relief and the willingness of patients to undergo the risks of surgery in order to secure its benefits. We used Hartford Foundation funds to recruit an international team of urologists, epidemiologists, biostatisticians, decision analysts, social psychologists, sociologists and computer scientists to undertake a series of studies to test these two treatment theories. Putting together information from the medical literature, claims data analysis, interview studies, and decision analysis, we could show that the preventive theory was in error. Using a wide range of possible assumptions, we could find no evidence that people would live longer if patients with BPH were operated upon to prevent subsequent development of bladder or kidney obstruction. As an assessment team, we drew the conclusion that the preventive theory was not a valid reason for early prostatectomy. The data we obtained from an interview study of patients who underwent surgery also showed a "slam bang" effect of the operation on symptoms, with outcome probabilities for symptom relief that were much more favorable than watchful waiting. However, this relief could only be obtained by risking certain complications, the probabilities for which were also documented by our study. Moreover, we could see from the data that there was no strong correspondence between patients' medical histories and their symptoms and the choices individuals would prefer to make between watchful waiting and surgery. We thus came to the further conclusion that rational choice in the decision to undergo a surgical procedure or to watchfully wait depends on patient preferences; these can only become known by actively engaging the patient in the decision process—by asking him what he wants. Values and attitudes are key because they provide the logical, rational reasons for undertaking the surgery. We therefore could conclude that the practice-style reasons for the variations we had observed in Maine derived from an incorrect professional theory about the value of early surgery and from the entanglement of patient preferences for treatments with those of the advice-giving physician. The ethical and the scientific conclusions thus lead in the same direction. The need was to communicate the message of choice to doctors

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Patient Outcomes Research Teams: Managing Conflict of Interest and patients in ways that would help them base choice more firmly on the preferences of patients. I will return to describe how we have handled this dissemination process a little later because the conveying of information that effects individual choice is a focus for conflict of the PORT mission. It was while undertaking the evaluation of surgical outcomes in Maine that we first noted differences in patient survival, depending on which type of prostate operation they underwent. Subsequently, we studied the phenomenon in Denmark, the United Kingdom and Canada, consistently finding an excess mortality in the five years following surgery among patients who underwent the transurethral prostatectomy (TURP), compared to those undergoing the open prostatectomy. A similar excess in mortality appeared when TURP was compared to other operations, such as cholecystectomy or hernia repair. We went back to the medical records, abstracting data on case severity and co-morbidity and were unable to explain the result on the basis of differences among patients. We also found a report in the literature of a small randomized clinical trial of open versus TURP that was consistent with the hypothesis that TURP, somehow, has a deleterious long-term effect on survival. However, neither our group nor consulting urologists could come up with any convincing mechanisms as to how this effect might occur. Left with this uncertainty, we concluded that a large scale randomized clinical trial would be required. The publication of the results of the open versus TURP studies opened a new phase in the development of our assessment team. The result was not a welcomed one for either patients or urologists, who in the United States perform nearly 400,000 TURPs a year. We appreciated an editorial in the Lancet stating that someone had rolled a boulder in the quiet pond of urology. We appreciated it because it did not dismiss the result out-of-hand, but rather called for thoughtful response of the urology community to the challenge. The major breakthrough for the mission of our PORT, however, has been the response of the leadership of American urology, in particular the officers and senior membership of the American Urological Association (AUA). We have been at work now for a year with the AUA, helping in the design of a large scale randomized clinical trial to test the hypothesis of excessive mortality following TURP. As the work has progressed, the focus of the AUA effort has widened to include a focus on new treatment theories as well. When our assessment team began its work four years ago, the field of urology was indeed like a placid pond. Other than surgery and watchful waiting, there were no serious options for the treatment of BPH. Not so today. The last few years have seen a plethora of new BPH treatment theories, some involving balloon dilation of the prostate gland, new drugs, microwave diathermy, and others involving

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Patient Outcomes Research Teams: Managing Conflict of Interest urethral stents and new ways of surgically affecting the prostate gland. Under traditional science policy, these new treatments would enter routine clinical practice without benefit of systematic evaluation. This is no longer the case. The AUA, working with our PORT team, is establishing a network of some 20 centers to undertake the protocol that will bring each of these new treatment theories under active assessment. Our PORT team is providing scientific direction on study design and help in managing the data collection procedures. The recent completion of the planning and grant writing phases and the initiation of a six center pilot study funded by the AUA brings the story to the present. A PORT mission has been defined which includes (1) explicating the causes of practice variations; (2) testing the underlying conflicts in practice theory; (3) establishing relationships with the leadership of the practice community to promote systematic evaluation of new as well as widely used technology; (4) the synthesis and integration of the results of assessments, including estimates of the probabilities for various outcomes; (5) the demarcation of the role of patient values in decisionmaking; and (6) the dissemination of results of the assessments, with a focus on communication about treatment options in a form useful to patients and physicians for clinical decisionmaking. Vulnerability of PORT Mission to Conflict of Interest and Corruption of Purpose Let me now examine the vulnerabilities of this mission to conflict of interest and corruption of purposes. I have noted four areas of concern: economic conflict of interest, ideological corruption, existential corruption, and corruption of discursive practices. Economic Conflict of Interest This is perhaps the easiest to deal with because the problem is well understood and certainly not unique to the PORT. The background reading and the scenarios for discussion at this conference represent this concern well. I do not want to deal with details, but it is worth noting that the mission outlined above requires active relationships between stake holders and the assessment teams. The latter's judgments concerning the relative advantages and disadvantages of a specific stake holders particular treatment theories have obvious economic consequences. PORT teams can expect active interest from industry in their activities and numerous opportunities for consulting fees and honoraria. PORT

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Patient Outcomes Research Teams: Managing Conflict of Interest teams also have the potential for access to insider information on the prospects for profit of technologies which affects their qualification to own stock in the companies they stand to influence. Policies to prevent the appearance and actuality of conflict of interest will be needed. In the case of our own group, we have chosen to forego any honoraria and consulting fees and not to own stock whose value is affected by urologic treatments. Economic interest cut into the mission of the PORT in another way in the case of drugs or devices that have not yet received FDA approval. On more than one occasion, our group has been asked to help in the planning of the evaluation of new drugs, prior to FDA approval. While the rational interests of efficient evaluation are promoted by this involvement (for example, making certain that phase II and III drug trials include evaluations of the probabilities for each of the outcomes that matter to patients), secrecy and exclusivity requirements of the drug industry, designed to protect proprietary interests, have gotten in the way of some collaborations. These barriers not withstanding, we have been gratified by the efforts to cooperate by the drug and the device industries as well as their respect of our interpretation of the PORT mission. We have also been impressed by the willingness of manufacturers to contribute directly to the costs of outcomes research. For example, the balloon manufacturers are contributing resources to the AUA pilot study mentioned above. However, such direct financial dealings between manufacturers and PORTs or its collaborators raises red flags and should be avoided. If we can learn to harness the energies of industry, to help them in their need to have their products developed, the outcomes research agenda can be accelerated. One suggestion is for an institute that can serve as a depository and distributor of industrial (or perhaps third party payor) funds to outcomes research which would avoid the need for a direct relationship between PORTs and their evaluatees. Ideological Corruption PORTs may be susceptible to another kind of conflict, one I have chosen to label "ideological". This is the way I label a tendency to lose objectivity that a member of a PORT may experience if he or she becomes invested in a specific treatment theory rather than in the ethic of evaluation. A temptation we all experience as researchers is to believe that somehow we have gotten hold of the truth, that we know the answer. In our determination, we can loose sight of the role of the PORT which is to manage the process of evaluation. There is probably no specific remedy that guards against this temptation; it comes from ingrained recesses in minds and souls. However, PORTs can protect themselves

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Patient Outcomes Research Teams: Managing Conflict of Interest from its consequences by virtue of the fact that assessment teams are multidisciplinary, that they engage in ongoing dialogue and membership is replaced and refreshed. Existential Corruption The mission we have defined for the PORTs is one that challenges the conventional wisdom and raises intellectual barriers to the influx of new, underevaluated medical theory. This is an inherently conflict-ridden role, one susceptible to what, for want of a better label, I call existential corruption. It is the bad faith that comes from fear of ostracism, of career instability, and other unfortunate outcomes that befall those who are whistle blowers, who challenge optimistic assumptions that all forms of medical technology lead to progress. To understand this problem in one extreme, imagine the possible fates of the evaluative scientist who shows that it is safe and in the public interest to close 700 beds in Boston. We need to worry about how to make it possible to provide stable careers to those who want to work in the evaluative sciences, to permit intellectual freedom to reign as the primary ethic driving the evaluative processes. A good deal of the needed protection may rest in the commitment of the federal government to ongoing funding in the area of the evaluative sciences. This, in turn, works to advance the evaluative sciences into the tenured faculty ranks, to make them and the ethics of evaluation central to the mission of the academic medical center. Corruption of Discursive Practices These are the biases that become introduced in the act of communicating and are the least well understood of all. I first became aware of the problem when we struggled to learn how to disseminate the results of our BPH assessment in a way that could help physicians and patients make decisions that more closely reflected the patient's own preferences for outcomes and attitudes toward risk. You will recall that one conclusion was the need to ask the patient what treatment he wanted, based on a detailed sharing of information about the outcomes of watchful waiting and surgery. We worked out a strategy based on the use of interactive videodisc technology. In developing the program, we encountered a number of problems concerning the adjudication of differences in opinion on the "fairness" of a given representation of a medical decision problem. (By making one version of the communication process "objective", the debate over fairness emerged for the first time; here-to-fore,

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Patient Outcomes Research Teams: Managing Conflict of Interest communication on options had occurred in the black box of the physician's office, unobserved, uncriticized and uncontroversial.) We worked out these conflicts through debate and argumentation, within the context of "focus groups" that sought to narrow the range of disagreement and to arrive at an overall judgment that the presentation was "as fair as it could be." The acceptability of the version we produced has withstood several test in clinical practice where both patients and physicians have found it helpful. I anticipate that other PORTs, as a result of their assessments, will come to similar conclusions concerning clinical practice: for many (probably most) medial conditions, there is no single "correct" or "appropriate" treatment; what is right for one patient—the treatment that best fits his or her preferences for outcomes and risks—is not the same treatment that is right for another patient faced with a similar situation. The PORTs are thus fated, if they follow this mission, to engage patients and physicians in a new discourse, the discourse of shared decisionmaking. The structuring of the institutions that produce and sustain the flow of information, and establish and maintain the rules of discursive practices are perhaps the greatest challenge of all. We are now taking steps to develop a not-for-profit corporation, the Foundation for Informed Medical Decision Making, which we hope can meet the challenge.