6
Points to Consider

When you assemble a number of people to have the advantage of their joint wisdom, you inevitably assemble with those people, all their prejudices, their passions, their errors of opinion, their local interest, and their selfish views. From such an assembly, can a perfect production be expected?

—Benjamin Franklin September 15, 1787, Constitutional Convention

This chapter raises issues regarding the management of conflicts of interest for consideration by PORTs and their sponsoring institutions, the AHCPR, the health services research community, the pharmaceutical and medical devices industry, and Congress. Many of the points noted here are addressed to PORTs and their institutions because the committee believes that the primary role of AHCPR should be to insist that institutions have a method in place for acknowledging, exploring, and managing these potential conflicts. The committee was not charged to develop these points as formal recommendations, nor does it regard them as such, and it recognizes that individual PORTs and AHCPR may generate additional or different mechanisms to achieve the goals described. Box 6.1 provides the framework for discussion that guided these points to consider.

As the committee considered conflicts of interest that may arise from both financial and nonfinancial sources, two conclusions emerged. First, regarding financial relationships, the committee recognizes that AHCPR cannot assume the role of sole supporter of PORTs and PORT investigators. PORTs may need, or even require, other sources of funding, such as industry, insurers, or other public agencies. The manner in which such



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Patient Outcomes Research Teams: Managing Conflict of Interest 6 Points to Consider When you assemble a number of people to have the advantage of their joint wisdom, you inevitably assemble with those people, all their prejudices, their passions, their errors of opinion, their local interest, and their selfish views. From such an assembly, can a perfect production be expected? —Benjamin Franklin September 15, 1787, Constitutional Convention This chapter raises issues regarding the management of conflicts of interest for consideration by PORTs and their sponsoring institutions, the AHCPR, the health services research community, the pharmaceutical and medical devices industry, and Congress. Many of the points noted here are addressed to PORTs and their institutions because the committee believes that the primary role of AHCPR should be to insist that institutions have a method in place for acknowledging, exploring, and managing these potential conflicts. The committee was not charged to develop these points as formal recommendations, nor does it regard them as such, and it recognizes that individual PORTs and AHCPR may generate additional or different mechanisms to achieve the goals described. Box 6.1 provides the framework for discussion that guided these points to consider. As the committee considered conflicts of interest that may arise from both financial and nonfinancial sources, two conclusions emerged. First, regarding financial relationships, the committee recognizes that AHCPR cannot assume the role of sole supporter of PORTs and PORT investigators. PORTs may need, or even require, other sources of funding, such as industry, insurers, or other public agencies. The manner in which such

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Patient Outcomes Research Teams: Managing Conflict of Interest funds are juxtaposed with agency support needs serious consideration in each case and careful management to safeguard the conclusions of the PORTs from the conflicts of interest inherent in accepting such funding. Second, regarding nonfinancial sources of bias, such as those arising from professional training and loyalties and other academic pursuits, PORTs must be diligent in ensuring multidisciplinary representation. They should also actively encourage internal and external examination to recognize and counterbalance any nonfinancial sources of bias. ASSUMPTION One product of scientific research—including the particular form of health services research conducted by PORTs—is inference. Beyond using the best and most powerful scientific means available in their studies, researchers seek to maximize the validity of their inferences by identifying sources of bias and by minimizing the effects of those biases on their findings. The committee recognizes that biases from conflicting interests, whether financial or nonfinancial, are but some of the many sources of bias that should concern researchers. The central purpose of this report is to help PORTs identify the risks posed by conflicts of interest and to suggest measures that will enable them to reduce those risks. The committee believes that PORTs—from a self-interested desire to enhance and maintain their own credibility—will be responsive to suggestions for reducing bias. As a result, the committee has concluded that PORTs should not be constrained by a full set of prescriptions about how they should behave, and the committee advises restraint in the promulgation of rules. Yet investigators need guidance in recognizing a conflict of interest and knowing when to disclose it. The committee also recognizes, that complete reliance on informal mechanisms does not address the fact that the scientific community has not always been adequately self-regulating, especially when the expectation of replicability does not apply. Moreover, on the clinical side, physicians have, until lately, been reticent in bringing forward and examining marked differences in medical practices. PORTs, which combine research with involvement in clinical medicine, need to pay special attention to the appearance as well as the reality of conflict of interest, given the relevance of PORT findings to physician-patient interactions and policymaking and the consequent public scrutiny to which PORT research methods and findings will be exposed. Real or apparent conflicts of interest involving sources of support, other activities of PORT members, and the adequacy of representation of differing viewpoints will be primary targets for critics. Earlier chapters have shown that PORT research is similar to biomedical research or

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Patient Outcomes Research Teams: Managing Conflict of Interest clinical trials. In response to problems in the general scientific community, research institutions as well as research sponsors have begun to insist on more elaborate methods to protect the integrity of research from untoward effects of conflicts of interest. It seems reasonable that PORTs should use these methods and modify them, if necessary, to address unique features of their work. Every effort should be made to avoid separate processes that would be redundant or unduly burdensome for research institutions. At the same time, to the extent PORTs fall into a special, ''quasi-regulatory'' category they may require procedures for monitoring conflicts of interest that are more stringent than those for clinical trials, more like those that apply to officials in a regulatory agency. For example, if exacting rules govern the conduct of persons who approve new drugs, is it appropriate to allow broad latitude to a research process that can have as great an impact on the practice of medicine? Surely, the presence of a possible role in policy making for PORTs would seem to temper sole reliance on the institution for management of conflicts. Both approaches to managing conflict of interest—those based on a view of PORTs as belonging to the paradigm of academic clinical research and those based on a view of PORTs as a quasi-regulatory entity—have considerable merit and will be addressed below as the committee presents considerations for PORTs, their parent institutions, and others concerned with supporting, using, or overseeing outcomes research. CONSIDERATIONS FOR PORTS AND THEIR INSTITUTIONS Attributes of Conflict of Interest Management At this stage in the evolution of PORTs the committee believes it is more important to describe the attributes of a good conflict-of-interest management process than to devise specific rules. Such a process should include the following elements: education about conflicts of interest for researchers, faculty, and students; clearly stated expectations for early and complete disclosure of relevant interests; well-formulated, well-implemented institutional processes for responding to disclosures; and emphasis on the role of the principal investigator in managing conflicts.

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Patient Outcomes Research Teams: Managing Conflict of Interest Education for Researchers, Faculty, and Students PORTs need to elicit information about conflicts of interest and biases and help team members identify high-risk situations. PORT teams have clearly identifiable duties—for example, to report their methods and findings accurately and in a timely manner, to protect the credibility of their research, and to provide access to their data. These duties are comparable to those of investigators engaging in other forms of research, but PORT investigators may need help and resources to assist them in understanding potential areas of conflict that could prevent them from carrying out these duties. The committee assumes professional integrity on the part of PORT investigators; it assumes further that PORT researchers place a high value on independence in the conduct of their work and on maintaining collegiality. When difficult circumstances or potential conflicts are encountered and the PORT is unable to resolve them, it may want to seek the counsel of other PORTs. Under these circumstances, a PORT needs information about how others have acted in similar situations, the kind of assistance they may have received, and the results that were achieved. PORTs might wish to establish a working group on conflicts of interest comparable to those sponsored by MEDTEP to examine methodological problems (see Chapter 2). Faculty and others engaged in PORT research may not be aware of how their arrangements are perceived from outside because it is sometimes difficult for scholars to recognize or acknowledge their own conflicts. Discussing a related issue, Gunsalus and Brown (at the University of Illinois at Urbana-Champaign) caution: The benefits to both the institution and the individual entrepreneur [in regard to the licensing of spin-off technology in public universities] may be so clear to those intimately involved in the decisionmaking process that it may not occur to them that, taken out of context, the decisions might appear to be ill-founded. Reporters see themselves as watch dogs for the public. They are, by nature and by training, skeptics, and they are particularly sensitive to the abuse of the public trust and the misappropriation of public funds. In these cases, the appearance can be just as damaging as the reality. If a story about possible wrongdoing appears on Page One of the local newspaper, a follow-up story months later, setting the context or demonstrating exoneration, cannot undo the damage.

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Patient Outcomes Research Teams: Managing Conflict of Interest It may be difficult for the typical academic scientist, who is equally committed to principles of honesty and openness, to understand what could lead a reporter to question his or her motives in commercializing ideas developed with public funds. Nonetheless, it is prudent to expect motives to be questioned, and to be prepared to explain exactly why the course of action embarked upon is the one that best serves the public interest (Gunsalus and Brown, 1989:5–6). To overcome some of these investigator blind spots, PORTs may require education about the risk of being misperceived, about the obligations of PORT members to avoid giving that impression, and about how to recognize and manage conflicts. Examples of educational strategies are given below. Core course for research fellows. Currently, few university resources are dedicated to communicating professional standards and the ethics of research practice to young scientists (IOM, 1989). One direction for education might be to provide course work in ethics for young investigators. NIH now requires a core course for fellows supported by NIH training grants. Along with covering such topics as laboratory methods, research design, use of human subjects, and cases of scientific fraud, resource material for such a course might include case studies, workbooks, and other instruction on conflicts of interest in research. Conferences. Education need not involve formal course work, however. Departmental grand rounds or more informal conferences or seminars could be led by senior investigators to educate other faculty as well as students and to underscore the importance of addressing conflicts of interest. Such conferences could examine real problems, describe actions that were taken in response, and identify resources available within the institution. Clearly Stated Expectations for Early and Complete Disclosure Requirements for regular, detailed, and mandatory financial disclosure that includes relevant information about researchers, spouses (or companions), and dependents have increased during the past decade (McNeil and Roberts, 1990). This committee concurs with the AAMC and AAHC guidelines in this matter and endorses their call for annual disclosure within the research institution of relevant significant interests (such as equity, officership, consultant fees, or honoraria) to identify sources of possible research bias.

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Patient Outcomes Research Teams: Managing Conflict of Interest All research proposals should be reviewed by the principal investigator's academic department for any conflict-of-interest issues and preconditions. Reviews of routine university-initiated disclosure (e.g., annual faculty reports) could be conducted efficiently by specifying "red flags" that would trigger further inquiry. These review requirements would apply to ongoing activities of PORT investigators when the PORT is formed and to contemplated activities during the course of the study. The committee also supports investigator-initiated review of proposed collaborative agreements or other studies in which the investigator has financial ties to the subject of the PORT. Scrutiny would be greatest with respect to equity relationships. Other ties, such as consulting and management positions, would be given greater scrutiny if the positions involved a direct role in the evaluation or testing of actual or prospective products. A self-denying rule of the type voluntarily adopted by several major clinical research projects in recent years, whereby key scientific participants agree to forgo all financial ties to interested businesses during such studies, provides credibility for PORT studies (although not a qualitatively different credibility than would prohibition). Nevertheless, disclosure, supervisory controls, and monitoring may be sufficient to allow certain financial relationships to continue, provided (1) monitoring mechanisms are stringent and provide reasonable and publicly acceptable assurances that research will be free from bias; (2) there is no early, financially advantageous disclosure or exploitation of research results; and (3) any reference to the relevant research in speeches, writings, advertising, or collegial discussions is accompanied by disclosure of the financial relationship (McNeil and Roberts, 1990). These measures may not prevent the press, however, from viewing such arrangements with suspicion. Well-Formulated and Well-Implemented Institutional Processes and Responses In addition to the need for policies on and full disclosure of situations involving possible conflicts of interest, the AAMC guidelines point to the need for implementation of a wide array of enforcement procedures (including appropriate sanctions), review of research proposals, expeditious response to questions that are raised, and effective, appropriate management and resolution of conflicts of interest. Universities ought to play a large role in implementing conflict-of-interest guidelines, and the guidelines ought to be part of the institutional process. Each institution, or each PORT, or both, should have some declared model for disclosure and consultation. A PORT principal

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Patient Outcomes Research Teams: Managing Conflict of Interest investigator (and his or her institution) has a responsibility to ensure that institutional requirements for disclosure and any other relevant policies are met by all team members including subcontractors. A PORT might decide to implement additional mechanisms on its own if the home institution does not fulfill this role as fully as the PORT deems necessary. Whether the conflict-of-interest processes and policies of the lead institution are acceptable to members of PORTs at other institutions is an issue to be raised and resolved early in a PORT project. Each PORT should consider the following areas: the provision of a mechanism for open discussion among its members of potential conflicts and biases, clear identification in advance of the means by which differences in the interpretation of data will be presented and managed, and ground rules established in advance on access to PORT data both within the group and by outside researchers. PORTs might consider documenting all such decisions. Asking that someone with no interest in the arrangements be part of the review and approval process is another possible safeguard. At some later time PORTs might review this oversight process to determine whether it is effective, ineffective, or overly burdensome (Gunsalus and Brown, 1989). Other internal mechanisms and resources that will allow PORTs and their institutions to anticipate and manage possible conflicts of interest and to learn from one another are offered below. Institutional review of investigator agreements. Most research institutions expect to review contractual arrangements that involve the institution to be certain they present no conflict of interest or conflict of commitment; a few have gone further to require review of consulting arrangements. This review ensures that investigators do not give away data, patents, or other intellectual property that belong to the institution. In this case, the primary concern of institutional attorneys and administrators is to protect the institution rather than the investigator. This same mechanism might, however, be used voluntarily by the PORT investigator for advice on contemplated agreements—that is, universities might develop an "intramural consultancy" to provide support to principal investigators of projects or programs. Using such a service, investigators might ask for review (e.g., by the university counsel, the office of grants administration, the vice president or dean for research) of new contracts with outside agencies or industrial entities in order to understand their options and responsibilities under the terms of the proposed contract. Particular attention might be given to those attributes of the agreement

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Patient Outcomes Research Teams: Managing Conflict of Interest that might entail risk for conflict of interest. The elements reviewed could include access to and release of information, conditions under which the proposed work could be terminated, and so forth. There may be good reason to review statements pertaining to ownership rights or copyrights in cases where new instruments for outcomes measurement, clinical decision making supported by emerging new technologies, and other tangible goods are envisioned as a potential result of PORT work. For example, currently such new instruments as case-mix measures and measures of functional health status are copyrighted and may or may not be available for general use. Well-negotiated agreements with outside research sponsors might include specific attention to the following: selection of subjects (to avoid competition for participants with other secondary protocols); direction and control of the research (if external sponsorship depends, for instance, on interim results to determine incremental funding, discontinued funding by that source will jeopardize the PORT's continued study of that alternative technology); conditions under which the research design could be changed (again, because such changes may affect the PORTs work and the value of its data); peer review and outside sponsor evaluation of results (to ensure credibility); and acceptable conditions of secrecy (for instance, the rules that govern sharing of information with students, colleagues, and the scientific community through publication). Data that are gathered in part with public funds should be publicly available. Rules concerning student involvement should be clear and not involve excessive delay in the defense or publication of a dissertation. Establishment of a forum or other advisory group for discussion of ethical issues related to research. The 1989 IOM report Responsible Conduct of Research in the Health Sciences, refers to "the moral and professional climate of the research environment, which influences everyday

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Patient Outcomes Research Teams: Managing Conflict of Interest practice and sets the tone for future generations of researchers" (p. v). Manifestations of "climate" include provisions for discussion of these issues and assistance with problem solving and enabling structures, such as departmental research and ethics committees. An example of such an enabling structure that might be helpful to PORTs as well as other nonPORT investigators is a departmental, divisional, or other internal forum for disputation and problem solving regarding conflict-of-interest issues. If such institutional processes are available, conflict-of-interest problems may be examined and avoided prospectively—or at least dealt with more readily when they arise. For example, the IOM committee learned of one clinical department in which a research ethics committee operating under the aegis of the department chair has examined several difficult issues: seeking third-party payment for "experimental" clinical procedures undertaken in the context of a randomized trial; deciding when "state-of-the-art" treatments should be used for randomized trials rather than implemented nonexperimentally to "keep pace with the progress of medicine"; and the advisability or inadvisability of "finder fees" for residents who recruit subjects into trials. None of these questions yields a single best answer under all foreseeable circumstances. A forum such as the one suggested might not have decision-making authority, but if clear processes have been established to provide supportive resources to an investigator, at least the individual is not left to grapple with the questions alone. Such a role might also be filled by a experienced "conflict-of-interest consultant'' provided by AHCPR (see Considerations for AHCPR). Emphasis on the Role of the Principal Investigator The role of research team leaders is a crucial one. The team leader should determine what will permit or foster the maintenance of trust and collaboration among PORT members, convey the informal norms and values of science to the group, and anticipate problems regarding the mission of the PORT. He or she should also ensure that agreements with outside research sponsors are properly negotiated, that guidelines for PORT members' conduct are promulgated, and that a conflict management process is implemented within the PORT.

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Patient Outcomes Research Teams: Managing Conflict of Interest Professional Conflicts and Implications for PORT Research PORT research involves clinicians whose livelihoods may be affected by the conclusions reached by the PORTs. Specialty associations and medical societies might be expected to protect their members' economic interests, thus complicating the PORTs' efforts to conduct their studies. To gain the support of these groups PORTs may need to help them understand the potential short-and long-term effects of PORT findings. For instance, despite early findings highlighting large variability in the approach to management of prostatectomy and disputing some therapeutic approaches, the American Urological Association has been supportive of Dartmouth's study of treatments for BPH, recognizing its potential for improved care despite possible financial implications of the research. In some cases, however, appeals to professionalism may be unrealistic because the possible findings threaten entire specialities, subspecialities, medical or surgical approaches, or delivery systems. Researchers—especially the clinical members of the PORT who provide the treatments under study—may also have unrecognized personal biases and attachments to groups, organizations, and medical practices under study. Little can be done formally to obliterate such biases beyond assuming them as a given and seeking to detect them. This entails insisting on a priori disclosure of professional bias, prohibiting the most egregious appearances of conflict of interest, securing a multidisciplinary mix that is diverse enough and candid enough to ensure that such biases will be challenged internally as well as through an external process, and being open to post hoc secondary analysis of (as well as internal challenges to) methodology and findings by other, non-PORT health services researchers. A separate consideration is how to protect PORT researchers from petty or unwarranted accusations. In addition to early public as well as intra-PORT disclosure of relevant financial relationships to other members, individual researchers might minimize the appearance of bias and vulnerability to accusations in several ways: invite critics to look at their previous work; seek a mix of sources of funding for a given project; frequently include "memos to the file" on study decisions that might be later questioned; consider having data analysis handled by a center that is separate from the centers gathering data; blind analysts to the type of intervention (e.g., surgery, medication, watchful waiting);

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Patient Outcomes Research Teams: Managing Conflict of Interest not publish data until the findings are robust; not "overinterpret" results; call attention to areas of uncertainty; and make an effort to publish negative and equivocal results as well as positive results. Freedom of Communication for PORT Researchers The IOM committee believes that collaborative research agreements with industry should ensure freedom to publish the outcomes of studies, whether favorable or unfavorable, and that they should provide reasonable latitude for communication among PORT investigators and industry. These issues were discussed in Chapter 4; the discussion continues in this chapter in the later section "Considerations for Industry." Particular concerns include the kinds of information (e.g., ideas, specific. instruments or outcomes, preliminary findings) PORT investigators develop and may want to provide to either one specific group or all interested groups before information is available publicly. PORTs must determine and announce their policy on this issue early in the project to avoid giving a competitive advantage to any party. CONSIDERATIONS FOR AHCPR Because most PORTs are still at an early stage in their methodological development, organization, and experience, detailed direction of PORTs by AHCPR at this point would be premature. The PORTs' "quasi-regulatory" role requires that they be scrupulous about any appearance of conflicts of interest and have well-formulated policies for dealing with them. Nevertheless, like other forms of scientific investigation, PORT research is best carried out by people complying with the basic objectives of science; consequently, rules and regulations that excessively constrain that process add little and may actually impede it. For this reason, and for the time being, agency policy should avoid detailed guidelines and instead give broad direction. Thus, the committee believes that AHCPR ought not at this time to promulgate its own regulations regarding conflicts of interest and self-dealing in PORTs. However, it should, in awarding its grants, contracts, and cooperative agreements, require that a PORT (or its institution) have in place an appropriate conflict-of-interest mechanism or a process by which relevant conflicts of interest and biases are revealed. The PORT should be required in its funding application to file copies of the conflict-

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Patient Outcomes Research Teams: Managing Conflict of Interest ship of health care evaluation is worrisome because it is believed to imply a cost-containment approach, for many others it adds a significant measure of objectivity and detachment from commercial objectives. It is understandable that sponsors of newer technologies would want a relevant product included in an outcomes study and that PORTs themselves would want to include newer technologies to increase the timeliness of their findings, but if such a study is undertaken the conflict of interest issue will need particular attention. Given the importance of avoiding any appearance of conflict of interest, the prohibition model further argues that industry-sponsored research should be kept at arm's length. For instance, a first step would be to allow PORTs to seek supplemental agency funds to add studies of other relevant products or technologies. Second, if obtaining supplemental funds is unrealistic but a high test of relevance and social benefit is met, industry funding could be considered. If so, the agency should seek mechanisms to protect investigators against the appearance of conflict and allow PORTs—with government sponsorship—to fold new technologies into their studies while preserving maximum public credibility. Other protections might also be instituted whether one proceeds from the prohibition or the disclosure and peer review model. For instance, in accordance with policies already adopted by major journals, all sources of funding should be disclosed in all publications emanating from the PORT. Sponsors might be allowed to offer comments on draft articles and reports, but they should not be allowed to edit the research reports. Access to Data Grant specifications should include a requirement that both internal and bona fide external investigators have access to primary PORT data (as noted earlier, use of Medicare data is subject to restrictions as may be some insurance data bases). Given the scope and impact of PORTs, the data should be available within a specified time frame and in specified modalities—for instance, data tapes with patient identifiers deleted and adequate demonstration and documentation for secondary users. Such rules would allow the PORT to exploit its own research efforts in conducting and performing original analyses without precluding timely reanalysis by others, including PORT members acting independently. To become accessible resources for research, the PORT data sets need unusually well-developed documentation, recommended "test analysis" routines, code books, and so forth. Technical assistance for new users may have to be provided by PORT staff. All these requirements, however, pose financial and other costs to PORTs; if they are desired, AHCPR

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Patient Outcomes Research Teams: Managing Conflict of Interest should build appropriate auxiliary funding into PORT support. For instance, AHCPR might consider administrative funding for PORTs for a sixth year during which the PORT would prepare technical reports and documentation. The expectation of providing public-use documentation and justification for decision rules would also encourage PORTs to examine their biases during earlier years. Intra- and Inter-PORT Differences PORTs are too early in their development as institutions for this IOM committee to advise that AHCPR consider preempting all PORT differences by issuing uniform guidelines on managing conflicts of interest. Certainly there is no generally "right" method beyond what might be established as a minimum, core set of federal rules. Instead, PORTs need to be certain that all resources and approaches currently in use for avoiding or ameliorating such conflicts are known and that each group makes choices advisedly. PORTs and their institutions should be encouraged to develop a common understanding of what constitutes a conflict of interest. Development of such an understanding might eventually negate the need for specific rules regarding permissible behaviors; conversely, it might lay a foundation on which a sensible set of rules might be built. The committee does not at this time advocate the imposition of uniform standards for the sake of uniformity only, or for eliminating the supposedly competitive advantages that might accrue to an institution adopting particular conflict-of-interest rules and processes (especially permissive ones). Although differences in ways of addressing possible conflicts of interest may, in fact, put individuals in the same PORT or in different PORTs at a significant advantage or disadvantage, this seems a necessary price of academic freedom. Institutions will have as many reasons for developing their own rules on conflicts as on other matters (e.g., salary scales, research environments), and all will inevitably result in some differentials in competition for faculty and for research support. As noted earlier, within multi-institutional government-funded studies—as is the case with PORT grants—the primary grantee or lead institution is responsible for ensuring compliance with conflict-of-interest rules and other regulations such as those for the protection of human subjects and animals. Among the collaborating institutions of a PORT, either the policies and processes of one institution (e.g., the lead institution) should be accepted by all, or a separate agreement on such issues and their process of resolution should be specially developed if the lead

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Patient Outcomes Research Teams: Managing Conflict of Interest institution's policies are not entirely acceptable. Investigators might agree to be bound by the least or the most restrictive institutional policies. There may also be a role for infrastructures similar to those used in multicenter clinical trials, such as policy boards and data management committees. For clinical trials these structures are specified in the instructions from the funding agency and judged as part of the application, but it is not clear who sets, or should set, the policies for such groups. Resolving this problem for PORTs could be helpful to other areas of clinical research. Review of Grant Applications AHCPR might also consider using a standard disclosure form for study section grant reviewers to ensure that reviewers do not themselves have conflicts of interest and that biases are identified. The process of garnering information from review panels should aim to obtain only relevant information (e.g., financial or other interests in a company operating in a field that might be affected by the outcomes of the study). Beyond financial interests, other biases can be sought by plain questions about positions the individual has taken or practice patterns to which the individual is committed. As Chapter 3 notes, several groups have developed disclosure forms. For instance, FDA advisory committees have disclosure forms and rules of conduct (see 45 CFR, Part 73a, February 24, 1978), and, the quasi-public U.S. Pharmacopeial Convention also has guidelines for its Standards Revisions Committees (1990–1995). The National Research Council (NRC) of the National Academy of Sciences uses a statement-of-bias form (NRC, 1989) when assembling each of its study committees. (Biases do not necessarily preclude serving on a committee, however, because everyone approaches topics on which they are expert with some bias.) These sources might provide useful models for the AHCPR study sections to adopt or adapt. CONSIDERATIONS FOR THE HEALTH SERVICES RESEARCH COMMUNITY The principles or attributes of PORT conflict-of-interest management apply to other forms of health services research. The convening by AHCPR of work groups on methodological issues is an intriguing model for discussing the management of potential conflicts of interest, particularly for new PORTs. Relevant professional groups such as the Association for

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Patient Outcomes Research Teams: Managing Conflict of Interest Health Services Research should direct attention to these issues during their professional meetings and provide other informal channels of communication or forums for the exchange of ideas. If the agency is unable or unwilling to undertake such an activity, professional associations should consider assuming leadership or, at the very least, aid the agency in any steps it takes to foster communications and to develop appropriate standards. CONSIDERATIONS FOR INDUSTRY Just as there is a need for exchange of information and education within and among PORT researchers, there is a similar need among firms involved in funding academic research. Individual companies should consider establishing internal rules and standards of conduct comparable to university guidelines. Industry as a whole, through an association or another representative group, might also wish to establish industry-wide rules and standards within the limits of antitrust law. Industry should also consider whether it desires representation during any conflict-of-interest deliberations that may take place in PORTs. Publication and Communication of Findings among PORT Members and Industry Any agreements with pharmaceutical or device manufacturers who include their products as alternative treatments in PORT evaluations should neither distort the research design nor prevent or unduly delay publication of results. Although some delay of publication to allow for patent applications is reasonable, it should be held to the necessary minimum. Restrictions on the freedom of PORTs to publish the outcomes of their findings (other than the generally acceptable brief delay to permit patent evaluation and filing) are, in the view of the IOM committee, indefensible and unwarranted. Having evaluated a diagnostic procedure or treatment, the PORT must be able to report its findings and allow secondary analysis by others who may challenge them. Secrecy or exclusivity clauses should be tailored to address realistic dangers and permit collaboration with PORT investigators that might not otherwise be feasible under rigid restraints on communication. Generally, PORT investigators do not need access to what might be considered trade secrets. Maintaining confidentiality of proprietary information is a reasonable requirement on the part of industry, but prohibiting contact with other manufacturers is not. PORT investigators need to be able to talk freely

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Patient Outcomes Research Teams: Managing Conflict of Interest with manufacturers and one another (within the PORT) if they are to conduct their studies adequately. Such communication is also to the advantage of the manufacturer in ensuring that the most up-to-date information is available to the PORT when it analyzes its data. To allow PORTs to obtain these data from all relevant parties, the standard clauses that apply to basic biomedical research should not be applied to PORTs. In recent years, companies have modified their policies in collaborative agreements (CRADAs) with investigators at NIH and the Alcohol, Drug Abuse and Mental Health Administration (ADAMHA). NIH and ADAMHA CRADA agreements permit only two special stipulations: a brief delay of publication to allow companies to file patent applications or intellectual property applications, and nondisclosure by investigators of information marked by the company as "confidential" (NIH/ADAMHA, 1989a,b). This designation confers an exemption from Freedom of Information Act requests (P. Chen, Associate Director for Intramural Affairs and Chairman, NIH/ADAMHA Patent Policy Board, personal communication, 1990). As PORTs develop, they or AHCPR may need to develop similar model agreements with industry. Industry might wish to apply secrecy agreements to data with proprietary value (e.g., data involving the results of evaluations). An example might be when an off-label use of a pharmaceutical is being considered for FDA approval. Similarly, information about a company's plans for development or about the efficacy, safety, manufacture, or mechanism of action of a device or pharmaceutical may have enormous implications for the company and the value of its stock. It may be reasonable to insist that PORT investigators not share such proprietary information with competitors. Nevertheless, it is important for PORT investigators to know, for example, how a device is being modified by other firms or the characteristics of patient subgroups for which it may be desirable or undesirable. Industry agreements might well allow for secrecy to the extent that PORTs could not share with competing companies technical information (e.g., the chemical composition of a drug) that the investigators may need to do their work. Such secrecy would not compromise PORTs' ability to disclose their own findings. Agreements could stipulate that at the time of publication any information must be included that would be necessary to make the research findings understandable to the reader. A particularly thorny issue is agreements that seek to restrict or prohibit a PORT consultant from discussions with other investigators when the investigator has a consulting agreement or contract to evaluate a modality that is separate from but related to his or her PORT research. As remarked by Barbara Mishkin, a workshop participant who is not involved in a PORT, "I know from my own personal experience . . . that

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Patient Outcomes Research Teams: Managing Conflict of Interest the older we get, and the more experience and knowledge we accumulate, the harder it is to identify the source of any particular data. I just don't think it is possible for people to have split responsibilities and split allegiances and try [to] factor out information that came from A and B and from X, Y, and Z.'' The committee had considerable reservations about the propriety of arrangements that constrain communication. It concluded that such arrangements should always be disclosed to the lead institution and that the lead institution might sometimes find such an arrangement is unacceptable. A related problem concerns the kinds of information (e.g., ideas, specific instruments or outcomes, preliminary findings developed by the PORT) that PORT investigators will provide to outside interested groups before any information is publicly available. For instance, a PORT might learn during the course of its research that certain health outcomes that have not been previously measured seem to matter a great deal to patients. It is reasonable that investigators would want to share such information with others (e.g., those developing products, the subjects of evaluation, health services researchers outside the PORT). Three separate matters may be raised in this regard. The first is whether information shared with any party is to be shared with all, because to provide any information that is publicly available to one party but not another might give a competitive advantage. This issue might be particularly troublesome for a PORT researcher in his or her capacity as a consultant where one's professional obligation is to provide the best information to a client. The second matter is the timing of any information sharing. Although the best policy seems to be to make all such information available as it is developed, PORTs are likely to want to publish their results in peer-reviewed journals and will not wish to jeopardize this possibility by prior public dissemination of results. The third is the manner of dissemination, such as whether it should be public (e.g., press conference or professional meetings) or only through technical forums. Policies on these questions need to be discussed and formulated early in the PORT's studies. CONSIDERATIONS FOR CONGRESS Outcomes research has been funded for a variety of reasons, including improvement in information and knowledge, and better quality of care. Outcomes research projects, and PORTs in particular, have been funded with the hope of learning more about effective practices in medicine. Another aim of such research is rationalization of the nation's allocation of health care resources.

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Patient Outcomes Research Teams: Managing Conflict of Interest Additionally, there is a hope, if not an expectation, that health services, effectiveness and outcomes research, including PORTs, will save money for federal programs. In the short run, however, they may not specifically save money for the Medicare program, especially because it will take time for their work to become integrated with other efforts of AHCPR in facilitating the development of practice guidelines. The findings of some PORTs might even point toward appropriate increases in certain services and hence greater health care expenditures. Thus, PORT teams should not be overtly or subtly required to recommend cost-saving practices as a basis for renewed funding. By extension, continued or increased AHCPR funding should not depend on whether PORT findings are or are not consistent with congressional cost-containment objectives. Because PORT findings must necessarily rely heavily on observational studies, incomplete data bases, and qualitative outcomes, decision making should not be based on PORT results alone. Clinical trials, when available, remain important sources of new clinical information. Secure, multiyear PORT funding commitments are one way to minimize the risk of entanglements with conflicting interests. Congress should be alert to the fact that if outcomes research becomes well established and respected as a health services research activity, lower federal funding levels in later years will almost surely drive research teams toward private compensatory relationships with device and pharmaceutical manufacturers or toward other sources of funding, such as private insurers, whose primary motivation may be to find ways to reduce health care expenditures. CONCLUDING REMARKS This study was initiated following a request from the (then) National Center for Health Services Research to convene a workshop on potential conflicts of interest in its new patient outcomes research program. After AHCPR was established in 1990, it confirmed an interest in anticipating any conflict-of-interest issues that might affect PORTs. Thus, following its June 1990 workshop the IOM committee examined the issues that had been raised, with the purpose of providing the agency with "points to consider." During the work of this committee, new PORTs were funded, and new methodological issues were raised. Thus, the report represents the committee's views at a very early stage in the development of PORTs, a fact that has considerably influenced its thinking. As PORTs become established and, it is hoped, make valuable contributions to health services

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Patient Outcomes Research Teams: Managing Conflict of Interest research, unanticipated problems will undoubtedly arise, and the issues raised in this report will probably need to be revisited. The MEDTEP activity in AHCPR holds out the promise of greatly improving the value and effectiveness of the health care system. A fear that conflicts of interest may arise in PORTs should not inhibit commitment to outcomes research or the continued evolution of what must be seen as a bold new "social invention" on the part of Congress.

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Patient Outcomes Research Teams: Managing Conflict of Interest Box 6.1 Framework for Discussion Like other scientists, PORT researchers seek to maximize the validity of their inferences by identifying sources of bias and by minimizing the effects of those biases on their findings. The varieties of PORT relationships with other entities are evolving, and any pitfalls resulting from financial and professional conflicts of interest cannot yet be well delineated. PORTs may be exposed to accusations of conflict of interest because of connections to industry, professional associations, and the like, possibly with the intent of discrediting their findings when such results are at odds with the interests of other parties. PORT investigators need guidance in recognizing a potential or real conflict of interest and knowing when to disclose it. Each PORT or its home institution should have in place an appropriate mechanism by which relevant conflicts of interest and biases can be revealed and addressed. Each prospective PORT should be required in its funding application to file copies of the conflict-of-interest policies of the home institution and of its proposed subcontractors and to describe the process it will use to manage conflicts of interest. Requirements regarding conflict of interest should be at least as stringent as those that apply to clinical investigators. Where institutional rules distinguish between bench and animal research on the one hand and clinical trials on the other, PORTs should be subject to the rules that apply to the latter. Methods of dealing with conflict of interest include disclosure, followed by assessment and management or, where essential to the integrity of the research, outright prohibition. The PORT members and their institutions are best placed to determine the process by which they will manage conflict. Important aspects of such a process include education about conflicts of interest for researchers, faculty, and students; clearly stated expectations for early and complete disclosure of relevant interests; well-formulated, well-implemented institutional process for responding to disclosures; and emphasis on the role of the principal investigator in managing conflicts. Collaborative research agreements with industrial entities (firms) should ensure freedom to publish the outcomes of studies, whether favorable or unfavorable, and latitude for communication among PORT investigators and industry. Generally, PORT researchers (and their immediate families, including minor dependents) should not be equity holders in firms that produce technologies used for the conditions being studied.

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Patient Outcomes Research Teams: Managing Conflict of Interest To counteract nonfinancial sources of bias, such as those arising from professional loyalties and training and from other academic affiliations, PORTs should actively encourage internal and external scrutiny and should ensure that the team has representation from the full range of relevant clinical and scientific disciplines. PORTS of necessity rely heavily on observational studies, incomplete data bases, and qualitative outcomes, and their findings are no substitute for traditional clinical trials and should not be the sole basis for clinical or public policy decisions. Outcomes research (and PORTs in particular) has been funded for a variety of reasons including improvement in knowledge, and quality of care, and rationalization of the nation's allocation of health care resources. Although there is a hope, if not an expectation, that PORTs will save money for federal programs, this is unlikely in the short run, and PORT teams should not be overtly or subtly required to recommend cost-saving practices as a basis for renewed funding. Since AHCPR cannot assume the role of sole supporter of patient outcomes research, PORTs may need, or even require, other sources of funding, much of which may come from industry. The manner in which such funds are juxtaposed with agency support, however, needs serious consideration in each case and careful management to safeguard the conclusions of the PORTs from the appearance or reality of a conflict of interest. Uniform standards for conflict of interest and self-dealing in PORTs are not needed at this time. If AHCPR does establish minimum agency standards, it should do so in collaboration with the National Institutes of Health. Grant specifications should require that both internal and bona fide external investigators and analysts have reasonable and timely access to PORT data.

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