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7 Conflicts of Interest and Development of Clinical Practice Guidelines Clinical practice guidelines lie at the intersection of medical research, education, and practice. They build on medical research and serve an edu- cational function. In clinical care, they may influence patient and physician decisions about health care interventions, health plan coverage for medical services, and assessments of the performance of individual physicians and institutions that provide health care. Ideally, clinical practice guidelines are based on valid scientific evidence, critical assessment of that evidence, and objective clinical judgment that relates the evidence to the needs of practitioners and patients. Arguably, the most significant problem in the development of sound clinical practice guidelines is the lack of research that can be used to guide the development of comprehensive recommendations on clinical practice. Clinical trials of- ten exclude children, older adults, and patients with multiple or uncom- mon diagnoses or complex personal situations. Given the lack of evidence on many clinical topics and patient populations and the frequent lack of consistent research findings, expert judgment based on clinical experience remains a significant element in the development of evidence-based practice guidelines. As the methods manual of the American College of Cardiology and the American Heart Association states, it is not often that there is “an abundance of evidence available that leads directly to an indisputable rec- ommendation” (ACC/AHA, 2009, p. 27). Financial relationships with pharmaceutical, medical device, and bio- technology companies may create conflicts of interest and a risk of undue influence on judgment both for entities that sponsor the development of clinical practice guidelines and for the individuals who participate in their development. In addition to financial relationships with industry, other potential sources of bias in the development of clinical practice guidelines 

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0 CONFLICT OF INTEREST include professional affiliations and practice specialization, reimbursement incentives, intellectual preconceptions and previously stated positions, and the desire for recognition and career advancement (see, e.g., Kahan et al. [1996], Ayanian et al. [1998], Murphy et al. [1998], Fitch et al. [1999], and Detsky [2006]). This chapter begins with definitions and a brief historical overview and description of groups that develop clinical practice guidelines. It then reviews what the committee learned about the nature and the effects of sources of funding on the development of clinical practice guidelines, the financial interests of individual participants, and policies on financial re- lationships and conflicts of interest. A later section reviews other methods for promoting objectivity in the development of clinical practice guidelines and trust in those guidelines. The final section presents recommendations on how to reduce conflicts of interest in the development of clinical practice guidelines. BACKGROUND AND CONTExT Definitions As defined in an earlier Institute of Medicine (IOM) report, clinical practice guidelines are “systematically developed statements to assist prac- titioner and patient decisions about appropriate health care for specific clinical circumstances” (IOM, 1990, p. 8). The IOM report emphasized the role of formal evaluations of the evidence base for clinical practice guidelines and the linking of recommendations to those reviews. System- atic reiews, the common term used today for formal evaluations of the evidence, are highly structured assessments of the research literature that use explicit, previously defined methods and tools to identify, select, assess, and summarize research studies relevant to a technology, treatment of a clinical condition, or similar topic (see, e.g., OTA [1994] and Cochrane Collaboration [2005]). A meta-analysis is a quantitative summary of the data examined in a systematic review. As explained below, various groups have devised tools for assessing the extent to which a set of guidelines are based on systematic, evidence-based procedures. Evolution of Clinical Practice Guidelines The American College of Cardiology, the American College of Physi- cians, the National Institutes of Health (NIH) Consensus Development Program,1 the U.S. Preventive Services Task Force, the Blue Cross and 1 Since 1977, the Consensus Development Program at NIH has sponsored “an unbiased, independent, evidence-based assessment of complex medical issues” (NIH, undated). It orga-

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES Blue Shield Association, ECRI (now the ECRI Institute), and the RAND Corporation were, among others, leaders in devising systematic methods for assessing the evidence and developing clinical recommendations for practitioners, patients, payers, and others (see, e.g., IOM [1985, 1988] for contemporary descriptions of such activities). In 1989, the U.S. Congress created the Agency for Healthcare Policy and Research (AHCPR) and gave it responsibility for creating a public-private partnership to develop, dis- seminate, and evaluate clinical practice guidelines (P.L. 101-239). In 1995, the Congress came close to defunding the agency in response to lobbying by back surgeons who disagreed with the agency’s guidelines for the treat- ment of low back pain developed by an AHCPR Patient Outcomes Re- search Team (Deyo et al., 1997; Gray et al., 2003; see also Clancy [2003], Gaus [2003], and Wennberg [2003]). Other government bodies charged with some aspect of technology assessment have also been defunded under circumstances that underscore the political sensitivity of this activity (for example, the National Center for Health Care Technology in 1982 and the congressional Office of Technology Assessment in 1995) (see, e.g., Bimber [1996], Rettig [1997], Eisenberg and Zarin [2002], and Keiper [2005]). After its close call, AHCPR—rechristened the Agency for Healthcare Quality and Research (AHRQ)—withdrew from the work of developing clinical practice guidelines. Instead, the agency supports evidence-based practice centers that conduct systematic reviews that government agencies, professional societies, and other groups can request and use to develop guidelines and other recommendations. In 2008, AHRQ supported 14 such centers, 5 of which focused on assessments for the Centers for Medicare and Medicaid Services. One evidence review (performed under a grant from AHRQ) by the RAND Corporation’s Evidence-Based Practice Center concluded that the quality of practice guidelines suffered as a result of the retreat of the agency from guideline development (Hasenfeld and Shekelle, 2003; see also Grilli et al. [2000]). The U.S. Preventive Services Task Force, which was created several years before AHCPR/AHRQ but which is now part of the agency, continues to develop evidence-based guidelines for preventive services. It is currently supported by one evidence-based practice center. Other federal agencies, such as NIH and the Centers for Disease Control and Prevention, also develop practice guidelines. To support the dissemination of the clinical practice guidelines devel- oped and submitted by others, AHRQ sponsors the National Guideline nizes conferences that are jointly sponsored and administered by one or more NIH institutes or centers and the Office of Medical Applications of Research, which is located in the Office of the Director of NIH. Other federal agencies may participate if their expertise is relevant to the topic. Currently, the Agency for Healthcare Research and Quality provides a systematic review of the conference topic from one of its Evidence-Based Practice Centers.

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 CONFLICT OF INTEREST Clearinghouse. The guidelines posted by the clearinghouse are summarized in a common format that includes headings for information about the source(s) of funding and about financial disclosures or conflicts of interest.2 Although the clearinghouse is the most comprehensive source of informa- tion on the funding of guideline development activities and on financial dis- closures and conflicts of interest, its data have some significant limitations. The analysts who compile the guideline summaries primarily rely on source documents provided by the guideline sponsor, and those documents may be incomplete. For example, because the source documents are silent on the topic, “Not stated” entries for “financial relationships/conflict of interest” may be found in clearinghouse summaries of guidelines for groups such as the American College of Physicians and the U.S. Preventive Services Task Force. These two groups do, in fact, have a process of disclosing, evaluat- ing, and managing conflicts of interest.3 Given these and other limitations in the clearinghouse database, the committee used information from the database on funding sources and disclosures with caution. The guideline initiatives described above and other initiatives have gradually but not fully replaced less rigorous guideline development efforts that lacked formal procedures, clear reporting of the authors involved with and the methods used for the systematic review of the evidence, and explicit links between the recommendations and the supporting evidence. Shortcomings in the processes for the development and reporting of clini- cal practice guidelines persist. These shortcomings include the incomplete disclosures of the financial relationships of the participants and the fund- ing sources and informal procedures, which increase the opportunity for undue influence and bias (see, e.g., Shaneyfelt et al. [1999], Burgers et al. [2003], Harpole et al. [2003], Hasenfeld and Shekelle [2003], Shiffman et al. [2003], Boluyt et al. [2005], Guyatt et al. [2006], Poitras et al. [2007], Nix [2008], and Nuckols et al. [2008]). 2 The criteria for the inclusion of a guideline in the clearinghouse relate to sponsorship, evidence of some kind of literature review, adoption of the guideline within the last 5 years, and print or online availability of the complete text of the guideline. 3 To cite one example of how such omissions may occur, when U.S. Preventive Services Task Force guidelines are published in journals that require disclosures, they include a state- ment (compare, e.g., the guidelines on screening for lipid disorders in children as published in Pediatrics at USPSTF [2007a] and as published online at USPSTF [2007b]). In contrast, guidelines presented on the agency’s website do not routinely include information about the group’s conflict of interest policies and procedures or about the authors’ financial relationships (see, e.g., guidelines on screening for sickle cell disease in newborns at USPSTF [2007c]). The processes for developing the guidelines were the same, but the information in the clearinghouse varies because the source documents varied in the information that they provided. A discus- sion of task force policies can be found online in the procedure manual, but the site does not highlight it (USPSTF, 2008).

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES Systematic Process for Developing Clinical Practice Guidelines The adoption of explicit, systematic methods for reviewing evidence and developing and documenting practice guidelines is, as discussed fur- ther below, an important strategy for reducing the opportunities for bias, whether the source might be intellectual and professional preconceptions, financial interests, or something else. Table 7-1 depicts a generic process for developing evidence-based guidelines that is similar to that used by a number of government and professional societies. (Sponsor means the entity developing the guideline.) At each step in this process, financial relationships may create conflicts of interest. Any of the responsible parties identified in Table 7-1 could have financial relationships with industry that could unduly influence rec- ommendations—even when systematic reviews and other safeguards are employed. Thus, some groups have conflict of interest policies that apply not only to the expert panels that develop guidelines but also to some or all of the other responsible or involved parties. As described in Chapter 4, the evidence base itself can be biased to the extent that the publication of TABLE 7-1 Basic Elements of Process for Developing Evidence-Based Practice Guidelines Responsible Party Activity Sponsor Select topic and provide financial and other resources Sponsor Appoint a panel to develop the guideline that balances relevant expertise and perspectives and that is subject to conflict of interest policies throughout the process Panel Develop a work plan and specify clinical questions and out- comes of interest Panel or contractor Conduct a systematic review of the relevant evidence by using standardized methods for selecting studies, analyz- ing and rating the evidence, identifying and evaluating benefits and harms, and presenting conclusions Panel Develop and agree on a draft guideline with recommen- dations explicitly linked to the evidence and expert judgment Panel or sponsor Distribute a draft for internal and external review Reviewers Review of guideline by external reviewers and internal reviewers (e.g., the governing board of a professional society) Panel Revise a draft and produce the final guideline Sponsor or journal Publish and disseminate the guideline Sponsor Monitor new research findings and determine whether a guideline should be updated

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 CONFLICT OF INTEREST negative findings or findings unfavorable to a product have been delayed or suppressed. Professional societies and other groups sometimes rely on evidence re- views conducted by AHRQ’s Evidence-Based Practice Centers. (Professional societies and other groups can nominate topics for reviews. In late 2008, the agency’s website listed 11 evidence reports on clinical topics as under development.) Others groups may use a combination of staff and expert panel members to conduct reviews. One reason for the latter course is the expense. Systematic reviews for a complex clinical topic may cost in the range of $300,000 to $350,000 or more (personal communication, Beth A. Collins Sharp, director, Evidence-Based Practice Centers Program, Agency for Healthcare Research and Quality, November 14, 2008). On the basis of the committee’s review of descriptions of the systematic review process for several professional and patient advocacy groups, groups that rely on staff or volunteer experts vary considerably in the resources that they devote to such reviews, the rigor of their evidence review processes, and the products of these reviews. Possible Benefits and Risks of Industry Involvement in Guideline Development The committee found little systematic information about the funding of guidelines, the financial relationships of participants, or the effects of both. In developing this discussion and the recommendations in this chapter, it drew on testimony at its meeting and a convenience sample of information available on the Internet, as well as its experience and judgment. Potential Benefits of Industry Relationships Industry funding for the development of clinical practice guidelines may allow some groups to create guidelines on new topics when they otherwise would not. Groups that develop practice guidelines may also benefit from presentations by industry employees as part of the evidence consideration process, and industry employees may be asked to review evaluations of the evidence for their technical accuracy. Individual panel members who have financial relationships with industry often have expertise that is pertinent to the development of a guideline. Risks of Industry Relationships As observed above, relationships with industry and conflicts of inter- est in the development of clinical practice guidelines may exist at both the individual level (i.e., participants may have industry ties) and the institu-

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES tional level (i.e., the sponsoring group may rely on industry funding for guidelines). These relationships raise the possibility of conflicts of interest and undue influence at each step in the guidelines development process. Selection of topics Groups that require industry funding for the develop- ment of practice guidelines may propose topics that will attract industry funding (e.g., a guideline on how to use a product but not whether it should be used). Among the topics proposed to potential funders, companies may favor topics and questions for which the evidence is most likely to support conclusions favorable to a particular company. Review of evidence Studies examining the association between industry ties and the outcomes of systematic reviews or meta-analyses raise concerns.4 Although these studies do not deal explicitly with the entire process of developing clinical practice guidelines, they examine a key element. In one study, industry-sponsored meta-analyses of drug trials were less transparent about the methods that they used, were much more likely than Cochrane Collaboration reviews to recommend the experimental drug without res- ervation, and had fewer reservations about the methodological limitations of the trials included in the analysis (Jorgensen et al., 2006).5 All of the industry-sponsored reviews but none of the Cochrane Collaboration re- views recommended the experimental drug without reservation. Another study examined review articles on the health effects of second- hand smoke (Barnes and Bero, 1998). Ninety-four percent of the review ar- ticles written by individuals affiliated with the tobacco industry concluded that passive smoking is not harmful to health, whereas 13 percent of the reviews written by authors without such an affiliation made that conclu- sion. The association between the conclusion that secondhand smoke is not harmful and an affiliation with the tobacco industry persisted even after the analysts took into account the methodological quality of the review, the year of publication, the clinical topics examined, and whether the review was subject to peer review. 4 As described in materials prepared for the Cochrane Collaboration (2002, unpaged), “meta-analysis is a two-stage process. The first stage is the extraction of data from each indi- vidual study and the calculation of a result for that study (the ‘point estimate’ or ‘summary statistic’), with an estimate of the chance variation we would expect with studies like that (the ‘confidence interval’). The second stage involves deciding whether it is appropriate to calculate a pooled average result across studies and, if so, calculating and presenting such a result. Part of this process is to give greater weight to the results from studies which give us more informa- tion, because these are likely to be closer to the truth we are trying to estimate.” 5 The authors identified 24 Cochrane Collaboration reviews for which another meta-analysis studied the same two drugs in the same disease and was published within 2 years of the Co- chrane Collaboration review. (Eight of the 24 comparison guidelines were industry supported; 9 had no declared source of support; 7 reported nonprofit support or self-funding.)

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6 CONFLICT OF INTEREST As discussed in Chapter 4, which describes additional studies, a review of meta-analyses on hypertensive drugs found that financial ties to a single pharmaceutical company were not associated with findings that favored the company but were associated with favorable conclusions (Yank et al., 2007). The authors further noted that peer reviewers and journal editors did not prevent the publication of biased conclusions. Expert panel deliberations The committee found no systematic studies of the relationship between participant financial relationships and the con- tent of guidelines. One study did find, however, that only 7 percent of participants in guideline development surveyed believed that their own relationships with industry influenced their recommendations, but 19 per- cent believed that their coauthors’ recommendations were influenced by such relationships (Choudhry et al., 2002). Because more than half of the participants reported no process for disclosing financial relationships, it is not clear how well informed the respondents were about their colleagues’ relationships. (The extent of the relationships identified in the study is discussed below.) Dissemination of guidelines Even if industry support is limited to the dis- semination of guidelines, such support could influence the overall strategy for dissemination in ways that unduly favor a company’s product. This is one interpretation of the controversy over guidelines related to sepsis sum- marized in Box 7-1 below. GROUPS THAT DEVELOP CLINICAL PRACTICE GUIDELINES A range of public and private groups develop or collaborate in the de- velopment of clinical practice guidelines (Table 7-2). On the basis of guide- lines included in the National Guideline Clearinghouse, medical specialty societies are the most common developers of the guidelines; they accounted for almost 40 percent of the guidelines in the clearinghouse database in April 2008. Professional societies report that practice guidelines are among the most valued services that they provide (see, e.g., Bennett et al. [2003], Masur [2007], and Sagsveen [2008]). Evaluations of specialty society guide- lines have sometimes been critical of their lack of systematic reviews of the evidence and other characteristics (see, e.g., Grilli et al. [2000]); but the committee’s review indicates that many specialty societies have taken steps to make their procedures more systematic, transparent, and evidence based by hiring knowledgeable staff and developing methods, process manuals, and policies that include conflict of interest policies and procedures. The committee found less information about the clinical guideline development- related activities of disease-specific groups.

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES TABLE 7-2 Number of Clinical Practice Guidelines in the National Guideline Clearinghouse by Selected Types of Sponsors, as of March 16, 2009 Type of Sponsor Number of Guidelines Medical specialty society (U.S. and other) 959 Professional association (U.S. and other; mostly nonphysician or 408 mixed groups) Government agency (non-U.S.) 214 Federal/state/local government agency 165 Nonprofit organization 142 Independent expert panel 97 Academic institution (U.S. and other) 98 Disease-specific society (U.S. and other) 202 Hospital/medical center (U.S. and other) 26 For-profit organization 21 Managed care organization 11 Total, all guidelines, all sponsors 2,343 NOTE: Some guidelines are developed collaboratively by more than one type of sponsor. For example, a guideline may list as developers one or more professional societies and one or more disease-specific societies. The National Guideline Clearinghouse (NGC) search option does not generate unduplicated counts by category of sponsor. The unduplicated count presented here was provided by NGC staff. Nineteen of the 26 guidelines from a hospital or medical center were submitted by a single institution. SOURCE: Personal communication, Mary Nix, Health Scientist Administrator, National Guideline Clearinghouse, March 22, 2009. Public agencies also develop practice guidelines. U.S. federal and state agencies and public agencies from other countries accounted for more than 500 of the guidelines in the National Guideline Clearinghouse. Some groups involved in guideline development have sought partners. For example, the American College of Cardiology and the American Heart Association have collaborated in their guideline development program since the 1980s (ACC/AHA, 2009). Several groups are investigating an international collaboration to develop guidelines for the care of respira- tory diseases (personal communication, Holger Schunemann, M.D., Ph.D., chair, Department of Clinical Epidemiology and Biostatistics, McMaster University, February 19, 2009). Compared with the complexity of simply adding individuals with different professional and other backgrounds to a guideline development panel, the management of partnerships between and among agencies tends to be more complicated because each partner usu- ally has, for example, its own policies and procedures. Nevertheless, the

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 CONFLICT OF INTEREST potential benefits of collaboration include the sharing of costs, broadening of the scope of the questions examined, and reductions in the number of dueling guidelines that may undermine the credibility and acceptance of recommendations. FINANCIAL RELATIONSHIPS IN GUIDELINE DEVELOPMENT Sources of Funding for Guidelines and Systematic Reviews The committee found no systematic assessment of the public or private sources of funding for the development of clinical practice guidelines (see, e.g., Boyd [2008]) or systematic reviews of funding sources (Jorgensen et al., 2006). Nearly all (98 percent) of the summaries of more than 2,000 guidelines included in the National Guideline Clearinghouse as of April 21, 2008, contained a statement about the funding source, usually indicating that the group that developed the guideline had funded it (Nix, 2008). Some information is inconsistent. For example, in the summary statement for guidelines on bronchial intraepithelial neoplasia/early central airways lung cancer, the section on the source of funding states that a professional society funded it, whereas the section on financial disclosures/conflict of interest states that funding came from five pharmaceutical or biotechnology compa- nies (NGC, 2009c; see also Kennedy et al. [2007]). Similarly, a guideline on the prevention and treatment of mucositis listed the two authoring groups as the source of funding, but the information on financial disclosures/con- flicts of interest referred to unrestricted grants from unnamed companies (NGC, 2009h; see also Keefe et al. [2007]). Some professional societies, such as the American College of Physicians, the American Academy of Neurology, the American Society of Hematol- ogy, and the American Society for Clinical Oncology, fund their guide- line development programs from general revenues and, in some instances, grants from independent nonprofit organizations (ASCO, 2008; Sagsveen, 2008; personal communication, Martha Liggett, executive director, Ameri- can Society of Hematology, February 24, 2008; personal communication, Vincenza Snow, director, Clinical Programs and Quality of Care, American College of Physicians, February 23, 2009). As discussed in Chapter 6, a society’s general revenues may include a significant share from industry, for example, income generated by journal advertising or by pharmaceutical or device company exhibits at professional society meetings. The committee is aware that some smaller professional societies that have sought to fund clinical guideline development and systematic re- views without industry support have found it difficult to do so (personal communication, Roger Chou, assistant professor of medicine and medical informatics and clinical epidemiology, Oregon Health Sciences University, April 2, 2008). Professional societies can, however, nominate topics for

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES AHRQ-supported systematic reviews, and if such a topic is selected, even a resource-limited society will have an evidence-based review with which to work. Most, if not all, guidelines developed by government agencies in the United States (e.g., the U.S. Preventive Services Task Force) and elsewhere (e.g., the National Institute for Health and Clinical Excellence in the United Kingdom) are publicly funded. One controversial exception involving a Texas state agency is described in Box 7-1, which cites several controversies involving financial relationships in practice guidelines. Practice guidelines are sometimes developed by ad hoc groups, which by their nature are not likely to have a well-developed infrastructure for the performance of evidence-based reviews and other activities, including procedures for identifying and managing conflicts of interest. Box 7-1 de- scribed one ad hoc initiative related to heart disease screening guidelines that provoked concerns about bias and conflict of interest. The Cochrane Collaboration (an independent, nonprofit, international organization that produces systematic reviews, among other activities) does not allow industry funding for a review. It does, however, allow commercial contributions to a central pool of funds to be used for certain other activi- ties, such as the translation of reviews into different languages (Cochrane Collaboration, 2006). Although the committee found no systematic information, industry involvement in the dissemination of guidelines appears to be fairly com- mon. For example, companies may buy copies of the journal issue in which a guideline is published. They may also develop derivative materials (e.g., summaries for lay audiences) based on the guideline. The committee was unable to systematically investigate whether dissemination activities re- sulted in materials that altered or elaborated on a guideline in ways that departed from the conclusions in the guideline itself. Nature and Extent of Individual Relationships with Industry The committee found little systematic study and documentation of fi- nancial relationships between industry and the individuals who author clin- ical practice guidelines. A 2002 study reported that the authors of practice guidelines had widespread financial relationships with the pharmaceutical industry (Choudhry et al., 2002).6 Of 44 practice guidelines that Choudhry et al. initially reviewed, only 2 included disclosures of the authors’ financial relationships with industry. A follow-up survey of 100 authors involved with 37 of the guidelines found that 87 percent of the authors had some 6 The study covered guidelines that were published between 1991 and 1999, that had iden- tifiable authors, and that had been endorsed by a “recognized” North American or European professional society.

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0 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES and discussions with staff or members of organizations involved with guide- line development. It found no systematic information on the conflict of interest policies of groups that develop clinical practice guidelines. Reviews by Boyd and Bero (2006) and Boyd (2008) likewise found no systematic descriptions or assessments of these policies. The availability, representativeness, and quality of the available in- formation are limited in several important ways. As noted above, even if the developers of guidelines have conflict of interest policies, they may not refer to them in individual guideline documents. This in turn means that the summaries in the National Guideline Clearinghouse are likely to have no information either. A number of groups have recently revised aspects of their policies, and the committee is aware of other groups that are consider- ing changes. In some cases, these changes may not be reflected on websites or in publications. From the policies examined, the committee identified several variations in organization conflict of interest policies and procedures. They vary in the • information required for disclosure, including how detailed the information disclosed must be, how often disclosure is requested, and whether a panel member needs to explicitly state that he or she has no relationships to disclose; • management of disclosed information, including who reviews it and whether other panel members are told of conflicts; • procedures for managing the relationships disclosed, including limi- tations of participation by members with conflicts (such as serving as chair or cochair or voting); • provisions for public disclosure of conflict of interest policies, fund- ing sources, and individual financial relationships; • procedures for managing relationships with companies that provide funding for guidelines development; and • assignment of explicit responsibility for monitoring whether insti- tutional policies are followed. The frequent lack of transparency of conflict of interest policies lim- its the ability of guideline readers to consider financial relationships and conflicts of interest as part of their assessment of the credibility of a set of guidelines. To give a sense of what readers of guidelines may encounter, Box 7-3 includes additional examples of the range of summary statements in the National Guideline Clearinghouse. (See also Box 7-2.) The committee found few descriptions of the policies used to manage the relationship between guideline developers and industry for groups that accept industry funding for guideline development. One exception is the

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06 CONFLICT OF INTEREST BOX 7-3 Examples of Conflict of Interest Policy Descriptions Excerpted from Summaries in the National Guideline Clearinghouse Example A FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST Not stated. [This is the most common entry for the period from 1999 to 2006.] Example B FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST To assure the integrity of the Advisory Committee on Immunization Practices (ACIP), the U.S. Department of Health and Human Services has taken steps to assure that there is technical compliance with ethics statutes and regulations regarding financial conflicts of interest. Concerns regarding the potential for the appearance of a conflict are addressed, or avoided altogether, through both pre- and postappointment considerations. Individuals with particular vaccine-related interests will not be considered for appointment to the committee. Potential nomi- nees are screened for conflicts of interest, and if any are found, they are asked to divest or forgo certain vaccine-related activities. In addition, at the beginning of each ACIP meeting, each member is asked to declare his or her conflicts. Members with conflicts are not permitted to vote if a conflict involves the vaccine or biologic being voted upon. [NGC, 2009g; see also ACIP, 2007] Example C FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST The American Academy of Neurology (AAN) is committed to producing indepen- dent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recom- mendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were American College of Chest Physicians, whose policies are summarized in Box 7-4. Effectiveness of Policies The committee identified no evaluations of the impact of conflict of interest policies on the content of guidelines or other outcomes. The review by Boyd and Bero (2006) also found no rigorous assessments of conflict of interest policies for guideline development and no evaluations of different strategies for implementing or enforcing them.

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0 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of inter- est. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least three AAN committees, a network of neurologists, Neurology peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com. With regards to this specific report, all authors have stated that they have nothing to disclose. One of the authors performs epidural steroid injec- tions. [NGC, 2009b; see also Armon et al., 2007] Example D FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST Standards and guidelines are to insure that individuals participating in professional activities are aware of author relationships with commercial companies that could potentially affect the information presented. The American Thyroid Association has endorsed the requirement that authors disclose any significant financial interest or affiliations they may have with the manufacturers of products or devices that may be discussed in the development of guidelines. In compliance with this policy, a superscript number placed by the name of an author denotes an author who has indicated an affiliation with organizations which have interests related to the content of these guidelines. The intent of this policy is to openly identify potential conflicts of interest so that physicians may form their own judgments about the guidelines with full disclosure of the facts; it remains for the audience to determine whether an author’s outside interest may reflect a possible bias in either the expo- sition or the conclusions presented. [NGC, 2009f; see also Cooper et al., 2006a] NOTE: As explained in the text of this chapter, the documents on which guideline summaries are based may not include references to organizational policies that have governed the de- velopment of the guideline. Thus, a “Not stated” response does not necessarily indicate that a group has no policy. Other Strategies to Limit Bias in the Development of Clinical Practice Guidelines Those committed to the development and implementation of sound, credible, and useful guidelines have devised a number of methods and tools that can be used to support the creation of such guidelines. Several are listed in Box 7-5, roughly according to the step in the process of guideline development described in Table 7-1. Arguably, the most important steps are the conduct of a systematic review of the evidence and the linking of recommendations to the evidence in an explicit fashion. The strategies—and continuing areas of debate and methodological refinement—are described in depth elsewhere (see, e.g., Higgins and Green [2008] and IOM [2008]).

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0 CONFLICT OF INTEREST BOX 7-4 Policies of American College of Chest Physicians on Industry Funding of Guideline Development • Fund development activities are undertaken by the organization’s executive office without the involvement or knowledge by the organizational unit responsible for guideline development, and each guideline ideally is either self-funded or funded by at least three to five outside sources. • Names of sponsoring companies are not revealed to staff, society mem- bers, and other participants in guideline development until the information is disclosed in the final publication. • Sponsors do not nominate topics, participate in meetings, or review drafts. They see the guideline only upon publication. • The organization does not inform sponsors of the participants involved in developing a guideline, the specific questions investigated, the methodologists or evidence-based practice center involved in the evidence review, the reviewers, or meeting times or places. • Guidelines refer to pharmaceuticals only by their generic names and not by their brand names. SOURCE: Baumann et al., 2007; Lever and Lewis, 2008. In general, they reinforce conflict of interest policies by limiting the op- portunity for secondary financial interests to exert undue influence on the primary interest of developing sound guidelines. Unfortunately, as Steinberg and Luce (2005) have observed, rigorous methods for clinical practice guideline development and reviews of the clini- cal evidence are not applied consistently, and the conclusions of evidence reviews are not always interpreted appropriately. Furthermore, given that the evidence base is weak in many areas, they advise, “physicians, policy- makers, and others acting on the basis of judgments, recommendations, or measures . . . should not blindly assume that the label [evidence-based] truly applies” (p. 91). As noted earlier, in addition to developing methods to limit bias, in- dividuals and groups have been developing tools for standardizing the presentation of guidelines and assessing the quality of guidelines across several domains (see, e.g., IOM [1992], the AGREE Collaboration [2003], and Shiffman et al. [2003]). Methodologists have also developed tools ethodologists that can be used to assess the quality of systematic reviews (Shea et al., 2007; see also Oxman et al. [2006a]). The 23-item AGREE instrument, which was developed by experts from 13 countries with funding from the European Union, includes two elements that relate to conflict of interest, specifically, that the “guideline is editorially independent from the funding

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0 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES BOX 7-5 Other Strategies for Limiting Bias in Clinical Practice Guideline Development Using an explicit process to select topics for clinical practice guideline develop- ment. Various groups and individuals have recommended a formal process and the use of explicit criteria for the selection of topics for guideline development (see, e.g., Battista and Hodge [1995], IOM [1995], and Oxman et al. [2006a]). Although the primary rationale is to use limited resources to evaluate areas that offer the greatest potential to improve the quality or effectiveness of health care, another potential benefit is a reduction in the opportunity for financial relationships and other sources of bias to influence the selection of topics. Creating a diverse expert panel. The inclusion of individuals with a range of rel- evant professional and other backgrounds on guideline development panels can help check financial, professional, and other sources of bias; promote the fuller consideration of potential outcomes, relevant evidence, and aspects of implemen- tation; and help win broader acceptance by professionals, consumers or patients, health care plans, and others who play roles in the successful implementation of guidelines (see, e.g., IOM [1990, 1992, 2008] and AGREE Collaboration [2003]). Systematically reviewing relevant evidence. As summarized by Higgins and Green Higgins and Green (2008, Section 1.2.2) for the Cochrane Collaboration, key elements of this critical elements of this critical step include • “a clearly stated set of objectives with pre-defined eligibility criteria for studies; • an explicit, reproducible methodology; • a systematic search that attempts to identify all studies that would meet the eligibility criteria; • an assessment of the validity of the findings of the included studies, for example, through the assessment of risk of bias; and and • a systematic presentation, and synthesis, of the characteristics and findings of the included studies.” Using systematic procedures to evaluate the evidence, employing expert judg- ment, and linking recommendations to the evidence. Methodologists have de- veloped and tested formal processes for developing consensus and otherwise structuring the expert judgment process (see, e.g., Fink et al. [1984], Murphy et al. [1984], Murphy et al. [1998], Verkerk et al. [2006], and Renfrew et al. [2008]). In addition, considerable effort has been invested in developing and testing explicit methods for reporting and rating the evidence relevant to guidelines and for rating the strength of the recommendations (see, e.g., Guyatt et al. [1995], Lohr [2004], and Schünemann et al. [2006], and Schünemann [2008]). Obtaining expert reviews. An independent, expert review of the guidelines and related documents is an important tool that can be used to improve the identifi- cation, evaluation, and use of the evidence. The process used to select expert reviewers should explicitly identify and assess reviewer ties with potentially af- fected companies.

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0 CONFLICT OF INTEREST body” (Item 22) and that “[c]onflicts of interest of guideline development members have been recorded” (Item 23). In addition, the Conference on Guideline Standardization (COG) proposed a somewhat similar 18-item checklist for reporting (documenting) guidelines (Shiffman et al., 2003). The COG list includes the identification of the funding source or spon- sor, its role in developing or reporting the guideline, and the disclosure of conflicts of interest. These and other instruments are not intended to be used to assess the full substance of the guidelines. In and of themselves, they will not identify, for example, whether key evidence has been overlooked or incorrectly as- sessed, whether relevant benefits or harms have been ignored or improperly weighed, or whether critical barriers to implementation have been missed. Notwithstanding some shortcomings of guideline assessment tools, their development and application underscore that it is important for documents containing clinical practice guidelines to provide potential users of the guidelines with informative descriptions of the development process, the evidence base, the participants, and the applicable conflict of interest poli- cies. When users of guidelines confront guidelines that lack such descrip- tions, they would be prudent to treat the guidelines with caution and search for other guidelines that provide appropriate documentation. Even when the developers of clinical practice guidelines use sound methods, they are often limited by shortcomings in the evidence base. A review of the guidelines in the National Guideline Clearinghouse reveals recommendation after recommendation that is supported by weak, mixed, or no evidence. Both to support the development of practice guidelines and for other purposes, many groups in the United States and elsewhere have called for greatly increased public investments in comparative effectiveness research and analysis for at least two decades (for a small sampling, see IOM [1985, 2007, 2008], OTA [1994], CBO [2007], and MedPAC [2007]). At the end of the next section, the committee endorses the recommenda- tions for such investments that another IOM committee made recently. Overall, the combination of a better evidence base for clinical practice guidelines and better tools for assessing that evidence not only strengthens the usefulness of practice guidelines but also reduces the potential for con- flicts of interest to bias guidelines. RECOMMENDATIONS Given the important role that clinical practice guidelines play in many aspects of health care, it is important that these guidelines be free of indus- try influence and be viewed by clinicians, policy makers, patients, and oth- ers as objective and trustworthy. The committee found substantial variation in the extent to which different groups disclosed their conflict of interest

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES policies and the financial ties to industry of the sponsoring group and the members of the guideline panel. It also found little systematic descriptions or assessments in the literature. On the basis of its judgment and experience (including experience with conflicting guidelines and guidelines not based on formal reviews of the evidence), the committee believes that the risk of undue industry influence on clinical practice guidelines is significant, and that risk justifies that strong steps be taken to strengthen conflict of inter- est policies governing the development of guidelines. Recommendation 7.1 proposes several such steps. RECOMMENDATION 7.1 Groups that develop clinical practice guidelines should generally exclude as panel members individuals with conflicts of interest and should not accept direct funding for clini- cal practice guideline development from medical product companies or company foundations. Groups should publicly disclose with each guideline their conflict of interest policies and procedures and the sources and amounts of indirect or direct funding received for develop- ment of the guideline. In the exceptional situation in which avoidance of panel members with conflicts of interest is impossible because of the critical need for their expertise, then groups should • publicly document that they made a good-faith effort to find experts without conflicts of interest by issuing a public call for members and other recruitment measures; • appoint a chair without a conflict of interest; • limit members with conflicting interests to a distinct minority of the panel; • exclude individuals who have a fiduciary or promotional rela- tionship with a company that makes a product that may be affected by the guidelines; • exclude panel members with conflicts from deliberating, draft- ing, or voting on specific recommendations; and • publicly disclose the relevant conflicts of interest of panel members. Transparency is one key element of Recommendation 7.1. Groups should disclose their conflict of interest policies and their process for seek- ing members without conflicts of interest and its results. The disclosure of the relevant financial interests of members of guideline development panels should be sufficiently specific and comprehensive that it helps others judge the severity of the conflicts of interest, including allowing the identification of fiduciary interests (e.g., membership on company boards) and promo- tional relationships (e.g., participation in industry speakers bureaus).

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 CONFLICT OF INTEREST Groups that develop guidelines should also disclose the sources and the amounts of funding provided for guideline development, including un- restricted company grants. Some committee members also wanted groups that develop guidelines to report publicly all their sources, amounts, and purposes of funding because industry contributions to general revenues (e.g., from journal advertising or unrestricted grants) could also create un- due influence. The committee did not reach a consensus on this point. Other committee members were also concerned about the overall reliance of some professional and patient groups on industry funding, but they believed that this reporting of all sources and purposes of funding is not necessary, provided that groups developing guidelines adopt and implement rigorous evidence-based procedures, report indirect and direct funding sources for each guideline, and institute the conflict of interest policies and procedures recommended in this report. Another safeguard would be the continued development of processes for rating guidelines development processes, as described above. Moreover, if the U.S. Congress requires companies to report payments not only to individuals but also to a range of medical organizations, that information, in combination with the annual reports that many professional society and patient groups issue, should allow the calculation of industry funding as a share of total revenues. Transparency also involves the inclusion of the specified information with each guideline that a group sponsors. Preferably, the information would accompany the written text, but it could—particularly if it is very lengthy—be provided by an Internet link that is maintained through the life of the guideline. In addition to expanded disclosure about funding, the committee rec- ommends an end to direct industry funding of clinical practice guidelines. It recognizes that this step might have the undesirable effect of reducing the involvement of professional societies in guideline development but believes that it is necessary to avoid the conflicts that come from industry financing. It is also likely that an increase in public support for systematic reviews of the evidence would buffer such effects because these reviews are an expen- sive part of the process of developing evidence-based guidelines. Profes- sional societies and other groups with a shared interest in certain clinical problems could also collaborate on the development of guidelines and spread the costs. In addition, a pooling mechanism might be created—as has been suggested by some for continuing medical education—to support indirect industry funding of the development of clinical guidelines in certain broad categories. Another important step is to exclude or substantially limit the partici- pation of individuals with conflicts of interest on panels that develop clini- cal practice guidelines. As more academic institutions and other groups as well as individual professionals take the steps recommended in Chapters 5

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES and 6 of this report, it should be easier to find individuals who are free of conflicts of interest involving promotional relationships (e.g., participation in speakers bureaus). If groups conclude that participants with conflicts of interest are essential to provide the necessary expertise, they should demon- strate to the public that they have made a good faith but unsuccessful effort to find individuals with the required expertise and without conflicts of in- terest. They should also preclude individuals with conflicts of interest from chairing guideline development panels, restrict the number of individuals with conflicts of interest on panels to a distinct minority (e.g., to 25 to 30 percent of the membership), and prohibit members with conflicts of interest from drafting and deciding specific recommendations. In addition to actions by the institutions directly involved in the de- velopment of guidelines, organizations with an interest in unbiased clinical practice guidelines can create incentives for groups that develop guidelines to adopt the recommendations presented in this report. The committee understands that the National Guideline Clearinghouse will be phasing in a requirement for the disclosure of conflicts of interest, but the committee recommends that it extend the requirement to include the disclosure of funding and policy information, consistent with Recommendation 7.1. It would also be desirable for the clearinghouse or some other entity to begin substantive assessments of the quality of clinical practice guidelines. RECOMMENDATION 7.2 Accrediting and certification bodies, health insurers, public agencies, and other similar organizations should en- courage institutions that develop clinical practice guidelines to adopt conflict of interest policies consistent with the recommendations in this report. Three desirable steps are for • journals to require that all clinical practice guidelines accepted for publication describe (or provide an Internet link to) the developer’s conflict of interest policies, the sources and amounts of funding for the guideline, and the relevant financial interests of guideline panel mem- bers, if any; • the National Guideline Clearinghouse to require that all clinical practice guidelines accepted for posting describe (or provide an Inter- net link to) the developer’s conflict of interest policies, the sources and amounts of funding for development of the guideline, and the relevant financial interests of guideline panel members, if any; and • accrediting and certification organizations, public and pri- vate health plans, and similar groups to avoid using clinical practice guidelines for performance measures, coverage decisions, and similar purposes if the guideline developers do not follow the practices recom- mended in this report.

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 CONFLICT OF INTEREST The committee expects that the adoption of the committee’s recom- mendations will reduce the probability of undue influence from industry funding and may also reduce the number of conflicting and competing clini- cal practice guidelines. Some groups that have operated with undisclosed industry support or that have been unwilling to disclose the financial rela- tionships of guideline development panel members may remove themselves from the guideline development process. Other groups may collaborate to share the costs of developing guidelines on topics of common interest. Although the committee believes that an expanded role for public-sector sponsorship of the development of systematic reviews and clinical practice guidelines would be desirable, an examination of this issue is beyond its scope. The committee endorses the recommendation in a recent IOM report for expanded federal support for assessments of the effectiveness of clinical services (IOM, 2008). That report called for the U.S. Congress to direct the U.S. Department of Health and Human Services to designate a single entity with the responsibility and capacity to “to ensure production of credible, unbiased information about what is known and not known about clini- cal effectiveness” (p. 171). That entity would establish priorities for and manage the development of systematic reviews of clinical effectiveness, develop standards for such reviews and for clinical guidelines, and address conflicting guidelines. The report also recommended that accreditation organizations and other groups preferentially use guidelines developed by using the standards described in the report. In addition, it recommended that guideline development panels minimize bias by including a balance of competing interests, prohibit voting by participants with conflicts of inter- est, and publish conflicts that have been disclosed. Other Relevant Recommendations in This Report In addition to the two recommendations in this chapter, recommen- dations elsewhere in this report are relevant to institutions that develop clinical practice guidelines. Consensus standards on disclosure elements and procedures would make disclosures more informative as well as less burdensome for those making disclosures to multiple institutions (Recom- mendation 3.2). A national system for public reporting by companies of their payments to individuals and organizations would allow the easier verification of certain disclosures (Recommendation 3.4). Limitations on certain industry ties and practices (e.g., the receipt of gifts and participation in speakers bureaus) should reduce conflicts of interest among the pool of experts considered for participation in clinical practice guideline develop- ment (Recommendations 5.1, 6.1, and 6.2). The adoption of explicit policies and procedures on institutional conflict

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 DEVELOPMENT OF CLINICAL PRACTICE GUIDELINES of interest would challenge professional societies, patient advocacy groups, and other entities that develop clinical practice guidelines to confront the scope and appropriateness of their financial ties with industry, eliminate questionable ties, and prudently manage others (Recommendation 8.1). The next chapter discusses conflicts of interest at the level of institutions.