Conflict of Interest and Medical Innovation: Ensuring Integrity While Facilitating Innovation in Medical Research: Workshop Summary (2014)

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5 Managing Conflict and Facilitating Innovation Important Points Highlighted by Individual Speakers • Collaboration with industry is an integral part of the transla- tion process and should be viewed as a positive component of innovation. • Education of and commitment from faculty at academic re- search institutions about conflict of interest is necessary for fostering medical innovation. • Conflict of interest policies at research institutions should be flexible and tailored to specific relationships because a single organizational policy may not capture the complexities of col- laborations with industry. • Simple, routine disclosures and agreements should be consid- ered in an effort to reduce the potential resource burden for complying with conflict of interest guidelines. • Greater alignment of incentives with research goals could reduce conflict of interest challenges. • New models for managing conflict of interest policies could be tested in the precompetitive space to determine if they align with institutional goals. • Improved methods for determining who needs to be informed about which types of relationships are needed in order to effec- tively communicate with the public about conflict of interest. 39 

40 COI AND MEDICAL INNOVATION Individual workshop presenters described best practices for manag- ing conflict of interest at institutions that are dedicated to performing innovative medical research. The dissemination and implementation of best practices offers ways to facilitate collaboration and medical innova- tion within the existing conflict of interest policy framework. Throughout the workshop, individual speakers who represented patient advocates, regulators, academic researchers, and industry stakeholder groups dis- cussed alignment of incentives in the broader research ecosystem, in- creasing public knowledge about conflict of interest policies, and the need to keep patients as a priority (see Box 5-1). BOX 5-1 Themes of the Workshop Terry summarized the major themes identified by individual speakers dur- ing the workshop in order to provide an overview of the topics discussed and of the potential solutions for dealing with the challenges related to con- flict of interest policies: • Managing financial and non-financial academia–industry relation- ships is key to fostering productive and transparent collaborations. (Brem, Lavezzari, Pierce, Terry) • Conflicts of interest are inevitable in the collaborative translation process, and they need to be managed rather than avoided. (Cohen, Lavezzari, Lo) • In the absence of a strong evidence base for developing policies, using a preventive regulatory approach to conflict of interest is a possible solution for ensuring that quality, integrity, and trust are not compromised. (Rockey) • One approach to establishing conflict of interest policies that create effective solutions to undue influence is to allow several institutions to try different approaches and then evaluate the outcomes of the implemented policies. (Lichter) • The use of confidential disclosure agreements and the develop- ment of templates for collaborative research agreements can ease some of the challenges encountered when initiating academia– industry collaborations. (Balakrishnan) • Conveying the benefits of physician–industry relationships and their positive effects on medical innovation in addition to the risks of these relationships would provide more balanced information for patients. (Chisolm, Grealy, Lo) • A current and accurate central, public database with explanations of industry payments to physicians would offer patients a resource to consult when making health care decisions. (Ornstein) 

MANAGING CONFLICT AND FACILITATING INNOVATION 41 • Information about the context of a relationship in addition to pay- ment information for physician–industry collaborations is needed so that the value of partnerships is understood and so that advanta- geous collaborations are not avoided because of negative connota- tions. (Grealy, Pierce) • A centralized disclosure system for potential conflicts of interest would reduce the time spent on completing individual forms and would provide a standard format and a more efficient process for reporting. (Lichter) • Aligning conflict of interest policies with established innovation goals would encourage academia–industry collaborations. (Sherer) • Implementation of the Physician Payments Sunshine Act presents a mechanism for improving communication about physician– industry relationships and offers an opportunity for increasing public awareness about the risks and benefits of conflict of interest poli- cies. (Chisolm) • Best practices need to be defined to create more efficient conflict of interest policies to enable the younger generation of researchers to participate in collaborations. (Lavezzari) • Keeping the needs of patients front and center can facilitate the management of conflicts of interest so that medical advances can proceed. (Anderson, Lichter, Terry) MANAGING CONFLICTS OF INTEREST AND BALANCING INNOVATION AT INSTITUTIONS According to Chisolm, commercialization of medical innovations can improve the lives of patients, generate revenue, and support the eco- nomic revival of cities. These goals are supported through an aggressive commercialization arm and an effort to recruit, retain, and reward an in- novative staff at the Cleveland Clinic, said Chisolm. Over the past dec- ade it has secured hundreds of patents and product licenses and has been a platform for the launch of 55 companies. Johns Hopkins University also has a tremendous drive to improve medicine and also has an innovative and entrepreneurial spirit, said Brem. His own involvement in the development of Gliadel®, a treatment for high-grade malignant glioma, is an example of the sort of innovation that can be found at Johns Hopkins (Attenello et al., 2008). His research group was funded by NIH as a National Cooperative Drug Discovery Group, which required that industry be a collaborator. Through a partner- ship with Nova Pharmaceuticals, the Johns Hopkins group took the drug through Phase III clinical trials to receive FDA approval. Initially Medi- care did not pay for the drug, but advocacy by patient groups and others 

42 COI AND MEDICAL INNOVATION helped to change that decision. Through medical advances such as the development of Gliadel, the median survival time for patients with glio- blastomas has been improved (Chaichana et al., 2013). “In the end, pa- tients worldwide are benefiting,” Brem said. Today, Johns Hopkins University is working with the Coulter Foun- dation to set up innovative groups of biomedical engineers working with clinicians to build companies to deliver products to patients. The univer- sity’s Brain Science Institute supports the translation of therapies for brain diseases through an interdisciplinary research team. “I’m hopeful that people are building on these precedents and that there are ways to move forward despite the obstacles,” Brem said. The university has a legal team dedicated to protecting the reputation of the university and the safety of patients. But lawyers tend to be cautious and it can make pro- gress challenging, he said. “Collaborations with industry, whether those collaborations are vending relationships, scientific relationships, licensing, or philanthropy, are all essential to the goal of amplification of innovation,” said Billings. Collaboration with industry that takes the form of education or marketing is an important part of the translation and application process and is not necessarily bad. “The marketplace and capitalism are not antithetical to evidence-based medicine or to good clinical practice,” he said. The ra- tionality of the scientific process is a safety net for science, protecting against uncorrected error or bias, he added. An innovation-rich agenda requires managing conflicts of interest, and commitment from faculty is needed, Chisolm said. Considerable re- sources have been devoted to a conflict of interest program at the Cleve- land Clinic to work with investigators so that they can innovate within the context of an ethical environment. During weekly meetings, program staff members review every funded grant and the disclosures from inves- tigators of industry affiliations. They then contact investigators to begin a dialogue about conflict of interest regulations and principles. By educat- ing investigators about reporting requirements, the program takes on some of the burden of compliance for faculty members. The institution has good relationships with all of its investigators who have been in- volved in the management of conflicts of interest, Chisolm said. “The investigators want to publish data that they can claim is free of bias,” he noted. Specific management tools are used for conflict of interest, said Chi- solm. Disclosure is required in any presentations or publications, and all colleagues on a research project are also made aware. To remove the po- 

MANAGING CONFLICT AND FACILITATING INNOVATION 43 tential for bias, in some cases the management may call for data to be re- analyzed by another group that does not report to the investigator with the conflict of interest, Chisolm said. And some plans call for investiga- tors to have read-only access to data or other restrictions in its collection and analysis. Data can be independently audited in any program, and an- other physician may be put in charge of the final approval of subject se- lection and consent. External data safety and management provisions may apply, along with purchasing restrictions. Chisolm noted that institution-wide approaches are not always feasi- ble. For example, management of conflicts can be tailored to the individ- ual case. “It’s time consuming,” he said, “but I think in the end it’s better, because in conflict management one size doesn’t fit all. If you’re flexible enough to take these on individually, you can stop yourself from inhibiting innovation and the furthering of research findings.” Both Pierce and Sherer agreed that arrangements between an institu- tion and a company can take many forms and that it can be difficult to manage these arrangements as part of the conflict of interest policies at most institutions. Some situations are similar to managing conflicts in individual grants, though multiple projects are involved. In other cases the collaborations are more open-ended and may be more difficult to manage. Especially where people move back and forth between academ- ia and industry, conflicts can be troublesome. Examples of successful collaborations that have avoided conflicts can provide models from which others can learn. Conflict of Interest Challenges at Institutions The NIH conflict of interest regulations support the Cleveland Clinic by having the institution, rather than the investigator, decide whether a financial conflict of interest exists. The institution also is in favor of pub- lic disclosure and has been pursuing this policy on its own. However, some aspects of NIH’s regulations have required extra work and re- sources for uncertain benefits, Chisolm said. For example, reducing the threshold for significant potential interests from $10,000 to $5,000 tri- pled the institution’s workload for scrutinizing disclosures. In addition, the institution has had to monitor industry-sponsored travel, “which has [had] very little bang for the buck,” Chisolm said. Purchasing equipment at a university may be subject to conflicts, and even though these purchases can be on a much larger scale than purchases for individual researchers, these potential conflicts tend to receive less atten- 

44 COI AND MEDICAL INNOVATION tion than do the conflicts involving individual researchers, Brem said. This can breed cynicism among individual researchers, who feel that they are being held to a very high standard and being subjected to intense scrutiny. The AAMC came out with institutional conflict guidelines several years ago, but often the data do not exist to identify conflicts, Chisolm said. For example, conflicts between an institution’s investment deci- sions and its commercialization activities need to be avoided or man- aged, as do potential conflicts between those activities and research or between royalty streams and institutional activities, he said. It is possible that conflict of interest policies are chasing away inno- vative people with great ideas who refuse to participate because it is too difficult, Brem said. Young investigators could conclude that they do not have the time or energy for completing disclosures and they do not want to risk creating a poor impression while striving to be promoted academ- ically. But such concerns may be misplaced, he said. When a three- paragraph addition to a consent form was inserted to explain Brem’s role in the development of a treatment, patients welcomed that information because they interpreted it as meaning that their physician was an expert. Lavezzari said that rather than dealing with single issues in isolation, best practices for policies should be defined and taught to researchers so that the broader system can be improved. It is unlikely that any single conflict of interest policy will work for every situation, she said. A more granular ap- proach will be needed to describe relationships among collaborators. Marga- ret Anderson, executive director of FasterCures, agreed with Lavezzari that not all situations are the same and that solutions need to be devised to better account for the variety of types of conflict of interest that arise. Potential Solutions for Conflict of Interest Policies The Council of Medical Specialty Societies (CMSS),1 which is an organization composed of 39 leading medical societies, has developed a code of conduct2 for interacting with industry for use by its medical soci- ety members, and additional organizations have been signing on. The code mandates that each signer post details about the support it receives from health care companies, and, in doing so, it sets a standard of integrity. “We agonized for 15 years whether to put this [list of support] up, be- 1 ASCO is member society and a signer to the CMSS Code for Interactions with Companies and Allen Lichter is the president-elect of CMSS. 2 CMSS Code for Interactions with Companies. http://www.cmss.org/codeforinteractions. aspx (accessed January 9, 2014). 

MANAGING CONFLICT AND FACILITATING INNOVATION 45 cause we thought it would be so controversial,” said Lichter, but after being available for 3 years, it has not received such a response. CMSS also has strict policies on disclosures of relationships with companies, and it also has a new disclosure management system that combines previously separate systems for meetings and publications. Investigators now can disclose everything on a single site rather than dis- closing items on separate sites, Lichter said. The obvious question is whether a harmonized and centralized dis- closure system could be established for everybody. A recent discussion paper developed at the IOM has observed that it could be done (Lichter and McKinney, 2012; Lichter et al., 2012). Creating such a system would not be easy, Lichter concluded, but “it will make the world a better place for researchers.” McMurry-Heath said that the simple needs to be kept simple. Brem agreed that disclosure forms should take no longer than 1 hour to fill out. “These things should be automatic and simple, and there should be one central repository where this is done on a routine ongoing basis,” he said. McMurry-Heath added, “If we can find ways to streamline the most sim- ple of agreements [and] disclosures so that we can get those out of the way, we can focus our attention on the things that are more complex and more challenging. [That] would make a lot of this process less burden- some and therefore more attractive for more people.” ALIGNING INCENTIVES IN THE RESEARCH ECOSYSTEM Terry observed that many of the issues surrounding conflicts of interest arise because incentives are not aligned with goals and that where incentives are aligned with goals, fewer problems arise. Lines are blurring between clinical care and research, between single laboratories and team science, and across borders, which provides an opportunity to focus on research goals rather than a specific section of regulations, Pierce said. If current policies do not fit well with an emerging model, then the policies need to be rethought. Once objectives for innovation are established, institutional conflict of interest policies need to be aligned with those goals. For example, the reward system for tenure and promotion at most universities still dis- courages faculty members from working with industry, Sherer said. Fac- ulty members therefore may use conflict of interest policies as a reason for not collaborating. Anderson emphasized the importance of instituting broadly based, systemic changes to manage conflicts. “If we tackle this institution by 

46 COI AND MEDICAL INNOVATION institution, university by university, company by company, I don’t see us getting there,” she said. New management models for balancing conflict of interest and innovation have arisen in part because of a shortage of resources, and this period of experimentation may help develop creative ways to align incentives and accelerate progress, she said. One area for testing these models could be in the pre-competitive space for collaborat- ing on projects. Sherer suggested that including metrics related to tech- nology transfer in tenure and promotion considerations would encourage partnerships with industry, as would leave policies that permit faculty members to join a startup company. Increasing Public Knowledge About Conflict of Interest Clarification, simplification, and harmonization of conflict of interest rules could help foster the measurement of public knowledge about the value of relationships to research and the positive outcomes resulting from these relationships, Billings said. The value of collaboration needs to be documented so as not to let conflicts needlessly prevent medical advances. “All of the drugs that I use in my clinical practice, all of the technologies I apply to my patients, have come out of industry–academic collaborations,” said Cohen. “That relationship is absolutely critical to making advances.” The public dissemination of information about industry payments to physicians required by the Physician Payments Sunshine Act will pro- vide much-needed changes for conflicts of interest policies, several workshop participants stated. Chisolm observed that information dissem- inated by the Physician Payments Sunshine Act is going to generate questions, but these questions provide an opportunity for public educa- tion about the nature, benefits, and risks of industry partnerships with academia. Lichter predicted that disseminated disclosure information would not be damaging. In one case he described, when a local newspa- per published the salaries of faculty members, the repercussions were minor, despite fears that the information would be misused. Unless there are problems with an interaction that is revealed through the Physician Payments Sunshine Act, Lichter said, individuals should have nothing to fear from having their relationship made public. “If you’re ashamed of it, don’t do it,” Brem said. Providing the public and policy makers with information about rela- tionships requires thinking about what people need to know to arrive at a decision, McMurry-Heath said. Lichter stated that more research is need- 

MANAGING CONFLICT AND FACILITATING INNOVATION 47 ed about the views that patients, families, and the broader public hold about these kinds of relationships. Some relationship information will be relevant, while other information will not matter. “We need to think about who needs information about those relationships, in what context they need them, and how we can deliver it to them most readily so that they start to utilize the information that’s available,” McMurry-Heath said. PUTTING PATIENTS AT THE CENTER OF CARE Patients have a specific interest in biomedical research, and that in- terest is obtaining faster and more effective treatments, Anderson ob- served. She suggested that the needs of patients should be kept front and center in discussions of conflicts of interest. “If you do that, everything becomes easier—[determining] who you need to talk to, learn from, and share best practices with.” Conflicts of interest look very different to a patient who has just been diagnosed with a life-threatening disease, she said. Patients may also view relationships differently depending on the extent of the compensation, Chisolm said. Bringing patients into this conversation is critical, Pierce agreed, because a focus on the needs of patients can help reveal what the important issues are and how best to address those issues. A large body of evidence indicates that physicians are influenced by financial incentives, Lichter said. The challenge is to set up systems where those incentives become less prominent and where the needs of patients become the overriding concern. FDA still has difficulties incorporating patient advocates and indus- try representatives into advisory panels that are considering a specific product, McMurry-Heath acknowledged. Advocates may be nonvoting members of panels, but their voices need to be better incorporated into the decision-making process, she said. Recent legislation directed FDA to incorporate patient voices into its regulatory decision making, and the agency has an initiative designed to explore methodologies for measur- ing patient preferences. Patients should have a better understanding of what academic medi- cal centers do to identify, pursue, analyze, and restrict the activities of physicians and scientists because of their financial interests, Chisolm said. The medical community needs to do a much better job of informing patients what is done to eliminate bias and to maintain the integrity of research, he said. Patients should be able to make their own decisions 

48 COI AND MEDICAL INNOVATION about whether to let a conflict influence the care they receive, Brem said. For example, a patient may prefer to get a drug from a physician who helped to develop that drug because that physician is likely to be an ex- pert on that particular therapeutic. The critical issue is what is important to the patient, Cohen said. “What are we trying to accomplish, and then how can we together ac- complish that goal?” Conflicts need to be disclosed if they are relevant to the underlying goal for patients, but if they are not, conflicts may not be part of the dialogue, he said. There is not an effective mechanism for ad- dressing conflict of issues as they pertain to patients. Forming collaborations that foster innovation is one way to achieve the objective of meeting the needs of patients, Billings said. Cohen ob- served that personalized or precision medicine may mean bringing mul- tiple drugs to market for smaller populations, which will require new approaches to measuring the effects of treatments on patients. Terry add- ed that such data could also be used to measure the benefit or harm to a patient of a particular relationship. Lo agreed that the benefits of rela- tionships should be emphasized in addition to identifying potential harms. Terry noted that a number of themes emerged during the workshop (see Box 5-1). “I have the largest conflict of interest of anybody in the room because I represent my family who lives with genetic disease and also all the families that do live with disease. We’re not afraid of that conflict because at the end of the day, that’s why we’re all here,” said Terry. It is crucial, Anderson said, “to be sure that we are not protecting ourselves at the expense of accelerated delivery” because patients are waiting for treatments and physicians want to offer effective therapies. Everyone at the workshop, whether representing government, indus- try, or academia, also represents a patient who needs care, Terry said, and all of them therefore have an interest in improving patients’ lives through the management of productive relationships that allow collabora- tions to move forward. “The urgency we feel when we’re sick or when our parents are sick or when our children are sick, is the urgency we need to bring forward into all these conversations and actions.”