Eli Lilly and Company - Comment

July 17, 2009 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852. Via Internet to: http://www.regulations gov Re: Docket Number: FDA-2009-N-0192-0006 Dear Sir(s)/Madame(s), We are pleased to submit comments on the Sentinel Initiative contractual report entitled “Developing a Governance and Operations Structure for the Sentinel Initiative” [Docket Number: FDA-2009-N-0192-0006]. We support the Food and Drug Administration (FDA) in their efforts to develop the Sentinel Initiative as required by Section 905 of the Food and Drug Administration Amendments Act (FDAAA) of 2007. We also applaud FDA in soliciting input and comments from stakeholders and making this information available to the public. We look forward to the continued development of the plans for implementing the Sentinel Initiative. We also look forward to providing additional comments and insights once more specific information regarding the implementation of the Sentinel Initiative is outlined. As the Sentinel Initiative is envisioned to strengthen FDA’s ability to monitor the performance of marketed products, there are a number of elements that will need to be addressed in order to have a successful and sustainable Sentinel system. These include topics such as governance, operations, database models, data sources, scientific methods, communications, privacy, and legal considerations. For the current governance report, we would like to commend the eHealth Initiative in their efforts to outline options for governance and operations for a collaborative effort to support the Sentinel Initiative. Overall, this is a very good assessment of elements that need to be considered and decided upon for governance and operations. We recommend that FDA maintains regulatory authority over the Sentinel system, regardless of governance structure that is selected for the Initiative. The policy committee should think very carefully about how they will address various scenarios that are likely to occur in the collaborative efforts of the Sentinel Initiative, including considerations of communication plans, engagement of participating data environments, and issues regarding failure to notify, conflict of interest, and lessons learned. The details of our comments are provided below. Specific Comments on Sentinel Initiative - Governance Report 1) Communication Plans: The document outlines the potential scope of responsibilities of the policy committee. We would suggest that the policy committee also have a role in developing policies to guide the communication plans for the Sentinel Initiative studies. We believe that transparency will be critical to the success of the Sentinel Initiative. As part of the effort to achieve transparency and clarity in communication, the policy committee might provide guidance on how to communicate the different types of studies (e.g., signal detection, signal confirmation, etc.) that are being undertaken as well as the timing of communication of research results and the intended audiences for the communication. The policy committee should also consider communication that helps patients understand how this type of research is conducted. Patients may incorrectly assume that all data analyses are conducted on de-identified data, not realizing that patient charts are also being used to verify data in the databases. This would enhance the transparency of the initiative. 2) Research Experts: The document very clearly outlines some of the potential strengths and weaknesses of various governance models. Under at least one of the options, other sources of funding, including other government agencies and private sector entities, would be permitted. Given that this collaborative research initiative will be a tremendous resource for researchers seeking to address a wide range of questions on the benefit-risk profiles of medications, we believe that a governance structure that accommodates the needs of qualified external researchers in pharmacovigilance will contribute to the overall value of the Sentinel Initiative. 3) Role and Engagement of Data Environments: Under roles and expectations for participating data environments (page 22), the first bullet point states that the participating data environments will be expected to “apply agreed- upon methods to query their data environments, to confirm or rule-out suspected safety issues or to identify and evaluate new safety issues, delivering aggregated, de-identified results to the collaborative effort and the FDA”. While we recognize the importance of applying ‘agreed-upon’ methods, an important part of the governance model must include guidance on the role that the participating research groups in different data environments would have in helping to develop the analytic plan. Given that different groups of researchers working through a proposed research question may gain unique insights into how to approach the analysis (e.g., the recognition of potential confounding variables, the need for specific sensitivity, etc.), we believe that it is important that the governance model provides the different participating research groups with the opportunity to participate in providing suggestions for the development of the analysis plan. Some of the suggestions to improve the analysis plan might only be provided by researchers in the data environment after they have had an opportunity to review their data, including, for example, the distribution of values for variables that might be included in the analysis. We agree that the expert panel will need to play a significant role in determining the analysis plan. On page 29, the document notes that “An expert panel should be engaged to inform the methods that should be applied for each query and final decisions should be made by the FDA”. On page 31, it is written that “it is likely that the collaborative effort will want to engage an expert panel, and in some cases [italics added], the data environments themselves, to assist with addressing the above-identified questions”. We believe that the data environments should be involved in these issues as the usual practice rather than as an exception to the usual practice. 4) Communication of Study Results: The document notes that entities/data environments that are chosen to participate in a particular Sentinel Initiative study will need to agree to the conditions governing their participation. As part of these conditions, it will be important to provide some clarity on the roles and responsibilities around the communication of study results. For example, in cases where participating researchers in different data environments arrived at differing study results, would the different research groups be permitted to publish their results, in addition, to contributing data to a separate publication based on the aggregated study results from all participating data environments? This potential conflict might arise, for example, if researchers in one data environment believe that their analysis was improved by the inclusion of study variables (e.g., body mass index, blood pressure readings, measures of disease severity, patient- reported outcomes) that were not available to researchers in all of the other data environments. The expert panel and the policy committee will need to provide guidance on how inconsistent results across the data environments should be dealt with. We also believe it is important that any communications resulting from Sentinel analyses be conveyed in a manner that appropriately balances the risks and benefits of the studied medications and believe all participants must be committed to such balance regardless of whether individual researchers or the aggregate Sentinel effort are communicating results. 5) Failure to Notify: Under potential barriers to participation (page 23), the first bullet point notes the fear of potentially increased liability over “failure to notify”. This is an important area that will need to be addressed by the policy committee. In absence of clear guidance, it is possible that researchers in different data environments receiving different legal, ethical, and policy advice from within their separate institutions might reach different conclusions about potential liability. Prior to all of the results being aggregated it is possible that, without clear guidance, the individual institutions might feel that they are obligated to communicate their study findings even before the results are aggregated with those from other data environments and communicated as a whole in cases in which their analyses point to a potential problem with a particular product. FDA should spell out requirements for communicating results in agreements with data providers. At a minimum, FDA should be notified first. 6) Conflict of Interest: The document discusses the importance of addressing conflicts of interest (page 23). A number of the data environments that might be best suited to participate in the Sentinel Initiative through their databases and research expertise are the same data environments that independently analyze their databases to address research questions raised by entities in the private sector. For example, pharmaceutical manufacturers frequently fund retrospective database research in a range of data environments focusing on epidemiology, treatment patterns in different conditions, and the benefits and risks of medications. In addition to these retrospective studies, some of these entities may also receive funding for conducting prospective clinical trials of medical interventions. This research, disseminated in the medical literature, can make important contributions to the understanding of diseases and their associated treatments. It would be unfortunate if, as an unintended consequence of the conflict of interest policy for the Sentinel Initiative, this type of privately-funded research greatly decreased as data environments chose to avoid this research as a perceived barrier to their ability to participate in Sentinel. This potential is recognized on page 26 of the document with the language that barring from the collaborative effort data environments that currently receive funds from any medical product manufacturer “will likely reduce considerably the pool of data environments that will participate in the collaborative effort.” As researchers, we want the most suitable data environments to be available for both publicly –funded research like the Sentinel Initiative as well as privately-funded medical research. Simply receiving funding from the pharmaceutical industry for other retrospective database studies should not be considered a conflict of interest that prohibits participation in Sentinel. Rather, conflicts of interest should be decided on a case- by-case basis, focusing on the extent of the funding, whether the analyses in question have a significant relationship to each other, and the policies that protect research integrity. While the nature of the research studies is important to consider, we do not necessarily believe that a distinction should be made based on whether the queries are “research” or “active surveillance”. Both research and active surveillance are important activities for promoting patient safety. 7) Data Quality: On page 23, the document discusses important considerations when determining which data environments should participate in Sentinel studies. The “characteristics” of the data is included as one factor to consider. It may be worth explicitly including an evaluation of the quality of the data as one of the data characteristics. 8) Selection of Data Environments: We strongly agree with the ability of the collaborative effort to make adjustments to the list of data environments chosen to participate (and not base solely on the RFP scores, page 24). It is possible, for example, that the collaborative will want to select data environments for a particular analysis such that the appropriate mix of data environments (with different strengths and weaknesses) is chosen. 9) Lessons Learned: While we agree that it is important to have time to discuss “lessons learned” about process issues after each project (page 36), it also is important to consider whether there are some concerns or “lessons learned” that should be considered prior to an analysis or query being considered “completed”. It is possible that some of these lessons learned might actually impact the final analysis and the resulting study findings. We appreciate the opportunity to comment on the current governance report. Please let us know if you have questions or need additional clarifications. We would also welcome the chance to provide additional comments and insights as more detailed information is released on the Sentinel Initiative. Sincerely, Donald G.Therasse, M.D. Vice President, Global Patient Safety Lilly Research Laboratories Eli Lilly and Company