FDA’s Sentinel Initiative and CBER's Analytic Epidemiology Branch

1. FDA’s Sentinel Initiativeand CBER'sAnalytic Epidemiology Branch Robert P. Wise, MD, MPH Acting Deputy Director, Division of Epidemiology CBER Office of Biostatistics and Epidemiology for presentation to the Blood Products Advisory Committee Gaithersburg, MD, July 21, 2009 FDA’s Sentinel and CBER's AEB

2. Agenda • Background on Medical Product Safety Surveillance • FDA Sentinel Initiative • CBER Analytic Epidemiology Branch FDA’s Sentinel and CBER's AEB

3. SAFETY THROUGH THE LIFECYCLE FDA’s Sentinel and CBER's AEB

4. FDA Amendment Act (FDAAA)New Authorities and Roles Require postmarketing studies and clinical trials to assess a serious risk or signal of a serious risk Require sponsors to make safety-related labeling changes Require sponsors to develop and comply with risk evaluation and mitigation strategies (REMS) To develop validated methods to establish a postmarketing risk identification and analysis system to link and analyze safety data from multiple sources, with goals of including, in aggregate, at least 25 million individuals by July 1, 2010 and 100 million individuals by July 1, 2012 FDA’s Sentinel and CBER's AEB

5. FDA’s Sentinel Initiative FDA’s Sentinel and CBER's AEB

6. Sentinel Overview Develop an active electronic safety monitoring system to Strengthen FDA's ability to monitor postmarket performance of medical products Augment, not replace, existing safety monitoring systems Enable FDA to access existing automated healthcare data by partnering with data holders (e.g., insurance companies with large claims databases, owners of electronic health records, others) Data remains with data holders behind existing firewalls Data holders run queries requested by FDA or potentially others, or they can decline Convey only results for review According to strict privacy and security safeguards FDA’s Sentinel and CBER's AEB

7. How does Sentinel complement whatFDA already does? • Safety issues can be identified and evaluated in near real time • Sentinel expands the capacity for evaluating safety issues • Improved access to subgroups, special populations • Improved precision of risk estimates due to expanded number of populations available for study • Active surveillance can identify an increased risk of common AEs (e.g., MI, fracture) that health care providers may not suspect are related to medical products FDA’s Sentinel and CBER's AEB

8. Sentinel Work in Progress May 2008: Sentinel Initiative launched with initial report Long-term project; implemented in evolutionary stages Currently working on the “how and what” Using broad public forum and collaborations, FDA is : Delineating possible governance structure and functions Developing mechanisms for shared learning from on-going related activities (scientific and methodologic projects) Identifying steps necessary to ensure strict privacy and security safeguards 8 FDA’s Sentinel and CBER's AEB

9. Sentinel FDA Infrastructure Based in Office of Critical Path Programs (OCPP), OC Sentinel Senior Management Team (SMT): representatives from each Center plus OC informatics, privacy, and planning staff SMT ensures involvement of appropriate representatives and subject matter experts (SMEs). Provides project briefings and updates to the FDA Centers and Offices Assists in prioritizing requirements and system functions Ensures the initiative is carried out responsibly and in a timely fashion 9 FDA’s Sentinel and CBER's AEB

10. Sentinel Methods Working Group • Agency epidemiologists from OCPP and the medical product Centers (CDER, CBER, CDRH) • Provides expertise to assist in developing scientific and technical aspects • Contributes experience from activities in Centers to inform Sentinel • Members function as Agency representatives to Sentinel-related activities conducted by outside organizations FDA’s Sentinel and CBER's AEB

11. Progress to Date - Meetings March-October 2008: Multiple stakeholder meetings December 2008 public workshop May 2009 CBER/CDER/CDRH Joint Rounds Sentinel overview for FDA community Presentations of contract deliverables by 4 of 8 contractors June 2009 Internal FDA Sentinel Summit Began discussions on how FDA will identify and prioritize the medical product – AE pairs that would potentially be studied in pilots and eventually within Sentinel Each medical product Center has internal processes for evaluating postmarket safety issues which will need to interface with Sentinel for input (queries) and output (results) FDA’s Sentinel and CBER's AEB

12. Progress to Date - Federal Activities Federal Partners Working Group Share information and discuss issues related to complementary efforts being carried out by the various Agencies within the Federal government Participants include FDA, ONC, NIH, CDC, CMS, DoD, VHA, AHRQ, IHS, HRSA, OHRP, and CPSC Collaborations with CMS, DoD, and VHA Several ongoing projects within medical product Centers to evaluate potential medical product-adverse event signals and develop active surveillance and statistical methodologies SafeRx project with CMS to develop near-real time active surveillance methods using Medicare data FDA’s Sentinel and CBER's AEB

13. Progress to Date - Contracts Scientific Operations • Defining and Evaluating Possible Database Models Harvard Pilgrim Healthcare • Evaluation of Existing Methods for Safety Signal Identification Group Health Cooperative Center for Health Studies • Evaluation of Timeliness of Medical Uptake for Surveillance in Healthcare Databases- IMS Government Solutions Governance 4. Developing a Governance and Operations Structure for Sentinel Initiative eHealth Initiative FDA’s Sentinel and CBER's AEB

14. Progress to Date – Contracts (continued) Data and Infrastructure • Evaluation of Potential Data Sources for Sentinel Booz Allen Hamilton • Evaluating Potential Sentinel Network Sources for Blood and Tissue Product Safety Surveillance and Studies Pragmatic Data 7. Evaluation of Potential Data Sources for a National Network of Orthopedic Device Implant Registries- Outcome Sciences, Inc. Privacy 8. Engagement of Patients, Consumers, and Health Care Professionals in Sentinel Initiative eHealth Initiative FDA’s Sentinel and CBER's AEB

15. Progress to Date - Communication Updated Website Include deliverables from completed contracts Open docket for comments Create listserv Implementing “Discuss This” capability to share comments Developed video explaining the Sentinel Initiative, now on the Sentinel Website http://www.fda.gov/Safety/FDAsSentinelInitiative FDA’s Sentinel and CBER's AEB

16. Progress to Date – Collaboration with Observational Medical Outcomes Partnership (OMOP) Public-Private Partnership with FNIH, FDA, and PhRMA Conducts experiments on value, feasibility, and utility of observational data to identify and evaluate safety risks and benefits of prescription drugs range of analytical methods applied to multiple data sources adjunct to and expansion of current tools and sources Tests approaches for creating the infrastructure for accessing and managing required data, e.g., in multiple claims and electronic health records data sources Enables evaluation of a possible governance model, consisting of an Executive Board with scientific and technical advisory noards FDA’s Sentinel and CBER's AEB

17. Progress to Date – Collaboration with eHealth Initiative’s Drug Safety Collaboration Tests and analyzes the value and utility of using electronic health information to detect and evaluate drug safety signals with various kinds of data (claims, claims plus lab, clinical information) Explores opportunities for using clinical information in electronic databases of two large health information exchanges to identify and assess known drug-adverse event associations Warfarin & bleeding Statins & liver toxicity Designated Medical Events FDA’s Sentinel and CBER's AEB

18. Next Steps - Contracts Contract under development to allow for various task orders to support future development of scientific operations The first task order = "Mini Sentinel” RFI posted February 20, 2009 Synopsis posted May 15, 2009 Solicitation posted June 19, 2009 FDA’s Sentinel and CBER's AEB

19. Mini Sentinel Develop a distributed data model Access three health data environments with varied attributes to conduct analyses Convene a Planning Board to develop governing documents Establish a Safety Science Committee for day-to-day operations Develop an infrastructure for communication and queries Identify and prioritize potential medical product-event pairs for evaluation Engage appropriate legal counsel to identify and address data privacy and security issues related to the conduct of this pilot Evaluate epidemiologic and statistical methods for signal detection, signal strengthening, and hypothesis testing Synthesize lessons learned Identify obstacles to development of a working Sentinel System Prioritize obstacles and identify methods to overcome them Identify resources required to remove each obstacle FDA’s Sentinel and CBER's AEB

20. CBER’s Analytic Epidemiology Branch FDA’s Sentinel and CBER's AEB

21. Challenges Diversity of biologics products requires multiple surveillance and safety assurance strategies Open-ended and real-time safety surveillance essential for earliest detection of unanticipated AEs New authorities, funding and technologies offer important promise for more robust capabilities to recognize signals earlier and to evaluate them systematically and efficiently FDA’s Sentinel and CBER's AEB

22. Working with Medicare: Background • Approximately 45 million persons enrolled include • 38 million elderly (age >65 years) • 7 million others with disability or end stage renal disease • Individual health utilization data available for the approximately 85-90% enrolled in fee-for-service Medicare • Prescription drug benefit started 2006 • SafeRX: Collaborative effort (interagency agreements) between FDA and the Centers for Medicare & Medicaid Services (CMS): FDA’s Sentinel and CBER's AEB

23. Cellulitis vs. UTI* Hospitalizations <30 Days of Pneumococcal Vaccination† Number of Hospitalizations Days before vaccination Days after vaccination Date of vaccination * UTI 5% Sample † Among 1.7 million vaccinees in 2001 Spike in cellulitis hospitalizations after pneumococcal vaccination FDA’s Sentinel and CBER's AEB

24. TRALI among U.S. elderly inpatients in Medicare claims data, 2007 • Background: • No published population-based TRALI studies among U.S. elderly • AEB staff have previously employed CMS data to describe blood product utilization among the elderly • TRALI study: Assess occurrence in recent CMS data • Methods • Use ICD-9 diagnosis and procedure codes • Exploratory analysis of TRALI rates among inpatients using Medicare claims for 2007 among elderly with recorded transfusions FDA’s Sentinel and CBER's AEB

25. TRALI, continued • Assess TRALI by product (rbc’s, platelets, plasma) • Compare TRALI diagnosis hospitalizations to others by: • Demographic characteristics of transfusion recipients; • Clinical diagnoses and procedures; • Predisposing factors (transfusion, recipient, donor) for TRALI occurrence; • Identify possible preventive factors for TRALI occurrence • Describe TRALI severity and mortality; • Conduct Medical Record Review: • Validate TRALI diagnosis and further assess risk factors • Transfusion (product type, processing, quantity, age) • Donor (antibody status, demographic characteristics, etc.) • Recipient (diagnoses, procedures, demographics, etc.) FDA’s Sentinel and CBER's AEB

26. AEB’s 2008 RFP • In 2008, AEB issued a Request for Proposals (RFP). • Primary goal: access data to: • Respond to urgent public safety concerns on usage of vaccine, blood, and tissue products • Conduct collaborative mission-oriented pharmacoepidemiolgic research to test hypotheses on vaccine, blood, or tissue product safety and effectiveness, including those arising from adverse events reported to FDA. • Develop improved methods for rapid detection of adverse events from biological products in large U.S population-based data sources. FDA’s Sentinel and CBER's AEB

27. Example RFP Task Order:Idiopathic Thrombocytopenic Purpura (ITP) after Vaccination • In Collaboration with Harvard Pilgrim/HMORN, building on previous VSD study • Background: • Known association between MMR vaccination and ITP • Unclear if also with other vaccines. • Objectives • To assess incidence/risk factors for ITP after routinely administered vaccines • Enlarge and refine research network infrastructure for future studies, allowing for more efficient and timely monitoring of AEs, including near real-time monitoring FDA’s Sentinel and CBER's AEB

28. Other AEB Collaborations • Evaluation of Serious Adverse Events after Herpes Zoster Vaccine in the Medicare population • MMR and Anaphylaxis in DoD/MILVAX • Rapid cycle evaluations in CDC’s Vaccine Safety Datalink • H1N1 Vaccine Safety Evaluation in DoD/MILVAX • EMEA and Canadian regulatory authorities and Health Canada, for coordination of pharmacovigilance activities and information exchange. • FDA and CDC expect to collaborate with WHO and others to foster technical capacity for H1N1 vaccines adverse event investigations FDA’s Sentinel and CBER's AEB

29. FDA’s Sentinel and CBER's AEB