Wendy R. Sanhai, Ph.D., M.B.A. Senior Scientific Advisor Office of Chief Scientist

1. ANALGESIC CLINICAL TRIAL INNOVATIONS, OPPORTUNITIES, AND NETWORKS (ACTION)ACTION Inaugural Workshop 6-15-11

2. Evolution of the ACTION Initiative and Public Private Partnerships in the Context of FDA’s Public Health Mission and Regulatory Science Wendy R. Sanhai, Ph.D., M.B.A. Senior Scientific Advisor Office of Chief Scientist Office of the Commissioner, FDA 2

3. FDA’s Mission Statement • “The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. • The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate,science-basedinformation they need to use medicines and foods to improve their health.”

4. Public Health Context: “Unmet Need” • The most widely used analgesics are opioids, NSAIDs and acetaminophen • All have serious toxicities, even when used properly • Development of novel analgesic products has been slow and challenging • Clinical trials frequently fail to show efficacy • Pharmaceutical industry is reluctant to take on the risk of developing of novel analgesics due to hurdle of achieving successful outcomes in expensive clinical trials

5. Current State of Affairs • Clinical studies, particularly efficacy trials, notoriously flawed for analgesic drug development • Frequent studies failures with drugs known to be effective • Extremely small treatment effects even when successful • Multiple causes, e.g.: • Large placebo effect • Missing data • Study design flaws • Study analysis flaws • Investigator quality • Frequent use of foreign sites

6. Overall ACTION Objectives • To conduct critical research, including analysis of existing data to: • improve the success rates of analgesic trials and guide the design of future trials • facilitate efficient development of safer and more effective analgesic drug products

7. Why Public Private Partnerships? • Any single party: limited resources (staff, funds, infrastructure, equipment…), time and expertise • Leverage resources and expertise among stakeholders to minimize costs (time and money) • Align missions toward mutually beneficial goals • Open new lines of communication among partners • Create value added for all stakeholders: optimizing economies of scale…advancing public health • Whole = Greater than sum of individual parts/partners

8. …It will take a village • Pain researchers and clinicians(academia, other research institutions) • Professional organizations • Government agencies • Pharmaceutical and device companies • Patients and patient advocacy organizations • Non-profit foundations

9. Building the Foundation for ACTION(prior to ACTION PPP launch; All funding from CDER) • Three initial projects • 1 data reanalysis project • 1 clinical protocol development project • 1 data transformation/standardization project • Partners • Univ. Pennsylvania • SAS Institute/Executive Information Services (EIS) • Funding: • FY ’07: $50K; FY ’08: $250K; FY ’09: $500K

10. ACTION Timeline First ACTION Discussions (FDA) ACTP Workshop (Ashburn) ACTION Contract Solicitation ACTION Manuscript published ACTION Inaugural Workshop ACTION/ IMMPACT Discussions FDA-internal ACTION contract process begun ACTION Contract to U Rochester ACTION Cooperative Agreement RFP

11. 2010 ACTION Contract • Issued in September 2010, under the Critical Path Initiative • Aggressive 1-year timeline • Goals: • Establish ACTION PPP: robust foundation for future activities • Governance board • Operating principles • Scientific oversight committee • Perform analysis of selected pain trial data • Conduct scientific workshop (June 15, 2011)

13. PPP Operating Principles • Transparency: maintain public trust • Inclusion of interested/affected stakeholders • FDA, industry, academia, professional societies, patient advocates, NIH, other gov’t, … • Leveraging resources • Existing and prospective data • Claims data • Personnel & scientific expertise • Project funding • Focused on public health and efficient product development • Mutually beneficial to partners

14. ACTION PPP Governance Structure Executive Committee (EC) Board of Advisors (BOA) Scientific and Professional Advisory and Recommendations Committee (SPARC) ACTION Coordinating Center / Steering Committee Working Groups (WGs): EC and SPARC approved projects and activities

15. Identify gaps/opportunities (avoid duplication) • Identify partners: define roles/responsibilities • Co-develop: proposals, budgets, timelines etc. • Leverage resources/expertise • Implement joint Proof of Concept projects • Share data in public domain as quickly as appropriate: Pre & Pro-competitive tools Some Benefits PRIVATE PARTNERS: Regulatory Knowledge, Predictive Tools & Input in Project Selection FDA: Guidances, Standard-setting, Evaluative Tools PAITENTS: Faster, Safer and Cheaper Medical Products!!!! Basic Steps in Collaborating with FDA (not comprehensive! not consecutive!) Start with the Public Health Need, SCIENCE! Identify Priorities for multiple stakeholders

16. Elements of a PPP SCIENCE PPP BUSINESS • Develop business plan/strategy • Create governance/Adm Oversight • Identify & recruit partners • Negotiate agreements, IP etc • Administer/manage contracts • Manage conflicts of interest • Develop data sharing guidelines • Develop reports/output analysis • Develop protocols, timelines • Determine public health questions • Obtain stakeholder input • Identify other efforts: join, expand • Coauthor scientific articles • Interpret scientific data

17. Some Elements of Business Model • Pooling: IP, resources, expertise… • Share Data: Proprietary, Pre-clinical, clinical, pro-competitive? • Models: Sematech, SNP & Biomarker Consortia, C-Path Institute • Contracts/Agreements with timelines, deliverables, specific terms and conditions? (Licenses: non-exclusive commercial, research-use?) • Implement POC project/s • Develop: Research/predictive tools, know-how, guidances • Employ multiple mechanisms Data/Deliverables FDA Guidances R&D, CMS, Clinical Decisions

18. ACTION Plan • RFI issued on 12/18/09 • Responses reviewed and elements incorporated into ACTION RFP • ACTION Initiative RFP issued on 7/22/10 • Elements of the RFP….

19. ACTION RFP Develop Strategic Plan in order to: • Identify and establish relationships with key experts in the field • Create an Executive Committee with representation from key stakeholders • Establish an independent scientific oversight body to coordinate the overall scientific mission of the ACTION Initiative • Develop methodologies for the transformation of pooled trial data from multiple analgesic trials

20. General Funding Model Whole is greater than sum of parts/partners Public Private Only Private Public Only Individually or in groups launch project/s Launch PPPs with combination of public/private funds with mutually beneficial goals and objectives FDA, NIH, CMS Other government Data, new guidances, best practices, informed clinical decisions, evidence based medicine Effective & safe medical products to patients faster, and more efficiently

21. State Funds Grants Appropriations Other… Private Funders Potential Sources of Funding ACTION Project 1 Project 3 Project 2

22. ACTION Executive Committee Co-Chairs • American Academy of Neurology • American Academy of Pain Medicine • American College of Rheumatology • American Pain Society • American Society of Anesthesiologists • Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) • International Association for the Study of Pain • Outcome Measures in Rheumatology (OMERACT) • ACTION liaisons: • EuroPain • German Neuropathic Pain Research Network

23. Partners Agreements Partnership Projects Public Health Need

24. ACTION ongoing activities • Methodologically-focused meta-analyses of publicly-available randomized clinical trials • e.g., neuropathic pain, osteoarthritis • Methodologically-focused retrospective analyses of patient-level raw data provided by FDA and by industry • STandardized ANalgesic DAtabase for Research, Discovery, and Submissions (STANDARDS) • development of CDISC-compliant database format for retrospective pooling and prospective use • Request for Information Draft Strategic Plan Request for Proposals • Scientific Workshop at FDA White Oak facility (6/15/11) • identify obstacles and finalize Strategic Plan

25. FUTURE “ACTIONS” • Research • Facilitate collaborations among stakeholders • Sponsor analyses of pooled legacy data • Develop more efficient clinical trial designs • Reduce patient burden and study costs • Explore biomarkers and patient phenotyping

27. 2011 FDA Strategic Priorities • Transforming development of medical countermeasures against threats to US and global health and security • Innovation in product development and evaluation: biomarkers, personalized medicine and effective clinical studies • Harnessing diverse data through information science to improve public health • Modernizing toxicology and risk assessment to better predict safety • Supporting new approaches to improve product manufacturing and quality • Protecting the food supply • Assuring FDA’s readiness to evaluate new and emerging technologies • Advancing behavioral science to empower informed decision making and use of products by professionals and consumers