Octo ber 2013

1. October 2013 DIA Clinical Forum Workshop Pamela Tenaerts

2. The Clinical Trials Transformation Initiative • Public private partnership co-founded by Duke and FDA in late 2007 • All stakeholders involved • Through a MOU with FDA, Duke convenes the initiative Mission To identify and promote practices that will increase the quality and efficiency of clinical trials Vision A high quality clinical trial system that is patient-centered and efficient, enabling reliable and timely access to evidence-based prevention and treatment options

3. Why CTTI Formed  U.S. clinical trials in crisis • Trial start-up times lengthening • Enrollment slowing • Costs increasing • Many investigators pulling out of clinical research  Increasing need for reliable evidence • To evaluate new devices, drugs, biologics • To determine best medical practice • To compare effectiveness of diagnostic and therapeutic alternatives

4. Need for reliable evidence from clinical trials • Essential for appropriate decision making concerning the benefits and risks associated with clinical interventions. • Decisions made in the absence of reliable evidence may harm individual patients and public health • relevant trials have never been performed • trials that have been performed were poorly designed or conducted • trials have been performed but results are not known

5. Strategy Identify and shape potentialtransformational changesto the system Seekincremental improvements to current system Consider portfolio improvements of clinical trials being done relative to public health needs

6. How does CTTI seek to effect incremental change? • Involve all sectors in selection, conduct, and interpretation of projects • Identify and eliminate activities in the conduct of trials that do not add value • Understand incentives to maintain non-value-added activities • Maintain an open and respectful dialogue across sectors • Develop solutions that are mindful of the needs of patients and all sectors in the clinical research enterprise

7. Organization Provides oversight and strategic direction Gives input into strategy and project selection. Conducts projects and develops strategies for implementation of project results Engages patient advocates as integral part of CTTI activities Support projects and organization in pursuit of mission Executive Committee (EC) Steering Committee (SC) (member organizations representatives) Patient Leadership Council (PLC) CTTI Staff

8. EC Members Co-chairs Robert Califf (Duke) Rachel Sherman (FDA/CDER) Members Hans-Georg Eichler (EMA) Richard Platt (Harvard) Dalvir Gill (TransCelerate) Nancy Roach (Patient Rep) Louis Jacques (CMS) Jean Rouleau (Montreal Heart) Richard Kuntz (Medtronic) Joe Selby (PCORI) Michael Lauer (NIH/NHLBI) Robert Temple (FDA/CDER) Elliott Levy (BMS, SC rep) Veronica Todaro(PLC rep) Freda Lewis-Hall (Pfizer) Tom Walley (NIHR) Deven McGraw (CDT) Bram Zuckerman (FDA/CDRH) Briggs Morrison (AstraZeneca)

9. SC Membership

10. Patient Engagement • Patient representatives serving on Steering Committee and Executive Committee • Included in workshops, expert meetings, and projects CTTI’s Patient Leadership Council (PLC) • Collective voice with patient advocacy organizations (PAO) and voluntary health agencies (VHA) to work together to affect systemic improvement within the clinical trials enterprise • Initiate patient-driven panels, events and projects that improve the quality and efficiency of clinical trials

11. Patient Engagement In 2012, CTTI conducted interviews with key thought leaders in patient advocacy to gain an understanding of the patient perspective on clinical trials. Issues were raised around: • Informed consent • Inefficiencies in the system such as multiple IRB reviews • Waste of patient time and participation • Lack of access to research findings • Lack of meaningful inclusion of patient advocates in the clinical trial enterprise from study design to dissemination of research results

12. Finances • Financial resources from public and private sources • annual membership fees • infrastructure and projects • FDA cooperative agreement • additional support for projects • In kind contributions of effort from FDA and membership organizations

13. Why CTTI Works “Because of the broad array of engaged stakeholders, CTTI is in a unique position to drive major changes in the clinical trial system in the midst of massive global reforms.” Rachel Sherman, M.D., Director for the Office of Medical Policy at the FDA’s CDER Co-chair of the CTTI Executive Committee

14. Key CTTI Accomplishments • Generated evidence and formulated implementable recommendations that have informed regulatory guidance • Created an inclusive forum that is influencing policy • Increased patients’ voice to improve clinical research • Raised questions about the portfolio of clinical trials as it relates to public health needs

15. Future Direction • Focused on transformation • Strong, balanced portfolio of projects that inform and support policies and practices • Continue needed incremental improvements • Assist in transforming trials by better integrating clinical research with clinical practice • Larger number of projects/initiatives • Better engagement of stakeholders to facilitate meaningful change (members, patients, collaborators)

16. Methodology

17. Portfolio of CTTI Projects PROJECT PORTFOLIO – September 2013

18. GCP Training PROJECT PORTFOLIO – September 2013

19. Informed Consent PROJECT PORTFOLIO – September 2013

20. Large Simple Trials PROJECT PORTFOLIO – September 2013

21. Patient Engagement PROJECT PORTFOLIO – September 2013

22. Recruitment and Retention PROJECT PORTFOLIO – September 2013

23. Site Metrics PROJECT PORTFOLIO – September 2013

24. State of Clinical Trials PROJECT PORTFOLIO – September 2013

25. Uses of Electronic Data PROJECT PORTFOLIO – September 2013

26. Safety Projects • Original SAE project (2009-2010) • IND Safety Assessment and Communication • SAE case studies project

27. 2009-11 CTTI Project • Focused on expedited reporting from sponsors to site investigators • Investigators had complained of a large volume of expedited reports that were not interpretable as individual cases • Recommendations: • Decrease the volume of uninterpretable and irrelevant safety reports to investigators • Supply investigators with meaningful reports that would improve investigators’ understanding of a drug’s safety (benefit-risk) profile. • Engage patient groups to discuss optimal systems for safety reporting to investigators and patients during the conduct of a trial; re-evaluate consent language

28. IND Safety Assessment and Communication Project September 29, 2010: FDA issued a Final Rule on IND safety reporting (effective 3/28/2011) FDA intended to reduce the number of uninterpretable reports by clarifying sponsor and investigator responsibilities in reporting and analysis of serious, unexpected events suspected to be caused by the drug

29. FDA’s final IND safety rule FDA specified that sponsors should report serious events in an expedited fashion only if the sponsor judged that there was evidence to suggest a causal relationship between the drug and the event Stated purpose: enhance the ability of sponsors, FDA, investigators, and IRBs to focus on important safety issues

30. Concerns raised by sponsors regarding the final IND safety rule • Responsibility for determining causality- not harmonized globally • US: Sponsor’s determination of causality should drive decision on reporting • EMA: If either sponsor or investigator considers the event causally associated, it should be reported • Methodological questions regarding assessment of causal associations across a development program

31. IND Safety

32. Safety Case Studies PROJECT PORTFOLIO – September 2013

33. Central IRB Advancement PROJECT PORTFOLIO– September 2013

34. Monitoring Project Goal Identify best practices and provide sensible criteria to help sponsors select the most appropriate monitoring methods for a clinical trial, thereby ensuring reliable and informative trial results and human subjects’ protection Work stream 1: Describe the range of current monitoring practices and examine factors that drive their adoption Work stream 2: Define key quality objectives for monitoring clinical trials Work stream 3: Examine ways to build quality into trials to enable more focused and efficient monitoring

35. WS1: Survey of Monitoring Practices Results consistent with hypotheses: Wide variety of monitoring practices in use Choice of monitoring approach depends on type of organizational sponsor Rationale for using any specific monitoring approach does not appear to be evidence-based

36. WS2: Key Quality Objectives Major quality objectives are to Protect participant rights, safety and wellbeing Ensure the reliability of the study results Maintain adherence to the protocol Monitoring also provides An opportunity for focused training Feedback that can improve study processes

37. WS3: Building Quality into Trials Primary focus should shift from post-hoc monitoring / inspection to incorporation of quality into the scientific and operational design of a trial No single monitoring approach is appropriate or necessary in all circumstances Monitoring approach (which may combine several methods) should be tailored to the needs of the particular clinical trial

38. WS3: Building Quality into Trials Focus on what is important: • Importance of proper randomization • no foreknowledge of likely treatment allocation • minimize post-randomization withdrawals • minimize loss to follow-up • Sufficient numbers of relevant clinical outcomes • Unbiased ascertainment and analysis of study outcomes

39. WS3: Building Quality into Trials Oversight should focus on those errors most likely to adversely affect trial quality: Data elements vary in their impact on the safety of participants or on the reliability of trial results Single-minded focus on checking/ensuring accuracy of every data point is misguided Sponsors and regulators should agree up front what data points are critical and need to be verified Sponsor should institute metricsto prospectively ensure the quality of critical data

40. Recommendation Build quality into the scientific and operational design and conduct of clinical trials • Focus on what matters • Develop a quality management plan • Assess performance in important parameters • Improve training and procedures • Report findings of quality management approach

41. Quality by Design (QbD) & Quality Risk Management (QRM) PROJECT PORTFOLIO – September 2013