1. DIA BSWG face-to-Face Meeting JSM 2016 Chicago DIA-BSWG F2F, Chicago 2016 1

2. Agenda  Introduction  Subteam Updates  Historical data/prior specification  Safety  Education  Bayesian KOL Lecture Series  Status of the 21 st Century Cures Act  ACDRS Output  Future Impact DIA-BSWG F2F, Chicago 2016 2

3. Acknowledgments  Face-to-face planning committee  Amy Xia; Amgen  Carl Di Casoli; Bayer  Fanni Natanegara; Eli Lilly  Karen Price; Eli Lilly  Mathangi Gopalakrishnan; University of Maryland  Qi Tang; Abbvie  Ross Bray; Eli Lilly DIA-BSWG F2F, Chicago 2016 3

4. Who we are? Academia-Industry-Regulatory partners  Group of representatives from Regulatory, Academia, and Industry, engaging in scientific discussion/collaboration – facilitate appropriate use of the Bayesian approach – contribute to progress of Bayesian methodology throughout medical product development DIA-BSWG F2F, Chicago 2016 4

5. Vision & Mission of DIA-BSWG  Vision Ensure that Bayesian methods are well-understood, accepted, and broadly utilized for design, analysis, and interpretation to improve patient outcomes throughout the medical product development process and to improve decision making.  Mission To facilitate the appropriate use of Bayesian methods and contribute to progress by:  Creating a scientific forum for the discussion and development of innovative methods and tools.  Providing education on, and promoting the dissemination of, methods and best practices for Bayesian methods.  Engaging in dialogue with industry leaders, the scientific community, and regulators.  And to foster diversity in membership and leadership. DIA-BSWG F2F, Chicago 2016 5

6. Subteams & Chairs  Safety: Melvin Munsaka (melvin.munsaka@takeda.com), Karen Price (price_k@lilly.com), Amy Xia (hxia@amgen.com)melvin.munsaka@takeda.comprice_k@lilly.comhxia@amgen.com  Education: Fanni Natanegara (natanegara_fanni@lilly.com)natanegara_fanni@lilly.com  Historical data/prior specification: John john.zhong@biogen.com) and Satrajit Roychoudhury (satrajit.roychoudhury@novartis.com)john.zhong@biogen.comsatrajit.roychoudhury@novartis.com  Non-inferiority: Mani Lakshminarayanan (mani_lakshminarayanan@merck.com)mani_lakshminarayanan@merck.com  Standards/Reporting: Mani Lakshminarayanan  Missing Data: Frank Liu (guanghan_frank_liu@merck.com) and Stacy Lindborg (stacy.lindborg@biogenidec.com)guanghan_frank_liu@merck.comstacy.lindborg@biogenidec.com  Benefit/Risk: Carl DiCasoli (carl.dicasoli@bayer.com )carl.dicasoli@bayer.com  Joint Modeling: Larry Gould (larry_gould@merck.com)larry_gould@merck.com  Program-wide decision making: Bin Yao (byao@amgen.com) and Karen Pricebyao@amgen.com  Joint with Pediatric community and ADSWG: Meg Gamalo (gamalo_margaret@lilly.com)gamalo_margaret@lilly.com DIA-BSWG F2F, Chicago 2016 6

7. Action Items from DIA-BSWG F2F-JSM 2015 DIA-BSWG F2F, Chicago 2016 7 NeedsAction items Gain acceptance in medical community Propose “innovative clinical trials” session at DIA and medical conference(s) to focus on Bayesian trial designs/ analyses Include physicians in the DIA BSWG Publish in medical journals Showcase good projects with good science Work with DIA website administrators to showcase case examples Work with subteam leaders to work on case examples using template Few case examples mentioned; Dulaglutide ph2/3 seamless design, Pravigard Pac, missing data (data is accessible), noninferiority (Merck) Ensure Bayesian methods are applied appropriately including reproducibility Write best practices paper for Bayesian trial design including documentation of operating characteristics and rationale of the parameters that were chosen for simulation Have guidance /recommendation on “well-documented” Bayesian softwares Address 21 st Century Cures Act Stay abreast of the progression of the 21 st Century Cures act through Congress and identify areas to contribute. Propose JSM invited session, DIA?

8. Historical Data/Prior Specification Subteam Update  Organize a contributed session at the JSM 2016 on the topic of historical data borrowing (Chaired by Qi Tang)  Organize a session at the 2016 ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop (formerly FDA Industry Statistics Workshop) on the topics related to historical data borrowing (Chaired by Satrajit Roychoudhury)  Plan for a reflection paper on the FDA guidance on rare diseases (and potentially on pediatric rare disease). DIA-BSWG F2F, Chicago 2016 8

9. Safety Subteam Update  The subteam is focusing on two topics namely:  Making the case for Bayesian meta-analysis in safety data, and  Extending the Bayesian hierarchical models for safety signal detection in clinical trials to multiple treatment and meta- analysis settings  Develop a manuscript for each of the two topics  The team currently meets once a month and the plan is to have draft manuscripts for each of the two broad topics towards the end of the year DIA-BSWG F2F, Chicago 2016 9

10. MAPPs Subteam Update: Focus Statistical foundations for MAPPs (Medicines Adaptive Pathways to Patients 1-3 )  MAPPs “relate to the entire life cycle of a medicine from development, through licensing to patient access (reimbursement and healthcare delivery)”.  “Balance early patient access, public health and societal benefits”  “Early authorisation of a product focused on a well-defined and targeted population with a clear safety and efficacy profile”  “Target population is adjusted as the evidence base expands” 1 MAPPs summary from http://efpiamapps.euhttp://efpiamapps.eu 2 Eichler, HG, et al. From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients. Clin. Pharmacol. Ther. 2015 Mar;97(3):234-246. PubMed PMID: 25669457 3 Eichler, HG, et al. Adaptive licensing: taking the next step in the evolution of drug approval. Clin. Pharmacol. Ther. 2012 Mar;91(3):426-37. PubMed PMID: 22336591

11. MAPPs Subteam Update MAPPs Subteam launched January 2016  17 members (12 industry, 4 academia, 1 FDA)  Subteam Chairs: Zoran Antonijevic & Bob Campbell  Collaborative paper led by Mark Trusheim and Allison Shrier (MIT) was submitted in May to Clinical Pharmacology & Therapeutics: “PIPELINEs: Creating comparable clinical knowledge efficiently by linking trial platforms” Next steps for the team  Position team for greater impact by engaging other MAPPs stakeholders, especially patients and payers.  Prioritize statistical topics for team focus for 2016-early 2017

12. Education Subteam Updates  We have a new website! Bayesianscientific.org  Ongoing projects  Case example Case example  Medical outreach effort: draft charter document, 6 members, recruit medical colleague(s)  Best practice paper: focuses on major use in drug development, issues to consider, case examples (first draft Q4/2016)  Meet monthly; separate project meetings

13. BSWG-KOL series – new subteam  Kert to provide slides DIA-BSWG F2F, Chicago 2016 13

14. Bayesian KOL Lecture Series Subteam: Current Status  Chairs determined for 2016-2017  Mathangi Gopalakrishnan (Maryland)  Mani Lakshminarayanan (Pfizer)  Kert Viele (Berry Consultants)  Webinar series to start Fall 2016  Focus on interesting methodology, case studies, and communication within sponsors as well as regulatory aspects. BSWG KOL Webinar Series

15. Bayesian KOL Lecture Series Subteam: Action Items  Currently finalizing a larger committee to assist with topic and speaker selection.  Need to finalize schedule for maximum availability from interested audience  Suggestions for topics or speakers from anyone welcome! Please email any of the chairs. BSWG KOL Webinar Series

16. 21 st Century Cures Act Action Items from JSM 2015 Write guidance on document on the use of Bayesian methods in the development, regulatory review, and approval of drugs/biological products. (PDUFA VI) Propose JSM invited session, DIA? Empowering Bayesians through the 21 st Century Cures Act – August 3, 2016, Topic Contributed Panel; 10:30 AM – 12:20 PM DIA-BSWG F2F, Chicago 2016 16

17. 21 st Century Cures Update  Passed the House in July of 2015  Did not pass the Senate in its original form  Senate to prioritize topics from this bill and submit as separate bills  In parallel the PDUFA 6 negotiations have been finalized  Include some adaptive design elements  Published July 15, 2016

18. 21 st Century Cures Act  H.R. 6 Sec 2061 - “For purposes of assisting sponsors in incorporating adaptive trial design and Bayesian methods into proposed clinical protocols and applications”  Intent: to accelerate the discovery, development, and delivery of life saving and life improving therapies, and transform the quest for faster cures by:  Removing barriers to increase research collaboration  Incorporating patient perspective in the drug development and regulatory review process  Measuring success and identifying diseases earlier through personalized medicine  Modernizing clinical trials: application of Bayesian and adaptive trial designs  Removing regulatory uncertainty for the development of new medical applications  Providing new incentives for development of drugs for rare diseases  Helping the entire biomedical ecosystem coordinate more efficiently to find faster cures  Investing in 21 st century science and next generation investigators  Helps keep and create jobs here at home

19. Prescription Drug User Fee Act 2018-2022 PDUFA VI PDUFA VI  Sections most applicable to statistics including adaptive designs and Bayesian methods  Advancing Model-Informed Drug Development  Includes FDA developing expertise, conducting workshops, publishing guidance and conducting a pilot program  Enhancing Capacity to Review Complex Innovative Designs  Includes FDA developing staff capacity, conducting a pilot program, convening a public workshop, and publishing a draft guidance on “various complex adaptive, Bayesian, and other novel clinical trial designs, with a particular focus on clinical trial designs for which simulations are necessary to evaluate the operating characteristics”  Enhancing Capacity to Support Analysis Data Standards for Product Development and Review  Public Meeting for PDUFA VI – August 15, 9:00 AM – 2:00 PM (EDT); Silver Spring, MD Public Meeting for PDUFA VI – August 15, 9:00 AM – 2:00 PM (EDT); Silver Spring, MD

20. ACDRS Special Workshop Overview  Title: Substantial evidence in 21st century regulatory science: borrowing strength from accumulating data  Workshop held April 22, 2016  Link to workshop agenda and slides: http://pharmacy.ucsf.edu/events/2016/04/evidence http://pharmacy.ucsf.edu/events/2016/04/evidence  Intent was to open discussion on deriving substantial evidence of effectiveness based on a high probability of effectiveness, utilizing evidence from all reliable sources of effectiveness data (as opposed to traditional 2 studies at p<0.05)

21. ACDRS Workshop: Key Messages  Current paradigm not sustainable – innovative methods and designs must move forward to help us sustain  But we’ve been saying “Current paradigm is unsustainable” for several years -> so is this wrong or are we at a tipping point?  Also, several commented that in fact flexibility not as advertised – routinely need 2 trials at p<0.05

22. ACDRS Workshop: Key Messages (2)  Several hurdles remain, including broad misunderstanding of type 1 error control, definition of null space, role of simulations, etc.  Woodcock: Bayesian approaches need better explanation  Discussion about the role of formal utility functions, more holistic decision making.

23. ACDRS Workshop: Key Messages (3) BUT, there is also progress  CDER encouraging reviewers to be open about moving beyond the current approach, especially oncology, pediatric, rare diseases, antibiotics, antibacterial  CDER: 2013 snapshot, 8 Bayesian trials  CBER: 2006-2013, 4 Bayesian trials  Several presenters mentioned back to 2004 conference – while we are not where we need to be, significant progress has been made

24. ACDRS Workshop Discussion A Motivating Example: Bayesian Historical Data Borrowing

25. ACDRS Workshop: Discussion Questions

26. Vision for the Future: Continuing Activities  Sub team Efforts – please review the list of sub teams and volunteer to participate in areas you have interest!  Publications  Workshops DIA-BSWG F2F, Chicago 2016 26

27. Vision for the future: What Can BSWG do?  Many of our activities/goals align with, support, and help move forward some of the points discussed  Opportunity to help change the conversation about the role of simulations in trial design and in demonstration of type 1 error control  We should coordinate and plan publications to refer back to workshop and also to workshop publication (TIRS) to come soon  In light of the ASA statement on the use of p-values, what role can Bayesian methods play in decision making?  Education outreach to medical  Education outreach to patient community  Other ideas?

28. Membership  To join the DIA Bayesian Scientific Working Group please contact Karen Price at price_k@lilly.comprice_k@lilly.com DIA-BSWG F2F, Chicago 2016 28