FDA – IDSA - ISAP Workshop April 15, 2004

1. FDA – IDSA - ISAP WorkshopApril 15, 2004 Continuing Discussion on Incentives George H. Talbot MD On Behalf of the AATF

2. Presentation Objectives • Update workshop attendees on AATF’s efforts to clarify factors responsible for decreased antibacterial R&D • Discuss the full range of possible solutions… not just “financial” incentives

3. What has AATF Learned?Overview • There is a problem • Complex, multifactorial etiology • Susceptible to oversimplification: “If only….” • No easy, single solution • Potential approaches are apparent • Progress requires • Long-term commitment • Active collaboration of essential partners

4. The Problem “Drug options for treatment of infections are becoming increasingly limited, largely as a result of growing antimicrobial resistance. Many generic but essential antibiotics are in short supply, and the development of new antibiotics has been severely curtailed…. Only 4 large pharmaceutical companies with antibiotic research programs remained in existence in 2002….” (Institute of Medicine Report, 2003)

5. The ProblemTotal Approved Antibacterials: US Spellberg et al, CID 2004 in press

6. What has AATF Learned?Interactions with Stakeholders • Pharmaceutical companies • VCs • FDA • CDC, NIAID, HHS • The scientific and lay press • Congress

7. What Has AATF Learned?Issues for Pharma • Many individuals and groups within pharma are deeply concerned about, and committed to, the future of anti-bacterial R&D • “Big” pharma is becoming disengaged • There are notable exceptions • Greatest concern -- the dearth of resources being applied at the Discovery level

8. What Has AATF Learned?Issues for “Big” Pharma • “Big” Pharma sees better return from the treatment of chronic diseases. • In contrast, antibacterial therapies are: • Costly to develop • Short course, used for acute illnesses • Not embraced by the marketplace (cost, resistance, “satisfied” market) • Rarely “blockbusters”

9. What Has AATF Learned?Issues for “Big” Pharma • Any further uncertainty is a disincentive • Further IP protections - ? upside • Tax credits – interesting • Because of enormous hurdles for Discovery infrastructure, we must keep those companies that are “In” – “In”

10. What Has AATF Learned?Issues for “Small” Pharma • “Small” Pharma is more engaged • Financial return better matched to size • Market opportunity is more clear • Regulatory uncertainty: a lesser concern? • Focus • For some, in-licensed compounds only • Others, robust Discovery efforts Will it be enough?

11. What Has AATF Learned?Issues for VCs • Access to venture capital is – of course - essential for new companies • In a totally unscientific sampling: • Some VCs see the dearth of discovery efforts as an opportunity • Others consider the risks high because of restrictions on use of marketed products • Late-stage anti-infective products are drivers of some financing decisions

12. What has AATF Learned?Issues for FDA • FDA understands the problem • Wishes to partner in finding solutions • Regulatory uncertainty, when present, further clouds the development process (FDA’s 2004 “Critical Path” report) • Maintaining scientific rigor • Limited flexibility per statutory constraints • e.g., waiver of user fees not possible

13. What has AATF Learned?Issues forCDC, NIAID, HHS • Substantial, relevant efforts proposed • PHS Action Plan to Combat Resistance (2001) • NIH Roadmap for Medical Research (2003) • More funding needed for critical efforts • More could be done to foster inter-agency collaboration, training, and outreach regarding antibacterial drug development

14. What has AATF Learned?Issues for the Scientific and Lay Press • Pipeline concerns -- of interest to both the scientific community and the public • Articles directed to a wide readership • Our communications must highlight not only measures to decrease resistance, but also those to ensure the pipeline

15. “Bad Bugs, No Drugs”in theScientific and Lay Press Lay Press • Boston Globe, "Firms Abandoning Antibiotics Research; Drugs That Make More Money Sought" Christopher Rowland, Mar 13, 2004 • USA Today, "Scientists: Research Cuts are Troubling" Anita Manning, Sept 15, 2003 • Washington Post, "Tougher Bugs, Few New Drugs" Roxanne Nelson, Mar 30, 2004

16. “Bad Bugs, No Drugs”in theScientific and Lay Press General Scientific Readership • Nature, "Drug Companies Snub Antibiotics" Tom Clarke, Sept 18, 2003 • Science, "Orphan Drugs of the Future?" Robert Service, March 19, 2004, pg 1798 • The Lancet, "Antibiotic Development Pipeline Runs Dry" Roxanne Nelson, Nov 22, 2003

17. “Bad Bugs, No Drugs”in theScientific and Lay Press ID Specialty Journals • The Lancet Infectious Diseases, "Covering the Parts Other Bioshields Don't Reach" editorial, Jan 2004 • The Lancet Infectious Diseases, "Incentives to Lure Drug Companies to Antimicrobials" Marilynn Larkin, Jan 2004 • Clinical Infectious Diseases, “Trends in Antimicrobial Drug Development: Implications for the Future" Spellberg et al, in press 2004

18. What has AATF Learned?Issues for Congress • Some vocal & effective supporters for addressing the issues, but • Focus of policy-makers is elsewhere • Bioterrorism • Everything else… • BioShield I offers some hope of solutions, but has substantial constraints • More attention & action are needed

19. What is IDSA’s Role in Defining Solutions? • Raise awareness of the the problem • Multiple venues • Always speak to the needs of patients • Brainstorm on possible solutions • Many are not within IDSA’s area of expertise • Partners needed • IDSA can act as a catalyst

20. Raising Awareness • Visit with Dr. McClellan, senior FDA staff • Visits with senior pharma executives • Interactions with CDC, NIAID • Legislative contacts • Outreach to scientific and lay press • “White Paper”, to be released in May

21. Potential SolutionsPartnering of Stakeholders • IDSA, FDA, CDC, NIAID, Pharma, & Congress in the interest of public health • IDSA hopes that it can continue to play an important, constructive role in partnering efforts

22. Potential SolutionsChanges in the Marketplace • Greater marketplace receptivity to new antibacterials could alter economic equation • But, potential changes are constrained • Cost, concern re promotion of resistance • Desire to hold antibiotics of last resort Change unlikely, without scientific data to justify different usage patterns

23. Potential SolutionsRegulatory adjustments • Publish updated guidelines (on-going) • Periodic, timely review and revision • Encourage novel clinical trial designs to gather information on drug efficacy against resistant pathogens • Define surrogate endpoints, PK/PD parameters, & preclinical data that could reduce # of clinical studies

24. Potential SolutionsInitiatives by NIAID • Responsible for implementing “Roadmap” for translational research • Foster antimicrobial R&D • Collaborative planning with industry, academia • Fellowship curriculum in AI clinical trials • NIAID-FDA programs to streamline development • Fund research into rapid diagnostics • Fund placebo-controlled trials in AECB, AS

25. Potential SolutionsLegislative • Ongoing • The Project Bioshield Act • Best Pharmaceuticals for Children Act • Senators Gregg and Reed: GAO study • Future • S.666 (Lieberman and Hatch) • Unique problems require unique solutions

26. Potential SolutionsLegislative For investments in priority antibacterials • Incentives successful elsewhere to spur R&D • e.g., R& D tax credits • Supplemental IP protections • e.g., wild card patent exclusivity • Mechanisms to attract smaller companies • e.g., waiver of user fees for supplemental NDAs

27. Potential SolutionsLegislative • Commission on Antimicrobial Resistance (COAR) • Broad representation from stakeholders • Charges • Identify priority pathogens • Decide which antibiotics should receive the benefits of legislated incentives

28. Potential SolutionsLegislative Increase Funding for Essential Programs • CDC antimicrobial resistance program • NIAID antimicrobial resistance research • FDA programs re review/approval of antibacterials

29. Potential SolutionsCorporate • Industry can point with pride to many pro bono initiatives for human health • GSK: Malaria effort with the MVI • Merck: Ivermectin effort with WHO • AZ: TB discovery effort, Bangalore • Many others • If this impending crisis explodes, the public will need your help

30. Potential Solutions These considerations to be discussed in detail in IDSA’s White Paper, to be released in May

31. Conclusions • There is a problem • Etiology is multifactorial • No single, “easy” solution • Essential partners are engaged • Potential solutions apparent • IDSA stands ready to make a long-term, constructive commitment to help address this brewing public health crisis

32. Conclusions Bad Bugs, No Drugs…. How Can IDSA Help? We Want Your Input

33. Final Notes • Potential Conflicts • No external financial support for AATF effort • Some AATF members provide consultative services to industry • Acknowledgements • AATF members • Factual input from J. Powers & D. Ross • IDSA staff, esp. R. Guidos & D. Olson • The many people with whom we have spoken