13 Apr 041 FDA – IDSA - ISAP Workshop April 15, 2004 Continuing Discussion on Incentives George H. Talbot MD On Behalf of the AATF

13 Apr 042 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

13 Apr 043 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

13 Apr 044 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)

13 Apr 045 The Problem Total Approved Antibacterials: US Spellberg et al, CID 2004 in press

13 Apr 046 What has AATF Learned? Interactions with Stakeholders Pharmaceutical companies VCs FDA CDC, NIAID, HHS The scientific and lay press Congress

13 Apr 047 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

13 Apr 048 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”

13 Apr 049 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”

13 Apr 0410 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?

13 Apr 0411 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

13 Apr 0412 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 Apr 0413 What has AATF Learned? Issues for CDC, 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

13 Apr 0414 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

13 Apr 0415 “Bad Bugs, No Drugs” in the Scientific 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

13 Apr 0416 “Bad Bugs, No Drugs” in the Scientific 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

13 Apr 0417 “Bad Bugs, No Drugs” in the Scientific 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

13 Apr 0418 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

13 Apr 0419 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

13 Apr 0420 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

13 Apr 0421 Potential Solutions Partnering 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

13 Apr 0422 Potential Solutions Changes 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

13 Apr 0423 Potential Solutions Regulatory 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

13 Apr 0424 Potential Solutions Initiatives 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

13 Apr 0425 Potential Solutions Legislative 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

13 Apr 0426 Potential Solutions Legislative 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

13 Apr 0427 Potential Solutions Legislative Commission on Antimicrobial Resistance (COAR) – Broad representation from stakeholders – Charges Identify priority pathogens Decide which antibiotics should receive the benefits of legislated incentives

13 Apr 0428 Potential Solutions Legislative Increase Funding for Essential Programs CDC antimicrobial resistance program NIAID antimicrobial resistance research FDA programs re review/approval of antibacterials

13 Apr 0429 Potential Solutions Corporate 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

13 Apr 0430 Potential Solutions These considerations to be discussed in detail in IDSA’s White Paper, to be released in May

13 Apr 0431 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

13 Apr 0432 Conclusions Bad Bugs, No Drugs…. How Can IDSA Help? We Want Your Input

13 Apr 0433 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