1. 1 Development of Antibacterial Drugs for Infections with Resistant Pathogens Antimicrobial Working Group of the Pharmaceutical Research and Manufacturers of America (PhRMA) David Shlaes, M.D. February 20, 2002

2. 2 PhRMA’s Antimicrobial Working Group Offers a forum for exchange of scientific information among PhRMA companies with an R&D commitment to anti-infective drug products Provides industry’s scientific perspective in response to proposed rules, draft guidances, and relevant issues affecting anti-infective drug products

3. 3 Antimicrobial Working Group Participants

4. 4 Public Health Effort to Combat Antimicrobial Resistance PhRMA’s Working Group applauds the effort of the Interagency Task Force (co-chaired by FDA, CDC, & NIH) Task Force responded to the growing public health threat Published “A Public Health Action Plan to Combat Antimicrobial Resistance.” Action Items included: –Stimulate the development of priority products to treat antimicrobial resistance –“The regulatory process will continue to be streamlined” –“Identify ways (e.g. financial and/or other incentives) to promote the development …” of new antimicrobial agents

5. 5 Clinical Development of New Agents for Resistant Pathogens - Problems Difficulties and risks inherent in the development of any NCE Generally low incidence pathogens (particularly if development precedes major increase in prevalence in general population) Generally not limited to a single infectious disease indication Development timelines are long and uncertain, despite current & projected public health need

6. 6 Anticipated Issues For the Future Fewer companies developing novel antibacterial drugs Fewer new antibiotics being developed, especially parenteral Development costs continue to rise as size of databases required for efficacy and safety are increased Resistance will continue, but still too low incidence to be well-studied for each “traditional” indication –VRE will continue, with resistance to all current agents increasing –Multiply-resistant Gram negative bacilli will become more frequent in US hospitals Novel breakthroughs will be few, unless incentives are identified for these high risk, limited gain indications

7. 7 One Company’s Experience Clinical trials are not “real life” VRE: a “major nosocomial problem” 1996-2000 54 sites (US and ex-US) open for 2 years (1998-2000) –3 patients enrolled in study with entry criteria developed in consensus with FDA and academia - study closed for insufficient enrollment –2nd study launched, 45 subjects enrolled in 18 months –“Compassionate” use of other agents siphoned enrollment from well-controlled clinical trial

8. 8 Issues for the Future- Between a Rock and a Hard Place? Fewer Companies in R&D for Antibiotics Emphasis on “Blockbusters” to return cost of investment Limited agents for “novel” targets with known safety profiles Patent protection limited with “public health emergency”? Growing multiply resistant Gram (+) and Gram (-) Growing Fungal Resistance Growing cost of studies as safety/efficacy requirements increase FDA CDC Public Companies Higher risk for Limited Returns More restrictive labeling - prudent use of novel agents More safety requirements- ECG/HERG, class profiling

9. 9 Development of New Antimicrobial Agents for Resistant Pathogens - What is Needed? Early definition of regulatory guidance –Reasonable barriers to entry for new compounds Define mutually acceptable registration strategy –Efficient, cost effective development programs for very small but significant public health needs –Facilitate registration of safe & effective antibacterial agents Identify incentives to develop antimicrobial agents to treat “niche” indications –Explore supportive data, in addition to clinical trials –Patent protection? Exclusivity?

10. 10 Striking the Right Balance Reduce cost of development and maintaining license Protect Intellectual Property Level playing field Reduce barriers to entry More effective and timely responses to emerging public health needs FDA CDC Public Companies Acceptable risk for reasonable overall return Prudent use of novel agents supported by surveillance for emerging pathogens or resistance Better postmarketing surveillance for safety

11. 11 PhRMA’s Proposals for Further Discussion 1Acceptance of PK/PD data as evidence of efficacy –PK/PD studies are increasingly utilized in academia and industry, but have not yet been accepted as evidence for approval –well-understood animal models of infection can be a useful source of evidence for approval 2Acceptance of alternative or surrogate endpoints –time to clinical response ? –rate of progression ? –surrogate endpoints ? eg, resolution of bacteremia

12. 12 PhRMA’s Proposals for Further Discussion 3Encourage pooling of pathogen experience across related body sites –linezolid and quinupristin/dalfopristin precedents –Indications by pathogen, across multiple indications for rare multiply-resistant pathogens 4Acceptance of an observational cohort study for a marketed drug as evidence of efficacy against a resistant pathogen –collect well-documented cases of infection with a resistant pathogen –collect outcomes data for study drug vs. “standard of care” –highly representative of real-world practice

13. 13 Types of Incentives to Stimulate R&D for New Antibacterial Drugs Reduce the cost of development –smaller N for initial registration ? –fewer assessments per patient ? –acceptance of other data (eg, PK/PD) to determine efficacy ? Reduce time from discovery to market –smaller N for initial registration ? Increase the value proposition –enable pharmacoeconomic claims ? –quality of life claims ?

14. 14 Potential Approaches to Stimulate R&D for New Antibiotics Call a consensus conference to enumerate a list of resistant pathogens for priority attention over the next 10 years Consider multi-indication registration based on 1 study per indication, rather than the current norm of requiring 2 studies per indication Consider a potential role for placebo-controlled trials in non-life-threatening diseases –rapid exit for patients who fail to respond within 48 hours –should reduce sample size for some infections

15. 15 Potential Approaches to Stimulate R&D for New Antibiotics Consider the accelerated approval paradigm for drugs for resistant pathogens: Based on various precedents (e.g., oncology drugs, quinupristin/dalfopristin, HIV drugs, and a recent antifungal drug) Initial registration based on efficacy and safety results in limited studies of patients with resistant pathogen (eg, patients failing or intolerant to treatment of choice ) Confirmatory clinical study performed in Phase IV

16. 16 Proposals to Stimulate Development of Guidances and Promote a Common Approach to the Development of New Antibiotics Finalize the July 1998 draft antimicrobial guidances using a workshop approach –include clinical investigators and other stakeholders Hold a resistance workshop among stakeholders (include FDA, PhRMA, IDSA, other industry, EU, EFPIA, others) –Goals: Develop a mutually acceptable resistance policy Develop a U.S./EU resistance guidance document

17. 17 Summary PhRMA recognizes the importance of discovery & development of new drugs for resistant pathogens PhRMA welcomes dialogue on approaches to stimulate and foster development and registration of such products PhRMA will organize and/or participate in workshops with other stakeholders to foster progress in this area

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19. 19 Efficacy against resistant isolates Duration of therapy Oral vs IV formulation Cost Side effects Efficacy against resistance Cost Side effects Increasing Level of Importance Unmet Needs for Antibacterial Drugs HospitalCommunity