1. 1 Developing drugs for resistant pathogens: Problems and possibilities David Ross, M.D., Ph.D. Anti-Infective Drugs Advisory Committee February 20, 2002

2. 2 Acknowledgements DRP Working Group –Ed Cox, M.D. –Brad Leissa, M.D. –Jean Mulinde, M.D. –David Ross, M.D., Ph.D. Janice Soreth, M.D. - Dir., DAIDP Renata Albrecht, M.D. - Dir., DSPIDP Mark Goldberger, M.D., M.P.H. - Dir., ODE IV

3. 3 Overview Trends in antimicrobial resistance Problems in developing drugs for resistant pathogens Focused development: one possible solution

4. 4 Selected resistant bacteria of public health concern: 2002 Nosocomial –Methicillin-resistant S. aureus (MRSA) –Methicillin-resistant coagulase-negative staphylococci (MRCNS) –Vancomycin-resistant enterococci (VRE) –Multidrug-resistant Klebsiella, Pseudomonas Community –Penicillin-resistant S. pneumoniae (PRSP) –Multidrug-resistant Salmonella (non-typhi)

5. 5 Antibiotic resistance: Prevalence and incidence estimates * Bloodstream infections Mainous and Pomeroy (2001) Extrapolation from Edmond et al. (1999) Clin Inf Dis 29:239-44

6. 6 100 80 60 40 20 0 198019751985199019952000 1997 GISA VRE MRSA MRCNSPRSP Percentage of Pathogens Resistant to Antibiotics Gram-Positive Resistance - United States, 1980-1999 Paladino JA. Am J Health Syst Pharm 2000;57 Suppl 2:S10-2.

7. 7 Responses to resistance - PHS Action Plan Prevention Research Surveillance Product development –“... streamline the regulatory process” (Action Item 82) –“Identify ways... to promote the development of... priority AR products...” (Action Item 80)

8. 8 Regulatory tools Subpart E Subpart H Fast track Market exclusivity

9. 9 Regulatory Initiatives Subpart “E” (21 CFR 312.80) –Life-threatening and severely debilitating illness –Utilize risk-benefit analysis in the decision making process –Early consultation and increased communication –Approval possible earlier in the drug development process

10. 10 Regulatory Initiatives Subpart ”H” (21 CFR 314.500) –Serious or life-threatening diseases –Meaningful therapeutic benefit over existing Rx –Surrogate endpoint that is reasonably likely to predict clinical benefit –Confirmatory trials, expedited withdrawal, prior submission of promotional material, restricted distribution/use

11. 11 Regulatory Initiatives Fast Track Designation –Combines subparts “E” and “H” –Includes a provision to accept for review a portion of a marketing application prior to submission of the complete package Market exclusivity –Orphan Drugs: Seven years stand-alone marketing exclusivity (per indication) –Pediatric: Six months add-on exclusivity (per active moiety) –Waxman-Hatch: Now available for “new” antibiotics

12. 12 Sponsor considerations in drug development Market potential –Prevalence, duration of dosing Feasibility –Length of trial(s), screening requirements Complexity –Patient accrual, documenting diagnosis Development time –Clinical development time –Regulatory review time

13. 13 U.S. prescription drug sales, 2000 Source: www.pharmacytimes.com.

14. 14 Outpatient Antimicrobial Therapy, U.S. (millions of courses in 1992) McCaig LF and Hughes JM. JAMA 1995; 273:214-219 Otitis media URI (non-specific) Bronchitis Pharyngitis Sinusitis All other diagnoses 23.6 17.9 16.3 13.1 12.9 26.5

15. 15 Feasibility considerations A recent clinical CAP trial enrolled 745 patients... 561 of these completed the protocol 191 of these had a pathogen isolated 146 of these were S. pneumoniae 54 of these were bacteremic 0 of these had a PCN MIC  2 µg/mL  Even large controlled trials of common indications may not be sufficient to obtain data on treatment of infections due to resistant pathogens

16. 16 Categories for drugs active against resistant pathogens

17. 17 General considerations for focused development Development specifically for serious indications due to resistant pathogens May allow marketing of agents that would not otherwise be developed Safety may preclude broader program Approval may rely on Subpart H –Surrogate markers/confirmatory trials –Restricted distribution/labeling

18. 18 Characteristics of candidate agent for focused development Activity against resistant pathogen(s) Absence of alternative or comparable tx for pathogen + indication Pathogen + indication is an important public health problem Safety information supports an acceptable risk-benefit profile, given limited population exposure

19. 19 Risk vs. benefit “... these procedures generally reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses.” 53 FR 41516

20. 20 Development program - Phase I Dose-ranging studies PK (traditional or sparse sampling) Special population studies

21. 21 Development program - Phases II - III Dose-finding and proof of concept Demonstration of safety/efficacy –If sufficient data from controlled trials adequate/well-controlled trials enrichment strategies –If insufficient data from controlled trials: clinical data with historic controls data from infections with susceptible organisms surrogate endpoints PK/PD

22. 22 Data requirements Data quality is more important than quantity Databases of 300 - 500 patients may suffice For conditions with high mortality (e.g., VRE endocarditis), small numbers of successes may suffice if cure rate is acceptable Tradeoff: limited data may mean limited availability

23. 23 Traditional vs. focused anti- infective development Traditional Many indications Large Phase 3 database Controlled trials pivotal to efficacy demonstration; other data supportive but not central Toxicity  no development Broad availability Focused One or few indication(s) Small Phase 2/3 database Clinical data, surrogate markers, susceptible pathogen data, historical controls, PK/PD Toxicity weighed vs. benefit Limited availability

24. 24 Challenges At what point should a drug enter focused development? If there are potential toxicities, what populations should be studied? Is incentive of focused development worth limited market?

25. 25 Summary Focused development may: –increase market incentives –increase clinical trial feasibility –decrease complexity of drug development –decrease clinical development time

26. 26