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Developing drugs for resistant pathogens: Problems and possibilities

Developing drugs for resistant pathogens: Problems and possibilities. David Ross, M.D., Ph.D. Anti-Infective Drugs Advisory Committee February 20, 2002. Acknowledgements. DRP Working Group Ed Cox, M.D. Brad Leissa, M.D. Jean Mulinde, M.D. David Ross, M.D., Ph.D.

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Developing drugs for resistant pathogens: Problems and possibilities

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

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

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

  6. PRSP Gram-Positive Resistance - United States, 1980-1999 100 80 MRCNS Percentage of Pathogens Resistant to Antibiotics 60 MRSA 40 20 VRE GISA 0 1975 1980 1985 1990 1995 2000 1997 Paladino JA. Am J Health Syst Pharm 2000;57 Suppl 2:S10-2.

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

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

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

  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. Categories for drugs active against resistant pathogens

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

  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. 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. 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 Traditional vs. focused anti-infective development

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

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