Developing drugs for resistant pathogens: Problems and possibilities

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Developing drugs for resistant pathogens
Problems and possibilities

• David Ross, M.D., Ph.D.
• Anti-Infective Drugs Advisory Committee
• February 20, 2002

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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

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Overview

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

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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)

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Antibiotic resistance Prevalence and incidence
estimates
Mainous and Pomeroy (2001) Extrapolation from
Edmond et al. (1999) Clin Inf Dis 29239-44
Bloodstream infections
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Gram-Positive Resistance - United States,
1980-1999
100
80
MRCNS
Percentage of Pathogens Resistant to Antibiotics
60
MRSA
40
20
VRE
GISA
0
1980
1975
1985
1990
1995
2000
1997
Paladino JA. Am J Health Syst Pharm 200057 Suppl
2S10-2.
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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)

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Regulatory tools

• Subpart E
• Subpart H
• Fast track
• Market exclusivity

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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

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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

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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

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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

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U.S. prescription drug sales, 2000
Source www.pharmacytimes.com.
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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 273214-219
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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

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Categories for drugs active against resistant
pathogens
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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

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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

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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

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Development program - Phase I

• Dose-ranging studies
• PK (traditional or sparse sampling)
• Special population studies

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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

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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

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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

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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?

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Summary

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

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