Selection of Delta to Determine Efficacy in Noninferiority Trials of Antibacterial Drugs

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Selection of Delta to Determine Efficacy in
Noninferiority Trials of Antibacterial Drugs

• Antimicrobial Working Group of the
  Pharmaceutical Research and Manufacturers of
  America (PhRMA)
• David Shlaes, M.D.
• February 19, 2002

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PhRMAs Antimicrobial Working Group

• Offers a forum for exchange of scientific
  information among PhRMA companies with an RD
  commitment to anti-infective drug products
• Provides industrys scientific perspective in
  response to proposed rules, draft guidances, and
  relevant issues affecting anti-infective drug
  products

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Antimicrobial Working Group
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Outline of Todays Remarks

• Background - antibacterial clinical trials
  selection of delta
• Implications of delta for antimicrobial
  development
• Unintended consequences of smaller delta
• Alternative proposals to consider

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PhRMAs Key Messages

• Current system for designing clinical studies and
  registering antibacterial drugs has worked
• always room for improvement
• A single approach for all antibacterial drugs for
  all indications is unlikely to be optimal
• Clinical studies must be feasible
• practical sample sizes
• able to be conducted in a reasonable time
• encourage attention to areas of public health
  need
• Comparator agent should be consensus standard of
  care (to address concern of bio-creep)
• PhRMAs proposals are offered in this context

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Clinical Trials with Anti-infective Drugs
Unique Considerations

• Considerable information about activity against
  targeted pathogens can be obtained by in vitro
  testing, animal models and PK/PD determinations
• Rigorous design using an active control, rather
  than placebo, is essential for most studies
• Magnitude of efficacy observed in a given study
  varies with
• Severity of infection
• Specific pathogens
• Other factors (comorbid conditions, concomitant
  meds, adequacy of surgical intervention, etc.)

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FDAs Approach Throughout the 1990s

• Regulatory approval is based on evidence from
  multiple clinical studies, typically for multiple
  indications
• Evidence must show that the success rate of the
  new drug is reasonably close to the success
  rate of an active control (statistically
  speaking new drug is not inferior to the
  control drug by more than a pre-determined
  amount)
• Main assessment compare the lower bound of the
  two-sided 95 confidence interval on the
  difference in success rates for new drug vs.
  active control to a pre-specified limit (delta)

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Step-Function Delta and Clinical/Statistical
Issues

• Delta in non-inferiority trials (as described in
  FDAs 1992 Points to Consider document) has been
  useful for assessing efficacy, using reasonable
  patient sample sizes, especially when multiple
  Phase 3 trials are done.
• Cure Rate Delta
• ? 90 10
• 80 - 89 15

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Merits of Existing Step-Function Approach -One
size does not fit all

• Smaller margin when comparator success rates are
  higher higher hurdle for new treatments
  compared with very effective controls
• Recognizes magnitude and variability of the
  success rate to establish the non-inferiority
  criteria
• Recognizes need for both statistical and clinical
  aspects of efficacy evaluation
• Supports study designs using realistically
  achievable sample sizes
• The approach has been used effectively for a
  decade of drug development
• PhRMA is not aware of any evidence that newer
  agents approved to treat serious infections,
  especially those involving resistant pathogens,
  are less effective than previously approved
  products

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Many Effective Antibacterial Products Have Been
Developed Since the Early1990s Using This
Approach

• Examples
• meropenem
• linezolid tablets and injection
• levofloxacin tablets and injection
• cefdinir
• trovafloxacin
• ertapenem

• ceftibutin
• loracarbef
• moxifloxacin
• gatifloxacin
• azithromycin
• clarithromycin
• quinupristin / dalfopristin

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Implications of A Smaller Delta

• Increased Time to Complete Clinical Trials
• Increases time to drug availability
• Validity of a trial conducted over a number of
  years is suspect
• adds further to the inherent variability of a
  given infectious disease indication
• Increased Number of Investigators
• another source of variability
• Smaller delta ? larger sample size ? increased
  development time, cost, and variability

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Actual Example Pediatric Meningitis
TrialInvestigational Drug vs. Active Control

• Sponsors FDA
• Proposal Proposal
• Projected Response Rate 80 80
• Delta 15 10
• Evaluable Total Sample Size 224 504
• Projected Evaluable 70 70
• Total to be Enrolled 320 720
• Projected Enrollment Time 2-4 years 4-6
  years
• Impact proposed study is not feasible
• Note ? 5, power 80

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What is Gained by Reducing Delta ?

• Example
• Control cure rate 85
• New drug cure rate 75
• 120 evaluable patients/group (90 power)
• Using two trials powered at 15 delta, the risk
  of incorrectly concluding non-inferiority is
  2.7
• Therefore, there is a very low risk of
• approving a less effective product ! Little
• is gained by reducing delta .

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Potential Disadvantages of a Fixed Margin
Approach Regardless of the Response Rate of the
Comparator

• Will require considerably larger sample sizes
• Unrealistic for some indications/patient
  populations
• Disincentive to develop new antibiotics,
  particularly for indications with inherently low
  success rates (eg, osteomyelitis)
• Potentially unnecessary exposure of more patients
  to investigational treatments

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Unintended Consequences of Smaller Delta

• Increased cost and time will further disadvantage
  investment in new antibiotics in companies
  portfolios relative to other therapeutic areas
• fewer companies will develop new antibacterial
  agents
• Fewer new anti-infectives will be developed and
  existing drugs may be overused
• delay in the availability of new agents,
  particularly those intended for resistant
  pathogens
• exacerbated by current trend toward disinvestment
  in anti-infective RD infrastructure
• Potential public health risk of fewer new
  anti-infective agents for serious infections,
  especially infections caused by resistant
  pathogens

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Investigational Antibacterial Drugs are Already
Disadvantaged in an RD Portfolio

• Antibacterial drugs are usually intended for
  short duration of use for acute diseases
• Size of patient population is relatively
  unpredictable and can vary dramatically from year
  to year
• Economic justification is stronger for
  development of drugs in other therapeutic areas
  (eg, chronic therapies for chronic diseases) vs.
  antibacterial drugs

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Suggested Principles for Selection of Delta

• Continue to use step-function approach until an
  optimal alternative is agreed upon
• Assure rigorous comparison by study design and
  choice of comparator
• Comparator agent should be consensus standard of
  care (thereby addressing concern about
  bio-creep)
• For indication-specific delta, consider the
  seriousness of the disease, variability of the
  response rate, and feasibility of conducting the
  trial

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Specific Options for DeltaOptions for Various
Development Programs

• Conduct two independent Phase 3 trials with a
  delta of 15 or 20 for each trial (low risk of
  incorrectly concluding non-inferiority)
• Conduct two independent Phase 3 trials (e.g., 1
  larger trial and 1 smaller trial) with a combined
  analysis providing a power of 95 and combined
  sample size using delta of 10 to assess
  non-inferiority

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Specific Options for DeltaOptions for Various
Development Programs

• Analyze results by comparing the lower bound of a
  1-sided 95 confidence interval on the difference
  in success rates for new drug vs. active control
  to a pre-specified limit (consistent with ICH E9
  guideline on analysis of non-inferiority trials)
• Use FDAs general equivalence definition for
  selected indications (see next slide for example
  for nosocomial pneumonia)

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Example of General Equivalence Approach
Nosocomial Pneumonia (in 1992 FDA Points to
Consider)

• One well-controlled trial
• General Equivalence absolute clinical
  success rate of new drug is no more than 5 less
  effective than an agreed active comparator agent
• At least 80 patients in each treatment arm, with
  enrollment based on rigid case definitions
  (including entry sputum microscopy and
  radiographic findings)
• This sample size and measure of equivalence
  describe a design with 80 power and 20 delta
• Feasible

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Study Design OptionsNon-Life Threatening
Infections with Spontaneous Cure(eg, acute
bronchitis, AECB, acute otitis media)

• Rapid Cure Design Placebo controlled with
  escape 100 patient study (50/arm) with evaluation
  at day 4-5 to show active treatment provides 2 x
  success rate of placebo. No improvement
  failure. Then treat failures with open label
  antibiotics.
• Time to Cure Design Placebo controlled 200
  patient study (100/arm) to demonstrate 50
  reduction in time to symptom resolution

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Summary

• PhRMA recognizes the medical need for discovery
  development of new anti-bacterial drugs
• PhRMA companies welcome and rely on informative
  and realistic guidances to provide the latest
  thinking of FDA and its advisors
• PhRMA is planning a workshop for industry, FDA,
  IDSA, and other stakeholders in order to define
  clinical and statistical standards consistent
  with efficient development of safe effective
  anti-bacterial drugs