Historical Perspective, Selection and Implications of Delta

1
Historical Perspective, Selection and
Implications of Delta

• Renata Albrecht, M.D.
• Acting Director
• Division of Special Pathogen and Immunologic Drug
  Products, ODE IV

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Advisory Committee meeting originally scheduled
9/13/01

• Postponed due to national events
• Continued discussion in last six months
• CID letters
• Discussions with academia and industry
• Expanded agenda to include additional
  presentations

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Overview

• Historical Perspective
• Delta and Regulatory Decision
• Selection of Delta - 1992 PTC
• Impact of delta on clinical trials
• Consequences of delta on patient care
• Summary

4
Delta and Regulatory Decision

• What role has delta played in the regulatory
  decision process?

Delta
95 confidence interval
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Delta and Regulatory Decision (2)

• In general ...
• If delta is met, indication approved
• If delta is not met, indication not approved
• Rare exceptions to this
• Delta met, indication not approved due to
  concerns about safety
• Delta not met, indication approved due to overall
  risk benefit evaluation and results reflected in
  product labeling

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Delta and Regulatory Decision (3)

• In summary, delta has been one of multiple
  important factors considered in making a
  regulatory decision

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Historical Perspective

• Selection of Delta has been guided by
• 1992 Points to Consider Document -- Clinical
  Development and Labeling of Anti-Infective Drug
  Products
• available at www.fda.gov/cder/guidance/

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1992 PTC suggested 95 CI approach,delta based
on observed success rate
80 power
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1992 PTC Design and conduct of clinical trial
influenced by various factors

• PK/PD of test drug
• Microbiology data on test drug
• Approved indications for test drug
• Drug class properties
• efficacy
• safety

• Incidence of infection
• Natural history of infection
• Realistic number of patients available
• Cure rates of other drugs

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1992 PTC

• Demonstrating effectiveness is one part of
  burden of proof
• Risk-to-Benefit Profile must be established
• there are situations where the morbidity and
  mortality of the illness under evaluation will
  dictate that an absolute difference in success
  rateswillbe clinically unacceptable

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Over the years.

• 1992 PTC
• the step function has persisted
• the other elements have been lost
• 1998 Advisory Committee
• General Statistical guidance
• February 2001
• Disclaimer to PTC that sliding scale method for
  determination of delta no longer used

Nike of Samothrace
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Clinical Trial Implications1992 Points to
Consider approach
80 power
13
Clinical Trial Implications Smaller Delta
(e.g. 10)
80 power
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Clinical Trial Implications Smaller Delta
(e.g. 5)
80 power
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Clinical Trial Implications

• For a given delta, the lower the success rate,
  the larger the sample size
• For a given success rate, the smaller the delta,
  the larger the sample size

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Clinical Trial ImplicationsSample size per arm
to achieve 80 power
D
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Clinical Trial impact on

• Industry / Investigators
• time and cost commitment of doing clinical trials
• Physicians / HCP / Pharmacists
• availability of information for patient care
• Patients

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Consequence to Patients
As participants in clinical trials
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Consequence to Patients
As recipients of drug therapy
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Consequence to Patients

• If accept a delta of 15 instead of delta of 10
  as evidence of non-inferiority, the consequence
  is that
• the drug is potentially 5 less effective
• an extra 5000 patients may potentially fail
  therapy for each 100,000 patients treated

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Consequence to Patients

• What if the delta is small, yet unrealistic, and
  there is no clinical trial conducted ?
• Then no data are available
• Even under 1992 PTC approach, some diseases were
  rarely studied
• endocarditis
• osteomyelitis
• meningitis

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Summary

• A number of issues/ questions
• Committee discussion
• Availability of Docket 98D-0548 for written
  comments
• Goals after this meeting
• Review comments
• Future AC meeting(s)
• Finalizing guidance documents