Clinical Trial Design Issues

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Clinical Trial Design Issues

• Phill Price MD

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Contraceptive Drug Development

• Phase 1
• Phase 2
• Phase 3
• Phase 4

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Phase 1

• Safety
• Tolerability
• Pharmacokinetics
• Drug interactions

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Phase 2

• Ovulation suppression
• Dose finding
• Preliminary predictive (efficacy) information and
  some safety data

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Phase 3 (Safety Efficacy)

• Type of Trial
• Trial Size
• Entry Criteria
• Study Procedures
• Efficacy
• Safety Evaluation
• Cycle Control
• Discontinuation

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Type of Trial (Phase 3)

• Open labeled historical control
• Active control
• not basis of approval for presently marketed
  drugs

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Trial Size (Phase 3)

• New Molecular Entity (NME)
• 20,000 28-day cycles (or equivalent) within first
  year of treatment
• 400 women completing thirteen
• 28-day cycles (or equivalent)

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Trial Size (Phase 3)

• Non-NME
• 10,000 28-day cycles (or equivalent)
• within first year of treatment
• 200 women completing thirteen
• 28-day cycles (or equivalent)

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Entry Criteria (Phase 3)

• Sexually active and not using any other form of
  contraception on a regular basis
• Age
• BMI
• Smoking
• Percentage of switchers vs. fresh starts
• Labeled contraindications (are typical
  exclusions)
• Other exclusions

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Variability in Entry Criteria (Phase 3)

• Age (18- 50, majority less than age 35)
• BMI (generally less than 35 kg/m2)
• Smoking
• Switchers vs. fresh starts
• Other exclusions
• family history of VTE
• adverse bleeding patterns with prior hormonal
  contraceptive use

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Study Procedures (Phase 3)

• Standard entry procedures
• Pregnancy testing
• frequency
• urine vs. serum
• central lab vs. home

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Study Procedures (Phase 3)

• Diary (paper vs. electronic)
• pill use
• bleeding/ spotting data collection
• use of back-up contraception
• sexual activity
• Criteria for protocol driven termination
• Subject satisfaction data
• Use of Patient Reported Outcome (PRO) Instrument

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Study Evaluation

• Efficacy
• Cycle-control
• Discontinuation rates
• Safety

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Efficacy

• Efficacy based upon on-treatment pregnancies
• From start of study drug through end of study
  drug administration 14 days
• Failure rate assessment
• Pearl Index (point estimate 95 confidence
  interval)
• Life Table method

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Efficacy

• Failure types
• method failure
• user failure
• Study population for efficacy analysis
• no back-up contraception
• sexual activity
• age (equal to or less than 35 years)

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Cycle control

• Definitions and analysis vary

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Discontinuation

• Protocol driven termination
• Patient withdrawal

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Limitation of Phase 3 trials for assessment of
product safety

• Further investigation in Phase 4