DIVISION OF REPRODUCTIVE AND UROLOGIC PRODUCTS Clinical Trial Design Issues Phill Price MD

2 Contraceptive Drug Development  Phase 1  Phase 2  Phase 3  Phase 4

3 Phase 1  Safety  Tolerability  Pharmacokinetics  Drug interactions

4 Phase 2  Ovulation suppression  Dose finding  Preliminary predictive (efficacy) information and some safety data

5 Phase 3 (Safety & Efficacy)  Type of Trial  Trial Size  Entry Criteria  Study Procedures  Efficacy  Safety Evaluation  Cycle Control  Discontinuation

6 Type of Trial (Phase 3)  Open labeled historical control  Active control  not basis of approval for presently marketed drugs

7 Trial Size (Phase 3) New Molecular Entity (NME)  20, day cycles (or equivalent) within first year of treatment  400 women completing thirteen 28-day cycles (or equivalent)

8 Trial Size (Phase 3)  Non-NME  10, day cycles (or equivalent) within first year of treatment  200 women completing thirteen 28-day cycles (or equivalent)

9 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

10 Variability in Entry Criteria (Phase 3)  Age (18- 50, majority less than age 35)  BMI (generally less than 35 kg/m 2 )  Smoking  Switchers vs. fresh starts  Other exclusions  family history of VTE  adverse bleeding patterns with prior hormonal contraceptive use

11 Study Procedures (Phase 3)  Standard entry procedures  Pregnancy testing  frequency  urine vs. serum  central lab vs. home

12 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

13 Study Evaluation  Efficacy  Cycle-control  Discontinuation rates  Safety

14 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

15 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)

16 Cycle control  Definitions and analysis vary

17 Discontinuation  Protocol driven termination  Patient withdrawal

18 Limitation of Phase 3 trials for assessment of product safety  Further investigation in Phase 4