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Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006

Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006. Scott Monroe, MD Acting Director, Division of Reproductive and Urologic Products. 17- Hydroxyprogesterone Caproate ( G estiva). Proposed Indication

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Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006

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  1. Meeting of the Advisory Committee for Reproductive Health DrugsAugust 29, 2006 Scott Monroe, MDActing Director, Division of Reproductive and Urologic Products

  2. 17-Hydroxyprogesterone Caproate (Gestiva) Proposed Indication Prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth

  3. The Problem and Impact of Preterm Birth • ~12% of all live births in U.S. are preterm • Preterm birth (PTB) is • Leading cause of neonatal death • Major cause of early childhood morbidity and mortality including pediatric neurodevelopmental problems • No approved drug product for prevention of PTB • No approved drug for treatment of preterm labor currently marketed in the U.S. • Drugs used off-label for Tx of preterm labor not been shown to improve perinatal outcomes in controlled trials

  4. Prevention of Preterm BirthA New Indication for an “Old Drug”? • 17OHP approved in 1956 largely on safety considerations • Suggested uses of 17OHP (tradename Delalutin) included Tx of habitual, recurrent, or threatened abortion • Withdrawn from marketing in 2000 at request of NDA holder • Presently available only from compounding pharmacies • In 2003, findings from a multicenter randomized, double-blind, controlled trial of 17OHP for prevention of PTB sponsored by NICHD were published in NEJM • Showed reduction in rate of PTB < 37 weeks gestation • Application to be discussed today based largely on this trial and a follow-up safety study of the children from the trial

  5. Clinical Issues that Committee Will Be Asked to Consider • Adequacy of the clinical data to support a claim of effectiveness of 17-hydroxyprogesterone caproate for prevention of preterm birth • Percentage of preterm births in vehicle (control) arm of principal study (55%) was considerably higher than expected rate of ~36% • Possible safety concern based the relative increase in the percentage of second trimester miscarriages and stillbirths in the 17-hydroxyprogesterone caproate group

  6. Adequacy of Data to Support Effectiveness • FDA generally requires 2 adequate and well controlled studies for substantial evidence of effectiveness • Circumstance in which a single trial may be adequate • Trial has shown meaningful effect on mortality, irreversible morbidity, or prevented a disease with a potentially serious outcome, and • Confirmation of result in a second trial would be logistically impossible or ethically unacceptable • Applicant is seeking approval based on • Findings from a single clinical trial • Surrogate endpoint for neonatal/infant morbidity and mortality • Reduction in rate of preterm births prior to 37 weeks

  7. Questions for the Committee • Is the primary endpoint ─ prevention of PTB prior to 37 weeks gestation ─ an adequate surrogate for a reduction in fetal and neonatal morbidity or mortality? • If not, would prevention of PTB prior to 35 or 32 weeks gestation be adequate? • Does the high percentage of PTBs (55%) in the vehicle arm of the principal trial indicate the need to replicate the findings in a confirmatory trial? • Do the data provide substantial evidence that 17OHP • prevents PTB prior to 35 or 32 weeks gestation or • reduces fetal and neonatal morbidity or mortality ?

  8. Questions for the Committee • Is further study needed to evaluate the potential association of 17OHP with increased risk of second trimester miscarriage and stillbirth? • If so, should this information be obtained prior to approval for marketing or post-approval? • Are the overall safety data obtained in Studies 17P-CT-002 and 17P-IF-001 and Study 17P-FU (long-term follow-up) adequate and sufficiently reassuring to support marketing approval of 17OHP without the need for additional preapproval safety data?

  9. Agenda 8:20 Roberto Romero, MD ─ Causes of Premature Birth: The Premature Parturition Syndrome 9:00 Applicant (Adeza Biomedical) Presentation 10:30 Break 10:45 FDA Presentation 11:45 Questions from the Committee 12:00 Lunch 1:00 Open Public Forum 2:00 Discussion and Questions by the Committee 4:00 Committee Voting 5:30 Adjournment

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