1 Meeting of the Advisory Committee for Reproductive Health Drugs August 29, 2006 Scott Monroe, MD Acting 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 u ~12% of all live births in U.S. are preterm u Preterm birth (PTB) is  Leading cause of neonatal death  Major cause of early childhood morbidity and mortality including pediatric neurodevelopmental problems u No approved drug product for prevention of PTB u No approved drug for treatment of preterm labor currently marketed in the U.S. u Drugs used off-label for Tx of preterm labor not been shown to improve perinatal outcomes in controlled trials

4 Prevention of Preterm Birth A New Indication for an “Old Drug”? u 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 Suggested uses of 17OHP (tradename Delalutin) included Tx of habitual, recurrent, or threatened abortion  Withdrawn from marketing in 2000 at request of NDA holder  Presently available only from compounding pharmacies  In 2003, findings from a multicenter randomized,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 u Adequacy of the clinical data to support a claim of effectiveness of 17-hydroxyprogesterone caproate for prevention of preterm birth u Percentage of preterm births in vehicle (control) arm of principal study (55%) was considerably higher than expected rate of ~36% u 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 u FDA generally requires 2 adequate and well controlled studies for substantial evidence of effectiveness u 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 u 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 u 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? u 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? u 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 u 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 ? u 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 8:20Roberto Romero, MD ─ Causes of Premature Birth: The Premature Parturition Syndrome 9:00Applicant (Adeza Biomedical) Presentation 10:30Break 10:45FDA Presentation 11:45Questions from the Committee 12:00Lunch 1:00Open Public Forum 2:00Discussion and Questions by the Committee 4:00Committee Voting 5:30Adjournment