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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. Barbara Wesley, M.D., M.P.H. Division of Reproductive and Urologic Products. NDA 21-945 17 α 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 Barbara Wesley, M.D., M.P.H.Division of Reproductive and Urologic Products

  2. NDA 21-94517α Hydroxyprogesterone Caproate (Gestiva) Proposed Indication • Gestiva is indicated for the prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth Dosage & Administration • Gestiva is to be administered IM at a dose of 250 mg once a week beginning between 16-weeks 0-days (160 weeks) and 20-weeks 6-days (206 weeks) gestation to week 37 of gestation or birth

  3. Overview of Clinical Studies Study 17P-IF-001 • Randomized, vehicle-controlled study with target enrollment of 500 subjects • 150 subjects enrolled and treated • Study terminated prematurely: recall of study drug Study 17P-CT-002 • Principal efficacy and safety study • Terminated prematurely: crossed efficacy threshold • 463 of 500 planned subjects enrolled and treated • 17OHP = 310; vehicle = 153 Study 17P-FU • Follow-up for long-term health and development • 278 subjects enrolled: 17OHP = 194; vehicle = 84

  4. Study 17P-CT-002 Design • Double blind, vehicle-controlled with subjects randomized 2:1 to 17OHP or vehicle Inclusion Criteria • History of spontaneous singleton preterm birth • Gestational age of 160 to 206 at randomization Main Exclusion Criteria included • Known major anomaly • Prior progesterone or heparin Rx in current pregnancy • Hx of thromboembolic disease • Maternal medical/obstetrical complications including • Current or planned cerclage • Hypertension requiring medication • Seizure disorder

  5. Study 17P-CT-002 Study Medications • 17α-hydroxyprogesterone caproate (250 mg/mL) in castor oil, benzyl benzoate, and benzyl alcohol • Vehicle Dosing Regimen • Weekly IM injection through Week 366 or delivery Primary Efficacy Endpoint • Birth < 370 weeks Additional Efficacy Endpoints (post hoc) • Birth < 350 weeks and < 320 weeks • Composite index of neonatal morbidity • Death, RDS, bronchopulmonary dysplasia, Gr. 3 or 4 IVH, proven sepsis, necrotizing enterocolitis

  6. Overview of Subject DispositionStudy 17P-CT-002

  7. Preterm Births <370 Weeks Gestation in ITT Population (Study 17-P-CT-002) Primary Efficacy Endpoint • PTB rate of 54.9% in vehicle arm considerably greater than rate in other MFMU Network studies • PTB rate of 37.1% in 17OHP arm similar to PTB rate in control arms in another MFMU Network studies

  8. Percent of Preterm Births in Revised ITT Population (Study 17-P-CT-002) Confidence intervals adjusted for the interim analyses and the final analysis. To preserve overall Type I error rate of .05, p-value boundary of .035 used for the adjustment (equivalent to a 96.5% confidence interval).

  9. Proportion of Enrolled Subjects Continuing to be Pregnant by Gestational Age

  10. Gestational Age (Weeks) at Delivery (Study 17P-CT-002) Difference between groups (mean) 1.0 week [95%CI: 0.3,1.5]

  11. Birthweight (Study 17P-CT-002)

  12. Miscarriages, Stillbirths, and Neonatal Deaths (Study 17P-CT-002) • No net survival benefit

  13. Days from Onset of Treatment to Fetal or Neonatal Death 1.0 Proportion Surviving 17OHP Vehicle 0.8 100 50 150 Days to Fetal or Neonatal Death

  14. Literature Reports of Fetal Loss in Women Treated with 17-hydroxyprogesterone Caproate n = Number of fetal losses N = Number of subjects in treatment group From: Keirse MJ, Brit J Obstet Gynecol 1990; 97(2):149-54

  15. Composite Neonatal Morbidity (Study 17P-CT-002) * No. subjects with one or more of the listed morbidities.

  16. Maternal Safety Findings (Study 17P-CT-002) • Adverse event (AE) data not collected in usual manner • Subjects asked if had any symptoms related to study medication • No maternal deaths • 3 reports of serious AEs ─ all in 17OHP group • Pulmonary embolus 8 days post delivery • Cellulitis at study medication injection site • Postpartum hemorrhage, respiratory distress, endometritis • 11 subjects discontinued because of an AE • 7 (2.2%) in 17OHP group • Urticaria (n=3), injection site pain/swelling (n=2) arthralgia (n=1), weight gain (n=1) • 4 (2.6%) in control (vehicle) group • Pruritus (n=2), injection site pain (n=1), urticaria (n=1)

  17. Common Adverse Events (Study 17P-CT-002)

  18. Selected Pregnancy Complications (Studies 17P-CT-002 and 17P-IF-001)

  19. Overview of Study 17P-IF-001 • Study Design • Double blind, vehicle controlled, randomized 2:1 • Identical to that of Study 17P-CT-002 • Terminated prematurely: recall of study drug • 150 subjects randomized before recall • 104 subjects completed treatment or withdrew for reasons other than recall of study drug • 17OHP group: 65 subjects • Vehicle group: 39 subjects

  20. Key Findings from Study 17P-IF-001 Efficacy (Subjects not affected by recall) • Subjects with delivery < 37 weeks • 17OHP – 43.1% (28 of 65) • Vehicle – 38.5% (15 of 39) Miscarriages, Stillbirths, and Neonatal Deaths

  21. Overview of Study 17P-FU Objective • Follow–up of children whose mothers were treated with either 17OHP or vehicle in the principal study Study Population • 14 of original 19 study sites eligible to participate (children from 374 of original 463 patients - 80%) • 278 of 374 (80%) of eligible children enrolled • 17OHP: 194 children (82%) • Vehicle: 84 children (74%)

  22. Demographics of Children in Study 17P-FU • Mean Gestational Ages • Age at Evaluation in Study 17P FU

  23. Endpoints (Study 17P-FU) • Primary: Ages & Stages Questionnaire (ASQ) • Communication • Gross motor • Fine motor • Problem solving • Personal/social • Positive Screen: score 2 S.D. below mean in any of 5 areas • Secondary: Survey Questionnaire • Activity/motor control • Vision/hearing • Height/weight/head circumference • Gender specific play • Diagnosis by a physician • Subjects also underwent physical exam

  24. Number (%) of Children with ASQ Scores Suggestive of Developmental Problem

  25. Number (%) of Children with Low ASQ Score & Independent Diagnosis of Developmental Delay

  26. Summary of Issues • Applicant is seeking approval for 17OHP based on • Findings from a single clinical trial • A surrogate endpoint for infant mortality/morbidity (preterm birth < 37 weeks) • Concern about applicability to other populations • Preterm birth rate in vehicle arm that is higher than that reported in another MFMU Network trial • Safety concern • Potential safety signal of increased fetal wastage in 17OHP group

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