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

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NDA 21-945 17α 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

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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

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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

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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 weeksAdditional 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

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Overview of Subject DispositionStudy 17P-CT-002

17OHPN=310n (%)

VehicleN=153 n (%)

Completed Treatment

Withdrawn from Treatment

Due to Adverse Event

Lost to Follow-up

279 (90.0)

27 (8.7)

6 (1.9)

4 (1.3)

139 (91.0)

14 (9.2)

3 (2.0)

0

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Preterm Births <370 Weeks Gestation in ITT Population (Study 17-P-CT-002)

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

17OHP

N = 310

Vehicle

N = 153 % Difference [Adjusted 95%

Confidence Interval]Number (%) Preterm Births

115 (37.1%) 84 (54.9%) -17.8% [-28%, -7%]

Primary Efficacy Endpoint

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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).

Age at Delivery (Weeks)

17OHPN=310

VehicleN=153

% Difference [Adjusted 95%

Confidence Interval]Percent Delivered

< 370 37.1 54.9 -17.8% [-28%, -7.0%]

< 350 21.3 30.7 -9.4% [-18.7%, -0.2%]

< 320 11.9 19.6 -7.7% [-15.5%, 0.1%]

< 280 9.4 10.5 -1.1% [-7.4%, 5.2%]

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Proportion of Enrolled Subjects Continuing to be Pregnant by Gestational Age

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Gestational Age (Weeks) at Delivery (Study 17P-CT-002)

17OHPN=306

VehicleN=153

Median 37.5 36.5

Mean 36.2 35.2

Min, Max 18.1, 41.5 20.3, 41.6

Difference between groups (mean)

1.0 week [95%CI: 0.3,1.5]

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

17OHPN=301

VehicleN=151

Mean Weight (gm) 2760 2582

Gm Difference [95%CI] 178.2 [-13, 290]

Birthweight n (%) n (%)

<2500 gm 82 (27.2%) 62 (41.1%)

% Difference [95%CI] -13.8% [-23, -4.5]

<1500 gm 26 (8.6%) 21 (13.9%)

% Difference [95%CI] -5.3% [-11.6, 1.1]

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Miscarriages, Stillbirths, and Neonatal Deaths (Study 17P-CT-002)

No net survival benefitNo net survival benefit

Pregnancy Outcome17OHPN=306n (%)

VehicleN=153n (%)

Miscarriages (16 to <20 weeks)

Stillbirths

Neonatal Deaths

Total Deaths

5 (1.6)

6 (2.0)

8 (2.6)

19 (6.2)

0

2 (1.3)

9 (5.9)

11 (7.2)

Days from Onset of Treatment to Fetal or Neonatal Death

0 50 100 150

Days to Fetal Death

0.8

1

Pro

po

rtio

n S

urviv

ing

Days from Randomization to Fetal Loss

TREATMENT:17PPLACEBO

Days to Fetal or Neonatal Death

50 100 150

1.0

Pro

port

ion

Sur

vivi

ng

0.8

17OHP Vehicle

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Literature Reports of of Fetal Loss in Women

Treated with 17-hydroxyprogesterone Caproate

Study 17OHPn N

Vehiclen N

LeVine (1964) 3/15 7/15

Shearman (1968) 5/27 5/23

Johnson (1975) 3/23 0/27

Yemini et al. (1985) 8/39 3/40

n = Number of fetal lossesN = Number of subjects in treatment groupFrom: Keirse MJ, Brit J Obstet Gynecol 1990; 97(2):149-54

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Composite Neonatal Morbidity

(Study 17P-CT-002)

Morbidity17OHPN=295n (%)

VehicleN=151n (%)

Death (live births only) 8 (2.6) 9 (5.9)

Respiratory Distress Syndrome 29 (9.9) 23 (15.3)

Bronchopulmonary Dysplasia 4 (1.4) 5 (3.3)

Gr. 3/4 Intraventricular Hemorr. 2 (0.7) 0 (0.0)

Proven Sepsis 9 (3.1) 4 (2.6)

Necrotizing Enterocolitis 0 (0.0) 4 (2.7)

Composite Index of Morbidity* 35 (11.9%) 26 (17.2%)

* No. subjects with one or more of the listed morbidities.

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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)

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

Preferred Term 17OHPN=310n (%)

VehicleN=153n (%)

Injection site pain 108 (34.8) 50 (32.7)

Injection site swelling 53 (17.1) 12 (7.8)

Urticaria 38 (12.3) 17 (11.1)

Pruritus 24 (7.7) 9 ( 5.9)

Injection site pruritus 18 (5.8) 5 (3.3)

Nausea 18 (5.8) 7 (4.6)

Contusion 17 (5.5) 14 (9.2)

Injection site nodule 14 (4.5) 3 (2.0)

Vomiting 10 (3.2) 5 (3.3)

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

Pregnancy Complication

Study17OHP Vehicle

n (%) n (%)

Gestational Diabetes

CT-002 17 (5.6) 7 (4.6)

IF-001 8 (8.6) 0 (0.0)

OligohydramniosCT-002 11 (3.6) 2 (1.3)

IF-001 2 (2.2) 1 (1.9)

PreeclampsiaCT-002 27 (8.8) 7 (4.6)

IF-001 6 (6.5) 2 (3.8)

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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

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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

Pregnancy Outcome17OHPN=93 n (%)

VehicleN=54n (%)

Miscarriages (16 to <20 weeks) 1 (1.1) 1 (1.9)

Stillbirths 1 (1.1) 2 (3.7)

Neonatal Deaths 2 (2.2) 0

Total Deaths 4 (4.4) 3 (5.9)

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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%)

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Demographics of Children in Study 17P-FU

Mean Gestational Ages

Study Gestational Age (Weeks)

17OHP Vehicle

17P-CT-002 36.2 35.2

17P-FU 37.3 36.2

Months

17OHP Vehicle

Mean 47.2 48.0Range 30.2, 63.9 33.5, 64.3

Age at Evaluation in Study 17P FU

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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

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

17OHPN=193

VehicleN=82

Area of Development n (%) n %

Communication 22 (11.4) 9 (11.0)

Gross Motor 5 (2.6) 3 (3.7)

Fine Motor 40 (20.7) 15 (18.3)

Problem Solving 20 (10.4) 9 (11.0)

Personal-Social 7 (3.6) 1 (1.2)

Developmental problem in one or more areas 53 (27.5) 23 (28.0)

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

17OHP (N=193)

Vehicle (N=82)

n (%) n (%)

Total Number Affected 13 (6.7) 8 (9.8)

Area of Development

Communication 9 (4.7) 7 (8.5)

Gross Motor 3 (1.6) 2 (2.4)

Fine Motor 10 (5.2) 3 (3.6)

Problem Solving 5 (2.6) 5 (6.1)

Personal-Social 5 (2.6) 1 (1.2)

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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