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

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Meeting of the Advisory Committee for
Reproductive Health DrugsAugust 29, 2006

• Scott Monroe, MDActing Director, Division of
  Reproductive and Urologic Products

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17-Hydroxyprogesterone Caproate (Gestiva)

• Proposed Indication
• Prevention of preterm birth in pregnant women
  with a history of at least one spontaneous
  preterm birth

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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

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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• Withdrawn from marketing in 2000 at request of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 lt 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

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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

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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

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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
  ?

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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?

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Agenda

• 820 Roberto Romero, MD - Causes of Premature
• Birth The Premature Parturition Syndrome
• 900 Applicant (Adeza Biomedical) Presentation
• 1030 Break
• 1045 FDA Presentation
• 1145 Questions from the Committee
• 1200 Lunch
• 100 Open Public Forum
• 200 Discussion and Questions by the Committee
• 400 Committee Voting
• 530 Adjournment