Clinical Trials – Clinical Trials – Human Gonadotropin Drug Human Gonadotropin Drug

ProductsProductsA Regulatory PerspectiveA Regulatory Perspective

Shelley R. Slaughter, M.D., Ph. D.

Reproductive Medical Officer

Team Leader

Division of Reproductive and Urologic Drug Products

Food and Drug Administration

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Guidance Document for Industry

• “Represents the Agency’s current thinking on a particular subject. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations or both”

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Clinical Background

• Drs. Keefe and Toner

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Clinical StudiesIntroduction

• Review Gonadotropin Drug Products

• Overview of clinical studies for selected approved gonadotropin drug products

• Discussion by the Committee

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Approved urinary derived gonadotropins and recombinant gonadotropins

Trade Name Established Name

Pergonal Menotropins (LH, FSH)

Humegon® Menotropins (LH, FSH)

Repronex Menotropins (LH, FSH)

Metrodin HP (Fertinex)

Urofollitropin (FSH)

Bravelle Urofollitropin (FSH)

Gonal-F Follitropin alpha (FSH)

Follistim Follitropin beta (FSH)

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Gonadotropin Drug ProductsApproved Indications

• Ovulation Induction in Chronic Anovulatory Women

• Multiple Follicular Development in Ovulatory Women for ART

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Gonadotropin Drug Products

• The goal:The goal:

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Overview of Clinical Studies

• In the 30 years since the FDA approved the drug Pergonal, the technology used in the treatment of infertility and the resulting clinical pregnancy rates have improved

• Time for a re-examination of the clinical studies for gonadotropin drug products

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Overview of Clinical Studies

• Examine clinical study information on selected approved gonadotropin drug products –historical perspective – design– efficacy surrogate endpoints and analysis– safety endpoints

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Surrogate Endpoint

• Definition: A laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measuredirect measure of how a patient feels, functions or survives and that is expected to predict the effect of the therapy

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Pergonal®

Approved on:

• June 23, 1970 - Induction of ovulation

• March 1, 1988 - Development of multiple follicles in ovulatory patients participating in an IVF program

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Pergonal®

• Efficacy and safety data:– Literature reports:

• IVF data representing the clinical experience with 192 patients at the Jones Institute (1981 – 1984)

• IVF data from Australia and New Zealand (1979-1984)

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Pergonal®

• Primary Efficacy Endpoint:

– Mean number of oocytes retrievedoocytes retrieved at time of laparoscopylaparoscopy

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Metrodin®

• Approved: – September 18, 1986

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Metrodin®

• Efficacy and safety:– Literature review of retrospective data from

five open-label, non-comparativeopen-label, non-comparative, clinical studies of ovulation induction (n=80 patients)

• Observational reports of ovulation and pregnancy

– Discussed before Advisory Committee 1985

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Gonal-f®

• Approved: – September 29, 1997

• First gonadotropin drug product for which the actual data was submitted for review to the FDA– protocols for the studies were not submitted

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Gonal-f®• Efficacy and safety data from four controlled

studies:– Ovulation Induction-

• Two randomized, open-labelopen-label, active comparator (Metrodin), Phase 3 non-inferiority studies in chronic anovulatory women

– Cumulative proportion of subjects with serum progesterone > 10 ng/ml

– IVF• Two randomized, open-labelopen-label, active comparator

Phase 3 non-inferiority studies in normal ovulatory women

– FolliclesFollicles on ultrasound >14 mm

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Gonal-f® - Ovulation Induction Results

Efficacy Variable Gonal-f® Metrodin® Lower 95% C.I.bound

OI Study 1(Open-label)

(N=60) (N=63)

CumulativeOvulation Rate 81% 93% (-21%)CumulativeClinicalPregnancy Rate* 37% 36% N/AOI Study 2(Open-label)

(N=110) (N=112)

CumulativeOvulation Rate 84% 91% (-16.1%)CumulativeClinicalPregnancy Rate* 35% 46% N/A*Clinical Pregnancy defined as a pregnancy with a fetal sac with or without cardiac activity

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Gonal-f® - IVF resultsEfficacy Variable Gonal-f® Metrodin® Lower 95% C.I.

boundIVF Study 1(Open-label)

(N=60) (N=63)

Mean number offollicles = 14 mmon day hCG 7.8 9.2 (-2.9)Clinicalpregnancy perattempt* 20% 15.9% N/AIVF Study 2(Open-label)

(N=50) (N=53)

Mean number offollicles = 14 mmon day hCG 7.2 8.3 (-2.6)Clinicalpregnancy perattempt* 21.4% 22.4% N/A*Clinical Pregnancy defined as a pregnancy with a fetal sac with or without cardiac activity

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Follistim®

• Approved: – September 29, 1997

• The actual data was submitted for review to the FDA– protocols for the studies were not submitted

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Follistim®

• Efficacy and safety to support Follistim® was derived from four controlled studies:

• Ovulation induction:– One randomized, single-blindsingle-blind, active comparator

(Metrodin®), Phase 3 non-inferiority trial of Follistim® in chronic anovulatory women

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Follistim® - Ovulation Induction Results

Efficacy Variable Follistim® ActiveComparator(uFSH)

Lower 95% C.I.bound

OI Study 1(S-Blind)

(N=89) (N=42)

Ovulation Rate(One cycle) 85% 82% (0.8)OngoingPregnancy Rate*(One cycle) 23% 19% N/A*Ongoing pregnancy rate defined as a pregnancy confirmed at 12 to 16 weeks of gestationby ultrasound

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Follistim®

• IVF– Three randomized, assessor-blindassessor-blind, active

comparator (1-Humegon, 2- Metrodin), Phase 3 non-inferiority studies in normal ovulatory infertile women

– Mean total oocytes retrieved

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Follistim® - IVF resultsEfficacy Variable Follistim® Active

Comparator(uFSH)

Lower 95% C.I.bound

IVF Study 1(S-blind)

(N=585) (N=396)

Mean number oftotal oocytesretrieved 10.9 9.0 (1.0)

OngoingPregnancy Rateper attempt* 22% 18% (1.6)

IVF Study 2(S-blind)

(N=54) (N=35)

Mean number oftotal oocytesretrieved 9.9 7.6 (-1.2)

OngoingPregnancy perattempt* 22.2% 17.1% N/A

IVF Study 3(S-blind)

(N=57) (N=33)

Mean number oftotal oocytesretrieved 10.4 8.8 (-1.0)

OngoingPregnancy perattempt* 29.8% 18.2% N/A

*Ongoing pregnancy rate defined as a pregnancy confirmed at 12 to 16 weeks of gestation by ultrasound

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Safety

• Safety Endpoints:– Ovarian hyperstimulation syndrome rate

– Multiple birth rate

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Previous Gonadotropin Drug Approvals

• Since these selected gonadotropins were approved:– IVF technology has been broadened to include adjunct

procedures (ex. donor oocyte, intracytoplasmic injection)

– More IVF clinics are available, leading to a greater pool of patients for inclusion in studies

For Committee Discussion

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For Committee DiscussionIndications

1. Does the Committee agree with the Indications of:1. Does the Committee agree with the Indications of:– Induction of Ovulation and Pregnancy?– Multiple follicular development in ART?

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For Committee Discussion Study Population

– The following patient populations are enrolled:

• Ovulation Induction

– hypogonadotropic hypogonadal women

– chronic anovulatory women

- ART

– hypogonadotropic hypogonadal women

– normal ovulatory women (defined by serum progesterone) chronic anovulatory

2. Can the committee make a recommendation as to what 2. Can the committee make a recommendation as to what enrollment criteria should be used to adequately enrollment criteria should be used to adequately capture the population to be studied?capture the population to be studied?

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For Committee Discussion Study Stratification

3. Should enrollment be stratified by age? 3. Should enrollment be stratified by age?

4. How do we take into account 4. How do we take into account improvements in IVF and new adjunct improvements in IVF and new adjunct proceduresprocedures??

• Donor Oocyte

• ICSI

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Study Design

5. What study designs should be used: 5. What study designs should be used:

– Open or blinded?• assessor blind• double blind

– Comparator?• active • placebo

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Primary Efficacy EndpointDesired outcome - ““Take Home BabyTake Home Baby””

6. Is it feasible to power studies to detect a difference 6. Is it feasible to power studies to detect a difference in live birth rate? Ongoing pregnancy?in live birth rate? Ongoing pregnancy?

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Primary Efficacy Endpoint If it is notnot feasible to power studies to detect a

difference in live birth rate or ongoing pregnancy rate;Discuss the relevance, advantages /disadvantages of these surrogate surrogate endpoints:– Rate of patients with presence of a fetal heart beat– Rate of patients with presence of a gestational sac– Rate of patients with a Positive ß-hCG (biochemical pregnancy) – Ovulation rate [as defined by serum progesterone level(s)]– Follicular development rate (as defined by two or three criteria)

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Primary Efficacy Endpoint

77. . Can the committee come to a consensus on the Can the committee come to a consensus on the most relevant surrogate endpoint? and most relevant surrogate endpoint? and

• the clinically meaningful difference in that the clinically meaningful difference in that endpoint?endpoint?

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Primary Efficacy Endpoint Analysis

• The FDA typically looks at an Intent-to-Treat The FDA typically looks at an Intent-to-Treat

(per treatment initiation) analysis.(per treatment initiation) analysis.

8. Is this appropriate for:8. Is this appropriate for: • Ovulation Induction ?

• ART?

9. 9. If not appropriate for OI, should cycles be If not appropriate for OI, should cycles be analyzed per subjects who were given hCG?analyzed per subjects who were given hCG?

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Primary Efficacy Endpoint Analysis

10. If not appropriate for ART, should cycles be 10. If not appropriate for ART, should cycles be analyzed:analyzed:

– Per retrieval?– Per embryo transfer?

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Study Analysis

11. How should success be defined:11. How should success be defined:– Superiority to:

• Placebo?

• active control?

– Non-inferiority to active control?

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Safety Endpoint(s)

• The FDA has focused the product-specific safety review of Infertility drug products on:– Rate of ovarian hyperstimulation syndrome– Rate of miscarriages– Rate of multiple pregnancies– Rate of ectopic pregnancies

12. Can the committee make a recommendation as to 12. Can the committee make a recommendation as to what safety endpoint(s) should be evaluated? what safety endpoint(s) should be evaluated?

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Pregnancy and Birth Outcome

13. Is a pregnancy registry feasible?13. Is a pregnancy registry feasible?

14. If feasible, what information should be 14. If feasible, what information should be collected?collected?

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Urinary-derived Human Gonadotropins

• Urine (~250, 000 liters) is pooled from post-menopausal women

• Pooled urine is processed to concentrate gonadotropins

• Gonadotropins are purified by either antibody affinity column or conventional chromatography

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Manufacture: Recombinant Human Gonadotropins

CHO Cells

and

FSH or LH sequence CHO Cells

Transfected with FSH/LH