# Presentation: 913752

## Human Gonadotropins: A 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

## Introduction

- Review the physiology and role of gonadotropin therapy in female infertility
- Overview of the regulatory history of selected approved gonadotropin drug products
- Discussion: population, design, efficacy endpoints, analysis and safety endpoints for trials of these drug products

## Human Gonadotropins - Endocrinology

- Link between hypothalamic-pituitary axis and the ovary
- Required at threshold levels for follicular development

## Human Gonadotropins

- Control of gonadotropin release occurs through pulsatile hypothalamic production of gonadotropin releasing hormone (GnRH)
- Pulses vary over the course of the menstrual cycle.
- The timing and amplitude  of pulses determine gonadotropin release from the pituitary.

## Types of Gonadotropins

- In females, the reproductive axis is responsive to two main gonadotropin types:
- Follicle Stimulating Hormone (FSH)
- Luteinizing Hormone (LH)

## Follicle Stimulating Hormone (FSH)

- Half-life of 180 - 240 minutes
- Stimulates the growth of an ovarian follicle
- Increases the production of estrogen
- Stimulates production of luteinizing hormone (LH) receptors and other factors (inhibin, activin) in preparation for ovulation

## Luteinizing Hormone (LH)

- Half-life is 38-60 minutes
- LH role in folliculogenesis is unclear
- Induces follicular maturation and the sequence of events leading to ovulation
- Responsible for steroid production by theca cells

## Exogenous Gonadotropin Therapy

## Exogenous Gonadotropin Therapy

- The goal:

## Exogenous Gonadotropin Therapy

- Patient Types
- Substitution - hypogonadal women
- Stimulation – women with hypothalamic dysfunction
- Regulation - oligo-anovulatory women
- Hyperstimulation therapy – women undergoing Assisted Reproductive Technology procedures

## Exogenous Gonadotropin Therapy

- Objective: simulate a normal menstrual cycle
- Action:  override the hypothalamic-pituitary axis and direct:
- the onset and duration of follicular development
- the timing and number of follicles that reach maturity
- the production of gonadal steroids

## A  Typical U.S. Gonadotropin Treatment Protocol 

- Baseline serum estradiol (E2) level
- Baseline ultrasound scan
- Administer daily for 7 - 10 days
- Repeat E2 level and ultrasound approximately every 2 to 3 days until follicular maturity is achieved
- Administer human chorionic gonadotropin (hCG)

## Gonadotropin Drugs -  Development History

- 1926-1927: Discovery of pituitary hormones
- 1955: Clinical use of urinary hormone assays (steroids and gonadotropins)

## Gonadotropin Drug Development (continued)

- 1959: Extraction of gonadotropins from *human pituitary* and urine.
- 1979: Initial use of ultrasound to determine human ovarian follicle size
- 1985: Use of *human pituitary* extracts was abandoned after literature reports of patients contracting Jacob-Creutzfeldt disease

## Types of Gonadotropin Therapy Marketed

- Urinary derived human gonadotropins - **menotropins, urofolitropin, **
**      ****chorionic gonadotropin**
- Recombinant human gonadotropins
- 	 - **follitropin alfa and follitropin beta,**
**	****    ****chorionic gonadotropin alfa**

## Urinary-derived Human Gonadotropins

- Urine is pooled from post-menopausal women
- Urine pool is processed to concentrate gonadotropins
- Gonadotropins are purified by either antibody affinity column or conventional chromatography

## Manufacture: Recombinant Human Gonadotropins

- CHO Cells

- and

- FSH or LH
-   sequence

- CHO Cells
- Transfected
- with FSH/LH

## Manufacture:  Recombinant Human Gonadotropins

**DNA constructs containing coding sequences of either alfa or beta subunit of FSH or LH are prepared.**
**Chinese hamster ovary (CHO) cells are co-transfected with two DNA constructs**
**Stable CHO cell lines containing integrated FSH or LH sequence are selected**.
**Master and Working Cell Banks are prepared for production** **in bioreactors**
**FSH or  LH in the cell culture harvests are  purified by chromatography**

## Pergonal®

- Generic Name: menotropins for injection, USP
- Active Ingredients: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH)
- Derived: Post-menopausal human urine

## Pergonal®

- In women:
- “Pergonal and hCG given in a sequential manner are indicated for:
- Induction of ovulation in anovulatory women (Approved – June 23, 1970)
- Development of multiple follicles in ovulatory patients participating in an IVF program” (Approved - March 1, 1988)

## Pergonal®

- Efficacy and safety data :
- Retrospective IVF data representing the clinical experience with 192 patients at the Jones Institute (1981 – 1984)
- IVF data from Australia and New Zealand (1979-1984)
- Published Literature

## Pergonal®

- Primary Efficacy Endpoints:
- Mean number of oocytes retrieved at time of laparoscopy – 3.82

## Pergonal®

- Safety Endpoints:
- Rate of ovarian hyperstimulation syndrome– 1.3%
- (In the retrospective analysis of the Jones Institute data,  no severe ovarian hyperstimulation or other adverse reactions were noted in 192 IVF subjects)
- Multiple pregnancy rate – 20 %

## Metrodin®

- Generic name: urofollitropin for injection
- Active ingredient: FSH
- Derived: Post-menopausal human urine
- Approved:  September  18,  1986

## Metrodin®

- Indication:
- “Metrodin and human chorionic gonadotropin (hCG) given in a sequential manner are indicated for:
-  the induction of ovulation in patients with polycystic ovarian disease who have an elevated FSH/LH ratio and who have failed to respond to adequate clomiphene citrate therapy”

## Metrodin®

- Efficacy and safety data :
- Literature review of retrospective data from five open-label, non-comparative, clinical studies of ovulation induction (n=80 patients)

## Metrodin®

- Efficacy:
- Observational reports of ovulation and pregnancy

## Metrodin®

- Safety Endpoints :
- Ovarian hyperstimulation syndrome rate  *–  *6%
- Multiple birth rate  *– *17%

## Gonal-f®

- Generic Name: follitropin alfa for injection
- Active Ingredient: Follicle Stimulating Hormone (FSH)
- Derived: Chinese hamster ovary (CHO) cells (Recombinant)
- Approved:  September 29, 1997

## Gonal-f®

- Indications:
- “Induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is not functional and not due to primary ovarian failure”
- “Development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology program”

## Gonal-f®

- Efficacy and safety data from four controlled studies :
- IVF
- Study 5503 *-**  *multicenter (Europe),* *randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for multiple follicular development in IVF
- Study 5533 – multicenter (U.S.),  randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for superovulation in IVF

## Gonal-f®

- Efficacy and safety data from four controlled studies:
- Ovulation Induction
- Study 5642 - multicenter (Europe, Israel),* *randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for ovulation induction in WHO Type II anovulation
- Study 5727 - multicenter (U.S.),* *randomized, open-label, active comparator, parallel group, equivalence trial of Gonal-f® vs. Metrodin® for ovulation induction in WHO Type II anovulation

## Gonal-f® - IVF results

## Gonal-f® - Ovulation Induction Results

## Gonal-f®

- Safety Endpoints:
- Ovarian hyperstimulation syndrome rate
- Ovulation Induction (Study 5727) – 6.8%
- IVF (Study 5533) - 0%
- Multiple birth rate
- Ovulation Induction (Study 5727) – 13.7%
- IVF (Study 5533) – 25%

## Follistim®

- Generic name:  follitropin beta for injection
- Active Ingredient: Follicle Stimulating Hormone
- Derived: Chinese Hamster Ovary Cells (Recombinant)
- Approved: September 29, 1997

## Follistim®

- Indications:
- “Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to ovarian failure”
- “Development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology program”

## Follistim®

- IVF
- Study 37604 -  single center (Netherlands)*,** *randomized, assessor blind, active comparator, equivalence trial of Follistim® vs. Humegon® for infertile women treated with IVF
- Study 37608 - multicenter (Europe), randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for infertile women treated with IVF

## Follistim®

- IVF
- Study 37611 - multicenter (France),* *randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for infertile women treated with IVF
- Study 37613 - multicenter (non-U.S.), randomized, open-label, active comparator, equivalence trial designed to compare the safety and efficacy of two routes of administration of Follistim® subcutaneously and intramuscular for infertile women treated with IVF

## Follistim®

- Ovulation induction:
- Study 37609 -  multicenter (European)*,** *randomized, assessor-blind, active comparator, equivalence trial of Follistim® vs. Metrodin® for induction of ovulation in chronic anovulation who failed to ovulate and/or conceive during clomiphene citrate treatment (WHO Type II).

## Follistim® - IVF results

## Follistim® - Ovulation Induction Results

## Follistim®

- Safety Endpoints:
- Ovarian hyperstimulation syndrome rate
- Ovulation Induction (Study 37609) - 7.6%
- IVF (Study (37608) - 5.2%
- Multiple birth rate
- Ovulation Induction (Study 37609) - 6%
- IVF (Study 37608) - 23%

## For Discussion

## Study Population

**Ovulation Induction**
**The following populations are enrolled**:
- WHO Group I (hypogonadotropic hypogonadism)
- WHO Group II (chronic anovulation)
**Does the committee have any advice on these?**

## Study Population

**ART**
**The following populations are enrolled:**
- Normal ovulatory (defined by serum progesterone levels) women
- WHO Group I (hypogonadotropic hypogonadism)
- WHO Group II (chronic anovulation)
**Does the committee have any advice on these?**
**How do we take into account differences in the procedures?**
- IVF
- ICSI
- Donor Oocyte

## Study Design

- What study designs should be used?
- Blinding
**double or assessor blind**
- Comparators
**active or placebo**

## Primary Efficacy Endpoint

- Discuss the advantages and disadvantages of the following as primary or secondary endpoints:
- Live birth rate
- Ongoing viable pregnancy (presence of a fetal heartbeat) rate
- Gestational sac development rate
- Rate of Positive ß-hCG
- Ovulation rate [as defined by serum progesterone level(s)]
- Follicular development rate (as defined by two or three criteria)

## Primary Efficacy Endpoint

**How should the primary endpoint(s) be analyzed?**
- For Ovulation Induction** **
- Intent-to-Treat Population
- Per protocol population
- For ART** **
- Per treatment initiation?
- Per retrieval?
- Per embryo transfer?

## Study Analysis

- How should success be defined?
- Superiority to comparator (placebo; active control)
- Equivalence to active comparator
- Non-inferiority to active comparator

## Safety Endpoint Questions

- Discuss the advantages and disadvantages of evaluating the following safety endpoint(s):
- Rate of ovarian hyperstimulation syndrome
- Rate of miscarriages
- Rate of multiple pregnancies
- Rate of ectopic pregnancies

## Acknowledgements

- Audrey Gassman, M.D.
- Ridgely Bennett, M.D.
- Barbara Wesley, M.D., M.P.H.
- Phill Price, M.D.
- Dornette Spell-Lesane, C.N.P.
- Donna Griebel, M.D.
- Dan Shames, M.D.
- Florence Houn, M.D.