ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH DRUGS**
>
> Tuesday, September 30, 2003
>
> 8:30 a.m.
>
> Hilton Hotel
>
> The Ballrooms
>
> 620 Perry Parkway
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Linda C. Giudice, M.D., Ph.D., Chair
>
> Shalini Jain, PA-C, M.B.A.
>
> MEMBERS
>
> Susan A. Crockett, M.D.
>
> W. David Hager, M.D.
>
> Nancy W. Dickey, M.D.
>
> George A. Macones, M.D.
>
> Joseph B. Stanford, M.D.
>
> Scott S. Emerson, M.D., Ph.D.
>
> Vivian Lewis, M.D.
>
> Larry Lipshultz, M.D.
>
> Valerie Montgomery Rice, M.D.
>
> SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (Voting)
>
> Robert G. Brzyski, M.D., Ph.D.
>
> Adelina M. Emmi, M.D.
>
> David L. Keefe, M.D.
>
> Lawrence C. Layman, M.D.
>
> James H. Liu, M.D.
>
> James P. Toner, Jr., M.D., Ph.D.
>
> ACTING CONSUMER REPRESENTATIVE
>
> Lorraine J. Tulman, D.NSc.
>
> FDA
>
> Daniel Shames, M.D.
>
> Shelley R. Slaughter, M.D., Ph.D.
>
> Audrey Gassman, M.D
>
> Kate Meaker, M.S.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Call to Order
>
> Linda Giudice, M.D., Ph.D. 5
>
> Introduction of Committee 5
>
> Conflict of Interest Statement:
>
> Shalini Jain 6
>
> **Discussion of NDA 21-322**
>
> **(lutropin alfa for injection)**
>
> **Serono, Inc.**
>
> Genetics of Hypogonadotropic Hypogonadism in Women
>
> Lawrence C. Layman, M.D. 8
>
> Neuroendocrine Control of the Menstrual Cycle and
>
> Associated Disorders
>
> James H. Liu, M.D. 29
>
> Questions from Committee 58
>
> Opening Remarks
>
> Daniel Shames, M.D. 70
>
> Committee Discussion 72
>
> **Sponsor Presentations (Serono, Inc.)**
>
> Introduction and Regulatory History
>
> Pamela Williamson Joyce, RAC 85
>
> Need for and Role of LH:HH Women with Profound
>
> Gonadotropin Deficiency
>
> Jerome Strauss, M.D., Ph.D. 94
>
> Luveris Clinical Development Program
>
> Paul Lammers, M.D. 109
>
> Clinical Perspective and Risk/Benefit Assessment
>
> Nanette F. Santoro, M.D. 135
>
> Summary and Conclusions
>
> Pamela Williamson Joyce, RAC 143
>
> Questions from the Committee 146
>
> **FDA Presentations**
>
> Luveris: The FDA Perspective
>
> Shelley R. Slaughter, M.D., Ph.D. 185
>
> Kate Meaker, M.S. 198
>
> [C O N T E N T S]{.underline} (Continued)
>
> Questions from the Committee 210
>
> Open Public Hearing 230
>
> Presentation of Questions and Committee Discussion 241
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. GIUDICE: Good morning. I am Linda Giudice and I am the Chair of
> the Advisory Committee.
>
> Because we have new people in the audience today, I would like for the
> members of the Committee to please introduce themselves once again as
> we did yesterday, beginning with Dr. Hager.
>
> **Introduction of Committee**
>
> DR. HAGER: David Hager, University of Kentucky.
>
> DR. CROCKETT: Susan Crockett, Christus Santa Rosa, San Antonio, Texas.
>
> DR. MACONES: George Macones from the University of Pennsylvania.
>
> DR. LEWIS: Vivian Lewis, University of Rochester.
>
> DR. LAYMAN: Larry Layman, Medical College of Georgia.
>
> DR. TULMAN: Lorraine Tulman, University of Pennsylvania, Consumer
> Representative.
>
> DR. KEEFE: David Keefe, Women and Infants Hospital at Brown
> University.
>
> DR. DICKEY: Nancy Dickey, Texas A & M Health Science Center.
>
> DR. GIUDICE: Linda Giudice from Stanford University.
>
> MS. JAIN: Shalini Jain, Executive Secretary, FDA.
>
> DR. LIU: James Liu from Case Western Reserve University.
>
> DR. EMMI: Adelina Emmi from Medical College of Georgia.
>
> DR. TONER: Jim Toner Atlanta Center for Reproductive Medicine.
>
> DR. MONTGOMERY RICE: Valerie Montgomery Rice, Meharry Medical College.
>
> MS. MEAKER: Kate Meaker, FDA.
>
> DR. GASSMAN: Audrey Gassman, FDA.
>
> DR. SLAUGHTER: Shelley Slaughter, FDA.
>
> DR. SHAMES: Dan Shames, FDA.
>
> DR. GIUDICE: Thank you.
>
> As yesterday, we would appreciate it if your beepers and telephones
> would be put to vibrate or silent. I would like to begin the morning
> session by introducing Shalini Jain, who will talk about the conflict
> of interest.
>
> **Conflict of Interest Statement**
>
> MS. JAIN: Good morning and thank you for your participation today. We
> are on a very tight schedule, so I will quickly read the Conflict of
> Interest, and I just wanted to let everyone know that we are
> flip-flopping the first and second presentations due to some presenter
> conflicts, so Dr. Layman will be going first instead of Dr. Liu, so
> there is a slight change in the timing of the presentations this
> morning, but we will have both speakers presenting.
>
> The following announcement addresses the issue of conflict of interest
> with regard to this meeting and is made a part of the record to
> preclude even the appearance of such at this meeting.
>
> Based on the submitted agenda for the meeting and all financial
> interests reported by the committee participants, it has been
> determined that all interests in firms regulated by the Center for
> Drug Evaluation and Research present no potential for appearance of a
> conflict of interest at this meeting.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record.
>
> With respect to all other participants, we ask in the interest of
> fairness that they address any current or previous financial
> involvement with any firm whose products they may wish to comment
> upon.
>
> Thank you.
>
> DR. GIUDICE: Thank you.
>
> **Issue: Discussion of NDA 21-322**
>
> **Luveris (lutropin alfa for Injection)**
>
> **Serono, Inc.**
>
> DR. GIUDICE: I would now like to introduce Dr. Lawrence Layman who is
> Chief of Reproductive Endocrinology, Infertility, and Genetics at the
> Medical College of Georgia in Augusta.
>
> **Genetics of Hypogonadotropic Hypogonadism in Women**
>
> DR. LAYMAN: Thank you. Good morning.
>
> What I would like to do is go through what is known about the genetics
> of hypogonadotropic hypogonadism, which has been an area of interest
> of mine for a number of years.
>
> \[Slide.\]
>
> What I would like to do briefly is go through normal pubertal
> milestones, the diagnosis of IHH, and then talk about the mutations
> with the prospective phenotypes for the hypothalamic genes that are
> known and for pituitary genes that are known.
>
> \[Slide.\]
>
> As everyone knows, GnRH in the hypothalamus stimulates the pituitary
> to make the gonadotropins FSH and LH, which then stimulate the gonads
> to make steroids and gametes.
>
> \[Slide.\]
>
> Typically, these result in females who have breast development and
> pubic hair development around age 8 to 9, their growth spurt is about
> age 12, and menses begin approximately age 12.
>
> In males, testes and pubic hair begin at about ages 10 to 11 with
> penile growth about 13, and the growth spurt at about 14.
>
> \[Slide.\]
>
> What is often considered delayed is in females who have no breast
> development by 13 or no menses by 15, and in males who have no
> testicular enlargement by age 14.
>
> \[Slide.\]
>
> When hypogonadism is suspected, as manifested by physical exam or low
> sex steroids, one of the steps is to obtain gonadotropins, and that
> helps classify where the defect is.
>
> \[Slide.\]
>
> If the gonadotropins are elevated in the presence of low sex steroids,
> the patient has hypergonadotropic hypogonadism or gonadal failure.
>
> \[Slide.\]
>
> Hypogonadotropic hypogonadism results when there is a hypothalamic or
> pituitary defect in which gonadotropins are low and sex steroids are
> low.
>
> \[Slide.\]
>
> IHH is often defined as irreversible absent puberty. In females, we
> usually use by age 17, who have amenorrhea, and usually, those
> patients don\'t have breast development. Males, it is generally age 18
> with low testosterone. Gonadotropins are low or normal, and there is
> no CNS lesion by imaging, and there is normal prolactin, thyroid, and
> adrenal function.
>
> \[Slide.\]
>
> Gonadotropin responses are very variable to a single dose of exogenous
> GnRH, but Crowley\'s group, among others, have studied LH pulsatility
> patterns including Dr. Santoro, who is here, and the most frequent
> pattern is the apulsatile LH pattern, however, decreased frequency and
> decreased amplitude have also been described, as well as a nocturnal
> LH prepubertal pattern.
>
> \[Slide.\]
>
> As we know, the prospects for fertility are very good with IHH. You
> generally induce secondary sex characteristics with sex steroids, the
> defect is hypothalamic or pituitary, and if there is other pituitary
> failure, those hormones need to be replaced.
>
> For pregnancy, supplying the missing gonadotropins or GnRH gives
> excellent cycle fecundity rates.
>
> \[Slide.\]
>
> Looking at the genetics of this disorder, it is very complicated. I am
> only going to mainly speak about those in which IHH is the predominant
> feature, but just to be aware there are a number of syndromes in the
> on-line mendelian inheritance database.
>
> \[Slide.\]
>
> What I would like to do is first talk about the hypothalamic genes
> KAL1, FGFR1, and NROB1. In addition, I will mention briefly leptin and
> the liptin receptor, and then talk about the pituitary genes for which
> there are mutations.
>
> \[Slide.\]
>
> The GnRH gene, now called GNRH1, is clearly a pivotal gene in
> reproduction and it is expressed in the hypothalamus among other
> places, and its deficiency should lead to hypogonadotropic
> hypogonadism since IHH is felt to be due to GnRH deficiency.
>
> There is a deletion of GNRH1 in the mouse, however, none have ever
> been found in humans to date, so although this is highly likely to
> occur, one would think, none have been identified.
>
> \[Slide.\]
>
> Kallmann syndrome, which includes IHH plus anosmia, was the first
> disorder to have the gene identified. In addition, these patients can
> have neurologic abnormalities, such as synkinesia, which are mirror
> movements, visual abnormalities, renal anomalies, and midfacial
> defects, and in the original description, this was an X-linked
> recessive disease affecting males.
>
> \[Slide.\]
>
> It is known that GnRH and olfactory neurons migrate from the olfactory
> placode to the hypothalamus, and two groups of investigators in 1991
> cloned the gene by positional closing, and they identified it as KAL1,
> so that mutations in this gene result in anosmia and GnRH deficiency.
>
> \[Slide.\]
>
> In some of the original papers, when clear X-linked recessive families
> were studied, about 50 percent of these probands had mutations in
> KAL1, and very interestingly, of these, half of them had unilateral
> renal agenesis.
>
> In looking at unselected Kallmann syndrome males, only about 5 percent
> or less had mutations.
>
> \[Slide.\]
>
> When expression was examined in both the chick and the human, the
> phenotype correlates nicely with the expression patterns. Certainly,
> the olfactory bulb with anosmia, some of the CNS defects, because of
> the cerebellum and spinal cord, and also renal anomalies correlating
> with renal agenesis, it is also expressed in facial mesenchyme, which
> does explain cleft palate, and cartilage and limb bud, which can
> explain an occasional club foot.
>
> \[Slide.\]
>
> Crowley\'s group has studied familial and sporadic Kallmann syndrome
> and has found in general about 12 percent of total Kallmann syndrome
> males will have mutations. Whether they are sporadic or familial, it
> is fairly similar. In normosmic IHH, none of 42 did in their study.
>
> \[Slide.\]
>
> This gene is on the pseudoautosomal region of the X chromosome with an
> inactive pseudogene on the long arm of the Y, and it encodes the
> protein anosmin-1, which is the protein that has neural cell adhesion
> molecules.
>
> Orthologs have been identified in numerous other species including
> chicks, zebrafish, C. elegans, and Drosophila, but it hasn\'t been
> cloned yet in mice, but human antibodies detect it is present and at
> least as of last night, I didn\'t see it in Locus Link.
>
> \[Slide.\]
>
> The ortholog CeKall in C. elegans is required for ventral closure and
> tail formation in embryogenesis. It is involved in neurite branching,
> and it is also known that the human KAL1 cDNA can compensate for the
> loss of this, which suggests that this is a conserved function.
>
> Anosmin-1 is a secreted molecule that binds via heparan sulfate
> proteoglycans to its receptor to induce axon branching and misrouting.
> This is in vitro.
>
> \[Slide.\]
>
> There are several possibilities of how Kallmann syndrome occurs. One
> is the absent lateral olfactory track branches cause anosmia, and the
> lack of GnRH neurons getting to the forebrain causes IHH.
>
> It is also possible that anosmia could occur because of a lack of
> contact between olfactory axons and the olfactory bulb.
>
> \[Slide.\]
>
> Another disorder in which there are mutations is adrenal hypoplasia
> congenita and hypogonadotropic hypogonadism. Originally determined to
> be the DAX1 gene, it is now called NROB1, but these patients have
> adrenal failure in infancy usually to about age 10, and there are
> certainly exceptions, and if they survive, these patients get delayed
> puberty due to IHH.
>
> It is X-linked recessive and mutations in NROB1 gene appear to cause
> both defects. It is expressed in the adrenal, hypothalamus, and
> pituitary, and it\'s in the dosage-sensitive sex region on the short
> arm of the X chromosome.
>
> \[Slide.\]
>
> This is a study from Jamison\'s group suggesting that mutations have
> hypothalamic and pituitary defects. The double mutations shown at the
> top, one patient given exogenous GnRH had a normal response to GnRH
> suggesting a hypothalamic defect, however, with GnRH priming, had a
> minimal LH response suggesting pituitary effects.
>
> Similarly, with a different mutation, there was no response to GnRH
> suggesting a pituitary defect.
>
> \[Slide.\]
>
> In collaboration with Jamison\'s group and Crowley\'s, we studied,
> John Achermann with Jamison studied about 100 IHH males without
> adrenal failure and sequenced the entire coding region and no
> mutations were identified, suggesting that it is very uncommon in IHH
> unless there is adrenal hypoplasia.
>
> \[Slide.\]
>
> There has been a mutation in a few females, one that is well
> documented, who had hypogonadotropic hypogonadism. She did not have
> adrenal failure, but she had skewed X inactivation. Within that same
> family, there were two males who had hypogonadotropic hypogonadism and
> adrenal failure.
>
> There is a female who has a missense mutation that was presented at
> the American Society of Human Genetics a year ago. This gene has been
> proposed to have some function in the ovary, but a study done by
> Jamison\'s group, a conditional knockout, demonstrated that there was
> not an ovarian determining gene, but is instead important in
> spermatogenesis.
>
> \[Slide.\]
>
> Several other hypothalamic hormones are important, as well. The
> leptin-deficient ob/ob mouse has a phenotype consisting of obesity,
> hyperinsulinemia, IHH, hypothermia, cold intolerance, and elevated
> cortisol.
>
> \[Slide.\]
>
> In humans now, there have been several mutations identified. Normally,
> there is a correlation between the BMI and leptin, and leptin
> deficiency is extremely uncommon in obesity. However, several
> mutations have been identified.
>
> The first was an early onset obesity. None of these families had any
> children of pubertal age, so this couldn\'t be examined, but in the
> second paper by Strobel, IHH and obesity were found due to a mutation,
> and the proband in this study was a male who weighed 55, with a BMI of
> 55.8, a low serum leptin, and he had a missense mutation in the leptin
> gene and had two sibs with similar phenotype, and this mutant in vitro
> was not secreted from the cell.
>
> \[Slide.\]
>
> Likewise in obesity and IHH with elevated levels of leptin, leptin
> receptor mutations have been identified, several, and in this one,
> cause protein truncation, and this also appears to be autosomal
> recessive.
>
> \[Slide.\]
>
> Very recently, a second mutation, a gene with mutations causing
> Kallmann\'s syndrome, which as we know occurs in males and females,
> and this group described mutations in an autosomal dominant form in
> the FGFR1 receptor. They also termed this KAL2.
>
> It is interesting because gain of function mutations cause
> craniosynostosis disorder, Pfeiffer syndrome, and skeletal dysplasia,
> but these are inactivating mutations.
>
> \[Slide.\]
>
> What they basically did was they found two patients who had contiguous
> gene deletion syndromes, who also had Kallmann\'s syndrome, and in
> that region there were only three genes - FGFR1 was the prime
> candidate and although by Southern blot there were no mutations, upon
> sequencing, about 9 percent of patients had mutations, and these were
> males and females.
>
> Within these families, there is reduced penetrance and variable
> expressivity making it very difficult to follow.
>
> Interestingly, some of these patients also had cleft lip and palate,
> synkinesis just like in X-linked recessive Kallmann\'s syndrome and
> dentogenesis.
>
> \[Slide.\]
>
> These investigators hypothesized could anosmin-1, the KAL1 protein, be
> the ligand for FGFR1, and there is circumstantial evidence for this,
> they did not study it in this study, but FGF interacts with its
> receptor via heparan sulfate proteoglycans, and so does anosmin-1.
>
> In addition, KAL1 is expressed in olfactory bulb in human, and in the
> mouse, FGFR1 is expressed in the forebrain and is necessary for
> olfactory bulb evagination, so circumstantial evidence supports this
> possibility.
>
> \[Slide.\]
>
> Now, moving to the pituitary, there were two papers that came out
> fairly simultaneously. A French group described a patient with
> incomplete pubertal development, incomplete IHH, and we found
> mutations in a patient with no pubertal development or complete IHH.
>
> \[Slide.\]
>
> The French group identified a male who had absent puberty at age 18.
> He was hypogonadal, his testosterone was 80 ng/dL, his gonadotropins
> were low. There was normal frequency of LH pulses, but decreased
> amplitude. Interestingly, he had a semen analysis of 39 million
> although only 5 percent motility.
>
> \[Slide.\]
>
> They found a mutation and then demonstrated the function in vitro. To
> do this, you have to look at several actions of GnRH. One is binding
> to its receptor, and the next is the signal transduction to IP~3~.
>
> \[Slide.\]
>
> This group identified two mutations. missense mutation that reduced
> binding and then subsequently, IP~3~ formation and efficiency, and the
> second missense mutation also reduced IP~3~.
>
> \[Slide.\]
>
> We hypothesized that since when you treat patients with GnRH, there is
> variable responses to GnRH that GnRH receptor mutations would be
> possible, and we screened 46 IHH patients using denaturing gradient
> gel electrophoresis, and we identified compound heterozygosity in one
> proband, one family.
>
> Both of these mutations, actually one was the same the French group
> identified and another missense we identified, and both of them
> decreased receptor expression, binding was normal. The total IP~3~ was
> decreased, as well as the efficiency of IP~3~, so the EC~50~ was
> increased meaning it took an increased GnRH agonist to stimulate IP~3~
> production.
>
> \[Slide.\]
>
> This is the family showing these patients, but what I want to point
> out is that the basal LH levels were low in all of them, and it will
> be easier to see on your handout. I apologize, this is a little small.
>
> But two of the patients had LH responses that got over 12, and the
> other two had ones that were about half that. So, there is phenotypic
> variability within the same family.
>
> \[Slide.\]
>
> The prevalence of GnRH receptor mutations is not entirely known. In
> our original study, there was 2 percent. If you included normosmic IHH
> with the female as a proband, it was 7 percent. Although they didn\'t
> allow us to include in the paper, we had originally screened 50
> anosmics and did not find mutations.
>
> \[Slide.\]
>
> Crowley\'s group has studied approximately 50, and they identified
> mutations in about 10 percent. In the small number of autosomal
> recessive families, 2 of 5 had it, but again, in anosmic or hyposmic,
> they found no GnRH receptor mutations.
>
> \[Slide.\]
>
> At the Endocrine Society, we presented our data on 165 IHH patients
> studied, and this includes anosmic and hyposmic and euosmic patients.
> About 2 percent had mutations, and if there were two or more affecteds
> in the family, it was about 7 percent, and about 5 percent if there
> were female probands.
>
> \[Slide.\]
>
> So, at least about 15 mutations have been identified. Most of these
> are compound heterozygotes and they may affect binding and/or signal
> transduction. The phenotype can vary from complete IHH with no
> evidence of pubertal development to partial IHH.
>
> The patients to date don\'t have anosmia, and the gonadotropin
> responses to GnRH are very variable, in fact, there is even one
> pregnancy with multiple attempts of stimulating the GnRH, and the
> prevalence appears to be somewhere around 3 to 10 percent of normosmic
> IHH patients.
>
> \[Slide.\]
>
> Several other pituitary genes have also been identified that cause
> hypogonadotropic hypogonadism. It is known that an autosomal recessive
> form of combined pituitary deficiency, which causes a phenotype of
> short stature in IHH, has been due to a gene mutation called PROP1.
>
> This gene is important in growth hormone prolactin, thyroid, and
> gonadotropins, and occasionally ACTH is deficient. We screened IHH
> males and females who had no evidence of pituitary failure and found
> no mutations in this gene suggesting it is more common in patients
> with short stature and delayed puberty rather than just IHH.
>
> \[Slide.\]
>
> Another disorder of septo-optic dysplasia in which there is agenesis
> of the corpus callosum and panhypopituitarism along with some other
> CNS abnormalities may be due to mutations in HESX1, which is a
> homeobox gene expressed in Rathke\'s Pouch, which is the primordium of
> the pituitary, and autosomal dominant and recessive forms have been
> identified in some of these patients.
>
> \[Slide.\]
>
> In finishing with the gonadotropins, there are mutations in each of
> the gonadotropins. There are several polymorphisms that have been
> described in LH beta and there are two missense mutations on the same
> allele that are present in infertile and control patients, so they are
> probably polymorphisms, but it is interesting that they can interfere
> with the LH assay and that LH can be unmeasurable using an IRMA assay
> where you have a monoclonal antibody with the whole molecule and
> measurable in an immunofluorescent antibody with two antibodies
> against LH beta.
>
> \[Slide.\]
>
> The only real true mutation that I have seen is one originally
> described by Axelrod, studied by Jamison\'s group, in which they had a
> male with delayed puberty, his testosterone is very low, and
> interestingly, his gonadotropins are elevated.
>
> \[Slide.\]
>
> When he was given testosterone, they were able to induce secondary sex
> characteristics, but even more interestingly, when they gave him hCG,
> it restored his adult phenotype and he got sperm. So, it suggested it
> was not an LH receptor mutation. This was long before the days of it
> being cloned.
>
> \[Slide.\]
>
> Jamison\'s group found homozygous LH beta missense mutation that was
> detected by dimer-specific IRMA assay, but it was undetectable by
> radio receptor assay, so they hypothesized that this mutant LH was not
> capable of receptor binding. This was an autosomal recessive
> inheritance with normal in heterozygotes.
>
> \[Slide.\]
>
> There have also been several FSH beta mutations in which the females
> have not had breast development, are in partial breast development
> (1), but all of them have presented with primary amenorrhea, they all
> have low FSH and high LH, and a low estradiol.
>
> Their follicles do not go beyond the antral stage, and, of course,
> they have infertility, and the phenotype is similar in the knockout
> mouse.
>
> \[Slide.\]
>
> Interestingly, they have an elevated LH, however, they do not have
> hirsutism or hyperandrogenism, and some studies that I don\'t have
> time to go into suggest that maybe FSH is also necessary to make
> androgens in addition to LH.
>
> \[Slide.\]
>
> In males, there have been several mutations, as well. They have either
> had normal puberty or absent puberty where testosterone is either low
> or normal, but they likewise have a low FSH and high LH.
>
> However, unlike the mouse, these patients uniformly have azoospermia,
> and we have not found mutations in oligospermic males.
>
> \[Slide.\]
>
> Similarly, it is possible, the similar argument that possibly FSH is
> necessary for androgen production, as well, which we are interested in
> testing.
>
> \[Slide.\]
>
> When these mutants are looked at in vitro, we have studied all of the
> FSH beta mutants and wild-type, as shown on the left, immuno and
> bioactive FSH was studied, and when we generated these mutants in
> Chinese hamster ovary cells in a vector, one provided by Larry
> Jamison, another one by a graduate student in my lab, we showed that
> none of them had any immunologic and biologic activity, probably
> interfering with dimer formation.
>
> \[Slide.\]
>
> In summary, hypogonadotropic hypogonadism, the genetics is still not
> really well worked out. There are no GnRH1 mutations, so if they are
> present, they are very uncommon.
>
> KAL1 mutations appear to be present in about 10 to 15 percent of
> males. Interestingly, the KAL1 gene expression really explains some of
> the associated anomalies and may be useful in clinical management.
>
> FGFR1 mutations could occur in about 10 percent of males with
> Kallmann\'s syndrome.
>
> NROB1 mutations have generally been found in patients who have adrenal
> failure and IHH, and otherwise, it is not common.
>
> In the GnRH receptor, there are mutations in about 3 to 10 percent of
> patients, the phenotype is variable, and it can occur on males and
> females.
>
> Rarely, leptin and leptin receptors cause mutations in obese IHH
> patients. That still leaves most causes of inherited IHH unknown.
>
> Thank you.
>
> DR. GIUDICE: Thank you, Dr. Layman. I understand that you need to
> leave. Do you have a couple of minutes for questions?
>
> DR. LAYMAN: Yes.
>
> DR. GIUDICE: Are there any questions by the committee members? Yes,
> Dr. Crockett.
>
> DR. CROCKETT: Thank you for a very nice presentation, very
> informative.
>
> I have one question about the FSH beta mutations that you mentioned.
> Am I to understand that this patient may present as a PCO-type-looking
> patient, but actually has some differences?
>
> DR. LAYMAN: Actually, no, they are going to present with delayed
> puberty with absent breast development usually, maybe some breast
> development and primary amenorrhea, but they don\'t bleed the
> progestins, they are hypoestrogenic. Although the ovary is a little
> multicystic, which I didn\'t go into, on the patient we had, it is not
> a classical PCO-appearing ovary, but actually, multiple small cysts
> throughout the whole ovary.
>
> DR. CROCKETT: Thank you.
>
> DR. GIUDICE: Any other questions from the committee?
>
> Okay. Thank you very much.
>
> Our next speaker is Dr. James Liu who is from the Department of
> Reproductive Biology at Case Western Reserve University, and he is
> going to talk on Neuroendocrine Control of the Menstrual Cycle and
> Associated Disorders.
>
> **Neuroendocrine Control of the Menstrual**
>
> **Cycle and Associated Disorders**
>
> DR. LIU: Thank you very much. I was asked to discuss the basic
> neuroendocrine control of the menstrual cycle and focus and touch on
> some of the associated disorders that result in low gonadotropin
> states in which either GnRH or gonadotropins would be amenable for
> ovulation induction.
>
> \[Slide.\]
>
> So, I am going to start at a very basic elementary level and work up.
> As we all know, and what Dr. Layman has originally presented, is that
> the changes with regards to estrogen, namely, puberty changes in the
> breast and the female habitus, as well as the menstrual cycle, is the
> end product of a coordinated series of events beginning with the
> higher neuronal centers that have input into the hypothalamus, which
> then modulates the gonadotropin-releasing hormone secretion, which is
> then interpreted by the pituitary as a neuronal signal resulting in
> release of LH and FSH, which then, in turn, drives the ovary to
> secrete estrogen and progesterone, stimulating the endometrium for
> appropriate preparations for pregnancy, and then failure to achieve a
> pregnancy, the ovary then has a timing mechanism in which the corpus
> luteum fails and menstrual flow occurs. That is really the final end
> product.
>
> \[Slide.\]
>
> Let\'s focus first on the hypothalamic pituitary compartment. In the
> normal individual without gene defects, most of the GnRH neurons are
> localized in the arcuate nucleus, and they do migrate there from the
> olfactory bulb.
>
> There are small nests of GnRH cells also in the anterior commissure
> and the OVLT, but, in general, most of the GnRH neurons are localized
> here. They have a coordinated network histologically, such that they
> can secrete the GnRH in concert, so that there is some linkage, which
> we don\'t currently understand, and it results in boluses of GnRH
> delivered to the portal circulation to the lateral wings of the
> anterior pituitary.
>
> \[Slide.\]
>
> If we look at trying to mimic the effects of GnRH peripherally and in
> a normal human intact model, here is an example of a very early study
> that was done by Dr. Yen\'s group, looking at IV versus sub-Q
> administration of GnRH in a peripheral sense to try and mimic the LH
> pulsatile activity.
>
> These are GnRH, LH is in black and FSH is in the open circles, and you
> can see that there is a nice, very quick response within several
> minutes of exogenous GnRH in terms of response from the pituitary,
> whereas, if you give the GnRH in a sub-Q mode, there is atonic
> elevation of LH and atonic elevation of FSH.
>
> I will just briefly summarize it that sub-Q studies with exogenous
> GnRH were highly unsuccessful at inducing ovulation, and for the vast
> majority of clinicians that used GnRH for ovulation induction in
> patients with low gonadotropins, it was the intravenous mode.
>
> With regards to the pituitary compartment now, we know that the
> pituitary and hypothalamus works as a unit in the intact human. It is
> very difficult to discern and separate out whether it\'s a
> hypothalamic versus a pituitary abnormality when we see low
> gonadotropins.
>
> Systems that have been implicated based on animal studies in terms of
> regulating the secretion of GnRH are the opiate system, which the vast
> majority of studies would implicate a negative suppressive effect on
> GnRH secretion, the adrenergic system, the vast majority of animal
> studies would suggest an augmenting effect with regards to GnRH
> secretion.
>
> The dopamine system is somewhat controversial. There have been some
> papers that have suggested that this augments GnRH secretion, there
> are some that suggest that it may actually reduce GnRH secretion, so
> it is not clear, and the GABA system provides a negative suppressive
> effect on GnRH.
>
> With regards to the pituitary itself, if you do staining on the
> lateral wings of the anterior pituitary, you will find that there are
> gonadotropes that contain LH-only, there are some that contain both LH
> and FSH, and some that contain FSH-only intermixed.
>
> We now know that there is some paracrine regulation of FSH secretion
> in the sense of if the GnRH signal is a slow pulsatile signal, there
> is an increase in FSH beta message, as well as increase in FSH
> secretion. Within the pituitary are interstellar cells that secrete
> activin and follistatin. These two work in concert. One, activin
> enhances FSH beta message production, whereas follistatin decreases
> the FSH beta message.
>
> So, the pituitary then, if you will, is an interpreter of the GnRH
> signal in terms of the amount of FSH and LH put out.
>
> Now, we have taken advantage of the system in patients with low
> gonadotropins by artificially creating a pseudohypothalamus, and this
> is one of the orphan drugs that was approved by the FDA, the
> Lutrepulse pump in which intravenous GnRH at doses of between about 5
> micrograms every 60 to 120 minutes was capable of inducing a very
> characteristic physiologic response in terms of the LH pulsatile
> activity, and over a period of 14 days was able to stimulate normal
> follicular development and ovulation.
>
> \[Slide.\]
>
> Now, let\'s focus briefly on the ovary in terms of how the ovary
> interprets the gonadotropin message.
>
> The basic follicle unit in the ovary is the granulosa theca cell unit,
> and the current understanding with regards to how steroids are
> produced by this in response to gonadotropins is based on the two-cell
> theory that was first proposed by Roy Greet \[ph\], but really Ken
> Ryan\'s group was the one that worked out the details in terms of how
> the system worked.
>
> The theca cell, which is the red cells here, contain predominantly LH
> receptors, and it has the capability of cleaving the 27 carbon
> cholesterol to an androgen androstenedione by a series of enzymes
> under the direction of LH.
>
> It is hypothesized that it serves as a substrate which diffuses across
> the basement membrane, separating the theca from the granulosa cell
> compartment, and the granulosa cells, which contain initially FSH
> receptors, and as the maturation process of the granulosa cells in the
> follicle unit occurs, it begins to acquire LH receptors.
>
> At the time of the pre-ovulatory surge, there is abundant LH
> receptors, such that when the trigger for ovulation, either hCG or LH
> increases, these granulosa cells can then luteinize and the ovulation
> sequence is induced.
>
> The granulosa cell unit also is able to secrete inhibin, so it has two
> roles - conversion of predominantly androstenedione to estradiol
> because of aromatase activity. The FSH receptors are responsible for
> increasing the aromatase activity and conversion into estradiol.
>
> So, both of these key things, production of estradiol and inhibin,
> serve to control the pituitary secretion of FSH.
>
> So, to put the system together in terms of how it functions, pulsatile
> GnRH then drives pulsatile LH and FSH. The LH predominantly works
> initially on the theca unit to produce the androstenedione, which then
> serves as a substrate under FSH stimulation, which induces
> aromatization of this androgen substrate by the granulosa cells.
>
> Within the follicle unit on the basis of primarily rat studies, Greg
> Ericson and Erin Schwade being the principal individuals that looked
> at this particular model, the follicle that had the highest estrogen
> also had the highest number of FSH receptors, making the lead follicle
> much more sensitive to the FSH, because as the estradiol and inhibin
> are secreted into the peripheral circulation, pituitary FSH secretion
> is dampened, so that in a sense, the higher intrafollicular estradiol,
> higher FSH receptors within the granulosa cells promoted this
> particular follicle unit to continue to develop and the others to fade
> away.
>
> Now, obviously, at the time of the LH surge, there is a trigger for
> ovulation, so what mounts this LH surge has been somewhat
> controversial although we now know that the hypothalamus and pituitary
> have the ability to integrate the estradiol signal, so that if the
> pituitary and hypothalamic unit are exposed to an estradiol level of
> about 300 for at least 60 hours, it will spontaneously dump LH in the
> model.
>
> This then triggers the ovulation sequence in the ovary approximately
> 36 hours to 40 hours later with ovulation.
>
> With regards to what happens to the oocytes themselves, on the basis
> of studies by Gary Hodgins\' group in the lower primate model, we now
> know that there is essentially a vast pool of primordial follicles in
> the young reproductive age woman, and this particular pool declines as
> the woman ages.
>
> At some point, about two months prior to the onset of the menstrual
> cycle, a pool of follicles begin to undergo progression to an antrum
> form, and we don\'t know what controls this sequence of events from a
> non-committed primordial follicle to a committed follicle.
>
> This is not gonadotropin-driven. The vast majority of these committed
> follicles undergo atresia. Of the few that go on, become
> gonadotropin-responsive and develop FSH and LH receptors, and in the
> absence of FSH and LH receptors, would undergo atresia.
>
> As this pool of gonadotropin-responsive follicles begin to respond to
> the FSH, multiple follicles can be seen in the ovarian stroma. The
> follicle that has the highest intrafollicular FSH receptors among the
> granulosa cells and the highest estradiol level will eventually
> continue to develop in the face of declining FSH due to the feedback
> effect of FSH and inhibin on the pituitary, and so this selects out a
> dominant follicle or what I call the \"egg of the month.\"
>
> So, this process of selection is important for the human, which is a
> mono-ovulatory species. Obviously, if we add gonadotropin at some
> critical level back here, we end up with multiple follicular
> development and rescue of follicles that would otherwise have
> undergone atresia, and this results in the multiple ovulations that we
> see in fertility and for in vitro fertilization.
>
> \[Slide.\]
>
> Now, we can follow this process also in the ovary. Here is an
> ultrasound of an ovarian cross-section with a black area, which is the
> fluid-filled ovarian cyst, and this particular cyst increases in size.
> This is the pre-ovulatory follicle.
>
> The borders are less well seen in this photo because the patient had
> LH surge detected in the urine, so there is already changes going on
> within the follicle itself, and after ovulation, the corpus luteum
> forms and there is hemorrhage and other changes within the follicle
> structure suggestive of corpus luteum cyst formation, and by day 25 or
> 26 of the cycle, this corpus luteum will be scheduled to undergo
> apoptosis, and then there is demise of the corpus luteum in the
> absence of pregnancy.
>
> So, that is the normal menstrual cycle. So, what are some of the
> common programming that occurs in physiologic states? It turns out
> when the neuroendocrine axis reactivates, that it undergoes a very
> similar programming of essentially, if we look at peripheral LH levels
> being an indicator of endogenous GnRH secretion, since we have no way
> of sampling the GnRH compartment in the intact human, so assuming that
> there is a GnRH release for each LH pulse, we can make some
> suppositions as to what is going on centrally.
>
> So, here is an individual who is in essentially a quiescent state.
> This would be individuals that are pre-pubertal or after delivery of a
> baby, when the HPO axis is essentially at rest, or individuals with
> various forms of hypothalamic amenorrhea, which I will discuss.
>
> As the GnRH axis activates, there are low amplitude LH pulses, so it
> starts off with a lot amplitude, low frequency pulses, and as the axis
> matures, and this can take place in a matter of weeks in the
> postpartum state, or in a matter of years in the pubertal state, there
> is an enhanced secretion of high-amplitude LH secretion during the
> sleep phase of the woman, and then during the early follicular phase,
> a normal pattern of well-established, about every 60 to 120 minute
> pulsatile release occurs.
>
> \[Slide.\]
>
> This is an actual example from Boyar\'s study looking at the GnRH-LH
> activation in puberty, and here are the sleep staging based on EEG
> criteria, and you can see the high amplitude up to 41 mIU of LH
> secreted during the state, and then during the daytime period when the
> child is awake, there is a much lower amplitude LH secretion
> suggesting that with sleep, some of the suppressive effects on GnR
> secretion may be decreased.
>
> \[Slide.\]
>
> This is a study I did many years ago that looks at the same type of
> reactivation during the postpartum phase. These are women at various
> states after delivery day 19 though day 25, and you are looking at LH
> secretion. Primarily during the sleep hours, the LH is in black and
> the FSH is in open circles.
>
> This individual is not breast-feeding, so prolactin levels return to
> normal levels pretty quickly and as you can see, there is a similar
> pattern to puberty of high amplitude, low frequency LH secretion with
> sleep, and then a maturing of that process by about day 25 following
> delivery.
>
> \[Slide.\]
>
> Now, I have just gone through some of the physiologic anovulation
> aspects, and we see that during the prepubertal phase, we also see it
> postpartum. This phase can be prolonged by breast-feeding due to the
> higher prolactin levels and the effects of prolactin on the
> hypothalamic pituitary axis.
>
> But there are individuals that have a what we call \"functional
> hypothalamic amenorrhea,\" and I will define that in generic terms in
> that if you do an evaluation of these individuals, they have no
> anatomic abnormalities, they have no gene abnormalities, so these
> individuals may have a lifestyle-related shutdown of the hypothalamic
> pituitary unit.
>
> These are individuals that may exercise excessively. A good example
> would be the long distance runner. When you classify them, and there
> have been studies that have looked at this, these are individuals that
> usually run more than 30 miles per week, they are relatively thin, and
> they are extremely committed to their exercise on a long-term basis.
>
> There are individuals that have nutritional factors that affect their
> perception of body weight. An extreme form may be anorexia nervosa, a
> less extreme form may be bulimia, and there are individuals who are
> just plain stressed out from a variety of environmental changes, such
> as young girls going to college, having amenorrhea, or job stresses
> that may shut down the hypothalamic pituitary unit.
>
> There are other disorders that are associated with medications, either
> individuals who are on a variety of antipsychotics which are
> predominantly dopamine receptor antagonists until recently where new,
> non-dopamine receptor drugs are available, and there are extreme forms
> of psychiatrically associated disorders - pseudocyesis being an
> extreme form, and anorexia nervosa being the other, bulimia probably
> in an intermediate phase. I will discuss these in a little more
> detail.
>
> \[Slide.\]
>
> Let\'s talk first about the psychogenic hypothalamic amenorrhea.
> Individuals that have this particular trait usually are single, they
> are professional, highly intelligent individuals, that have sort of a
> Type A type personality, and many of them have obsessive-compulsive
> habits.
>
> The history may pinpoint a significant stressful life event. It may be
> an onset of sexual abuse. Up to 20 percent of these individuals have
> this background history. They may also have a prior history of already
> an irregular menstrual cycle in that from the time of onset of
> menarche to when you are evaluating them, they have irregular
> menstrual cycles or very few menstrual cycles.
>
> In general, they are involved in professional occupations just because
> of these particular traits that lend to success in professional
> settings.
>
> \[Slide.\]
>
> In terms of the hormonal parameters, Dr. Berga and I and other
> individuals in Dr. Yen\'s group have studied functional hypothalamic
> amenorrhea for a number of years and have published on some of the
> basis for the anovulation.
>
> If we look at some baseline hormone levels, knowing full well that
> many of these hormones are secreted in a pulsatile fashion, and we
> compare them to the early follicular phase versus individuals who are
> amenorrheic on a functional basis, we find that the LH is lower, about
> 8.5 versus 11.6 mIUs. FSH is higher than LH in our laboratory
> measurements, so a reversal of the LH-FSH ratio that you might see in
> the adult.
>
> Prolactin levels generally are a little lower perhaps related to the
> circulating estradiol levels, which can be lower, but not
> significantly, in this group of functional hypothalamic women. I will
> show you later on there are extreme forms, such as anorexia nervosa,
> where the estradiol levels are postmenopausal.
>
> Cortisol secretion is increased over a 24-hour basis suggesting that
> the stress response has resulted in a much higher level of secretion
> of a stress type hormone, cortisol. There is usually some decrease in
> T3. We didn\'t measure reverse T3, but I would suspect that reverse T3
> would be somewhat elevated, and the T4 levels are somewhat decreased.
>
> The yellow is the significant differences versus women that have
> regular menstrual cycles during the early follicular phase.
>
> So, these are sort of the hormonal levels you might find.
>
> \[Slide.\]
>
> Here is an example of what we felt was an evaluation of the general
> overall stress picture. On this graph is the serum cortisol levels
> over a period of time as it begins to fall from early morning to the
> noon hours.
>
> The dashed hatched area represents the normal levels of cortisol that
> we found in our control population, and these individual values
> represent the hypothalamic amenorrhea, and you can see with the
> exception of one individual, all of them have much higher circulating
> cortisol levels although they do all tend to have the same diurnal
> variation in terms of the decrease towards the noon hour.
>
> If we look at LH secretion in particular with normal weight women
> versus hypothalamic women, the mean 24-hour LH levels are certainly
> lower, but not statistically significant, and they do overlap with
> normal women.
>
> The amplitude of the LH secretion, based on pulsatile analysis, shows
> a higher amplitude LH in the hypothalamic women, about 8 mIUs mean in
> the hatch bars, however, what is most significant is the frequency is
> significantly decreased versus the normal weight women. So, this leads
> to an overall reduction in the average 24-hour LH secretion. This is
> for functional hypothalamic amenorrheic women.
>
> \[Slide.\]
>
> There are other abnormalities in our investigations that we found.
> This included, as I have alluded to, an increase in daytime cortisol
> secretion and a distortion of the melatonin secretion that normally
> occurs nocturnally, an increased amplitude, and increased melatonin
> secretion overall.
>
> There is also an increase in nocturnal secretion of growth hormone,
> and in individuals in later publications, not from our group, there
> was demonstration of elevation in corticotropin-releasing hormone
> levels in the CSF fluid, as well.
>
> So, there are a variety of other neuroendocrine abnormalities that are
> associated, not just isolated, to the gonadotropins.
>
> \[Slide.\]
>
> A second disorder that can result in amenorrhea is bulimia, and these
> individuals are generally female, 90 to 95 percent. It is very high
> among high school and college students, about a 4.5 to 18 percent
> incidence, and this disorder is characterized by individuals that
> essentially consume very large quantities of food over a short period
> of time, followed by either food restriction or self-induced vomiting,
> or the use of laxatives to get rid of the food load.
>
> \[Slide.\]
>
> The features that we found were individuals generally had irregular
> menstrual cycles although the majority of them were not amenorrheic.
> Because of the self-induced vomiting, they did have effects of stomach
> acid on their teeth, they may also have irritation in the esophageal
> area due to the gastric acids.
>
> There may have been electrolyte abnormalities due to the loss in
> stomach acid, as well as laxative abuse, and individuals may use
> various compounds like ipecac to increase their self-induced vomiting
> efficiencies.
>
> \[Slide.\]
>
> This individual, I think you all know is someone with extremely low LH
> and FSH and has anorexia nervosa, and is being studied.
>
> \[Slide.\]
>
> This is a psychosomatic disorder of a very severe nature,
> characterized by extreme weight loss of more than 25 percent below
> ideal body weight. There is essentially a body image distortion. These
> individuals believe that they are fatter than they truly are, and they
> have an intense fear of gaining weight.
>
> The incidence varies depending upon centers reporting between 0.64 to
> 1 per 100,000, and the vast majority are female between the ages of 12
> to 30. Of significance is this disorder has a mortality rate of at
> least 9 percent in some of the reported studies, so this is a very
> extreme example of a very serious illness with a high mortality rate
> in a very young population.
>
> \[Slide.\]
>
> If we look at anorexia nervosa\--and this is a study that I did on one
> isolated patient who was amenorrheic\--you can see that the LH levels
> are under 5 mIUs, probably between 2 to 3 mIUs, with really virtually
> no pulsatile pattern that you can discern.
>
> We also simultaneously measured ACTH. The normal ACTH levels in our
> lab are between 10 and 15, and she does run into that range, however,
> there are higher levels of ACTH that are above that normal range.
>
> In this individual, the cortisol secretion is tonically elevated with
> no diurnal variation over this 24-hour period of time, so she has lost
> her normal diurnal variation in terms of cortisol secretion.
>
> \[Slide.\]
>
> As with puberty and postpartum, recovery from anorexia nervosa follows
> that preprogrammed sleep-associated increase in LH secretion, and this
> is a study by Boyar looking at the reactivation during recovery from
> anorexia nervosa with again high amplitude LH secretion followed by a
> lower amplitude LH during the daytime hours.
>
> \[Slide.\]
>
> The behavioral features for anorexia nervosa include preoccupation
> with handling of food. These individuals will weigh their food,
> sometimes they will weigh their vomit, they will weigh their bowel
> movements, so there is very extreme abnormal behavior.
>
> They oftentimes exercise bulimic behavior and extreme calorie
> counting. When one asks them what their waist is based on moving a
> pair of rings on a broomstick, they will oftentimes distort their
> waist measurements to a considerable degree.
>
> They are very hyperactive in an effort to burn up the calories. In
> that one individual I studied, she was running up and down the stairs
> to the GCRC, which is nine floors, and she was doing it 30 or 40 times
> a day to try and increase calorie burn. They have total amenorrhea, as
> well as constipation.
>
> \[Slide.\]
>
> With regards to physical characteristics, they have coarse, dry skin.
> They have defects in thermal regulation with hypothermia. Heart rate
> is usually below 60. Because of electrolyte abnormalities, and this
> could be a fatal complication, they can experience cardiac
> arrhythmias.
>
> They have low bone mass and anemia, as well as low white counts, and
> their hepatic enzymes can become elevated with prolonged starvation.
>
> \[Slide.\]
>
> With regards to neuroendocrine abnormalities that have been described,
> I mentioned already the extremely low LH levels that I showed you in
> that example, both LH and FSH, and these would approach the same
> levels one would see with Kallmann syndrome or the isolated
> gonadotropin deficiency.
>
> Their ACTH cortisol axis is impaired, and this may be in part due to
> the higher baseline activity in their cortisol dampening the feedback
> response. They have low prolactin levels, high reverse T3, low T3
> levels, and decreased IGF-1 levels despite increased growth hormone
> levels.
>
> So, these are very, very distorted in terms of what the normal
> relationships are in both the hypothalamic- pituitary-ovarian axis, as
> well as the hypothalamic-pituitary-adrenal axis.
>
> \[Slide.\]
>
> So, how do we put this aberrancy in GnRH LH secretion into perspective
> with regards to what we have observed in individuals with functional
> hypothalamic amenorrhea, individuals with bulimia, and
> exercise-associated amenorrhea, which I haven\'t covered in great
> detail?
>
> Our feeling is that there is probably environmental, physical, and
> personal stresses that have an increased effect on the endogenous
> CRH-ACTH-cortisol axis. In animal studies at least, this results in an
> increase in beta endorphin activity, which has a negative impact on
> GnRH neuronal secretion.
>
> There may also be effects on the dopamine neurons although we are not
> quite sure, and this, in turn, then reduces the pulsatile activity of
> the GnRH neuronal system, dampening gonadotropin release, and our
> feeling is that this is a reversible process in these individuals as
> we remove or modify these life stresses.
>
> \[Slide.\]
>
> Just to reiterate this point, this is a group of individuals we
> studied with pituitary Cushing\'s disease versus a normal control.
> This is the LH secretion over a 24-hour period. Notice that in the
> Cushing\'s disease patient, the axis is half of what it is on the
> normal control.
>
> You can see that there are very few, if any, LH pulses during the day,
> and these are very low amplitude, less frequent pulses in this
> individual with excessive ACTH secretion. It\'s sort of an accident of
> nature with regards to high ACTH output.
>
> \[Slide.\]
>
> With regards to the organic defects that Dr. Layman has gone through
> with regards to genetics, he went through Kallmann\'s syndrome in
> great detail, isolated gonadotropin deficiency.
>
> There are other organic defects that result in the same picture, and
> these are individuals with a variety of pituitary tumors that may
> destroy the gonadotropin-producing capacity of the pituitary gland,
> individuals that have some sort of infarction of the pituitary gland,
> such as Sheehan syndrome, which is a postpartum pituitary necrosis due
> to excessive bleeding with the delivery.
>
> Individuals that have pituitary apoplexy, which is infarction of the
> pituitary usually associated with large macro adenomas. Individuals
> with empty sella syndrome, which is a misnomer in that in this
> syndrome, there is a defect in the diaphragmatic drainage of CSF
> fluid, such that the CSF pressure is increased in the sella tursica,
> and the pituitary, on its stalk, just cantilevers up underneath the
> brain, so it is not in its normal location. In general, prolactin may
> be elevated in these individuals due to the impaired delivery of
> dopamine through the stalk.
>
> Individuals that have HIV or TB may have an infection that affects
> that pituitary hypothalamic area. A variety of head traumas where
> there is abrupt acceleration of the head resulting in partial shearing
> of the pituitary stalk as the brain and the pituitary decelerate at
> different rates in head trauma, and obviously, post-radiation effects
> on the pituitary itself.
>
> \[Slide.\]
>
> Here is a clinical example of an individual with isolated gonadotropin
> deficiency. There is two females here and a male. Notice in this
> 17-year-old, she is quite tall. The bony epiphyses do not close due to
> the lack of sex steroid estrogen being produced, and so you can see
> that all three of these individuals have very long bones, and there is
> absence of breast development.
>
> In this individual, there was some delay in pubic hair development,
> but generally, we don\'t see a delay in pubic hair development. Here
> is a male with the same type of diagnosis.
>
> If we do close-ups of the breasts, they are usually Tanner Stage I,
> which means that there is very little breast tissue under the nipple
> due to the lack of estrogen production from the ovary, which is
> essentially at rest and unstimulated.
>
> There is usually no delay in pubic hair development. This is Tanner
> Stage II or III. In this case, this is a Tanner Stage II since the
> pubic hair hasn\'t filled the entire lower escutcheon.
>
> \[Slide.\]
>
> With regards to the diagnosis of isolated gonadotropins deficiency, as
> Dr. Layman alluded to, pituitary functions except for LH and FSH are
> normal, they do not have any other organic defects.
>
> Kallmann\'s syndrome, which is a version of this, is also associated
> with anosmia and midline defects.
>
> These individuals, as I pointed on the picture, are tall, slender,
> with long limbs. The treatment long term for these individuals is to
> induce puberty wit sex steroid hormone replacement. Individuals that
> require fertility would be treated either with pulsatile GnRH, if
> there is a center that does that, or injectable gonadotropins.
>
> \[Slide.\]
>
> With regards to the GnRH story, this is a series of patients studied
> from Bill Crowley\'s group looking at various doses of intravenous
> GnRH at 25 nanograms per kilo, 75 nanograms per kilo, and 100
> nanograms per kilo, and this is their estrogen and progesterone
> profiles during a stimulated cycle.
>
> As you can see, there are varying responses particularly with regards
> to the ovarian response to the gonadotropins that are generated from
> GnRH. All of them seem very similar although the progesterone
> production generally tends to increase a little bit more in the higher
> dose GnRH groups versus the 25 nanograms. Here, you can see some that
> have very low progesterone production during the luteal phase.
>
> The optimum doses for GnRH administration has been established and
> they range at around 2.5 to 5.0 micrograms per pulse at about a 60- to
> 90-minute pulse per day.
>
> With regards to the H-P-A axis, what I have shown you is that the
> activation of the H-P-A axis requires a program of GnRH pulsatile
> activity every 60 to 120 minutes. There is a sleep-associated rise in
> LH and FSH, and individuals with a slow wave GnRH will preferentially
> secrete FSH-beta initially, and this is seen in puberty and
> postpartum.
>
> The reproductive dysfunctions I have discussed, which is resulting in
> reduction of endogenous GnRH secretion, are associated with either
> exogenous stressors, exercise events, or eating disorders with
> anorexia being an extreme form.
>
> This results in an increased ACTH cortisol secretion and
> hyperactivation of this axis with a reduction in GnRH pulsatile
> activity.
>
> Let me stop there and not go further.
>
> DR. GIUDICE: Thank you, Dr. Liu, for this really comprehensive review.
>
> I think you have clearly demonstrated the heterogeneity of
> hypothalamic amenorrhea. Between your talk and that of Dr. Layman,
> there are I think some sort of take-home messages I think we all need
> to be aware of, and that is that there are individuals who have
> extremely low gonadotropins and those who have relatively low
> gonadotropins.
>
> From some of the studies looking at the mutations in gonadotropins,
> you can have immunoreactive gonadotropins or circulating levels that
> are measurable, but still have bio-inactive gonadotropins.
>
> **Questions from the Committee**
>
> DR. GIUDICE: With this as a background, I would like to take the lead
> and just asking you a couple of questions.
>
> One, can you talk briefly about low gonadotropins, and I think this is
> germane to the issue at hand today, and some of the assays that may
> have changed from the 1980s to now and what are low gonadotropins?
>
> DR. LIU: Most of the slides that I showed you, that measured LH
> activity from Crowley, Dr. Boyar, and Yen\'s group, utilized a
> standard that is no longer available, which is the Second
> International Reference Standard that was put out by the NIH and was a
> urinary standard.
>
> We were measuring essentially serum species. Subsequent to that, the
> WHO has put out other reference standards and, in fact, when you go
> back and re-run those serums, the gonadotropins are much lower with
> the newer standards.
>
> So, the numbers that we see, that I presented, are actually going to
> be lower if you use the newer assays and the newer WHO standards. That
> is my understanding. But I don\'t know the exact, I don\'t think
> anyone has worked out\--anyone could care to comment\--no one has
> worked out the translation between the old Second IRP Standards, which
> a lot of the research labs are using, versus the new commercial WHO
> Standards.
>
> DR. GIUDICE: I have one other question and that is, the data that you
> showed on GnRH pulsatility in replacement of GnRH with the pump, the
> Lutrepulse was the commercial pump that was available, this is IV
> administration, I am wondering if you could just comment for the group
> about the availability of this and essentially either gonadotropin
> replacement or gonadotropin supplementation in the setting of low
> gonadotropins.
>
> DR. LIU: There are only very small numbers of groups that have had a
> great deal of experience with intravenous GnRH, Nanette Santoro from
> Bill Crowley\'s group, myself, and Dr. Philip Corey \[ph\] in Italy
> are some of the ones that come to mind that have done a fair number of
> GnRH cycles.
>
> That particular approach works very well if you are very experienced,
> but if you are doing one or two cycles a year in the isolated
> individual with low gonadotropins, it is extremely difficult to keep
> the IV in place. As you saw, the sub-Q administration does not work
> well, if at all, and so when the IV infiltrates, what you end up with
> is essentially a sub-Q administration pattern.
>
> So, a lot of times when we do see couples referred to us for IV GnRH,
> it is because they have had troubles with the IV access on a long-term
> basis, because it takes about 14 days to achieve a dominant follicle.
>
> The other issue I think is the availability of the Lutrepulse. As far
> as I know, it is no longer being supported at least here in the United
> States. I don\'t know if Philip Corey has continued support in Europe,
> but it was manufactured by Ferring using the Ferring Cyclomat was the
> one originally, was the pulsatile pump.
>
> DR. GIUDICE: Thank you.
>
> Dr. Hager and then Dr. Keefe.
>
> DR. HAGER: Dr. Liu, as a follow-up to Dr. Guidice\'s question, in
> partner to our considerations, what level of LH and/or FSH would you
> accept to differentiate FHA from IHH?
>
> DR. LIU: I don\'t think that you can find an absolute level. In
> general, the functional hypothalamic amenorrhea women will have higher
> gonadotropin levels than IHH, but I think you will see some overlap,
> so, for example, the IHH less than 1.2 has been used in this
> particular trial. That is an appropriate cutoff.
>
> For FHA, you will find some women at the same level, that mimics it,
> but most will be above that level. A level of 5, again, this is based
> on the new assay and not the old assay. The old assay, the mean was 8.
> something. In our particular study, I believe it was over 40 women
> with functional hypothalamic amenorrhea.
>
> So, I don\'t know how to translate those numbers to the new one, but I
> would assume 5 would be an approximate level for those.
>
> DR. GIUDICE: Dr. Keefe.
>
> DR. KEEFE: I have two questions related to the nocturnal LH pulses
> that one sees physiologically, as well as with recrudescent to the
> reproductive system and pathological states.
>
> The first is I always see the LH secretion measured. What is happening
> with FSH, does it ever go up at all?
>
> The second one is has anyone attempted to mimic that nocturnal LH when
> using the Lutrepulse? You can imagine, you know, you show that there
> is some disconnect between the growth hormone and IGF-1, and, of
> course, at night, there are elevations of growth hormone, so you can
> imagine physiologic rationale for why hitting with GnRH at night, at
> least during the early phase, might have some advantages. So, those
> are two related questions.
>
> DR. LIU: With regards to FSH, it does increase, and let me show you
> that slide if I can find it.
>
> It does increase, but not as dramatically as LH because the half-life
> is much longer for FSH. Here you can see the FSH go up, and here, it
> slowly increases, so you see both go up, but the FSH is much more
> minimal than the LH. It may be reflecting the pituitary secretory
> capacity. It is reading the signal, but it may not be able to
> manufacture the FSH as quickly and release it as quickly as the LH, so
> that is number one.
>
> What was the second question?
>
> DR. KEEFE: The second was a biologic intervention, you know, if you
> intervene with gonadotropin or GnRH pulsing at night initially, do you
> gain any advantage?
>
> DR. LIU: The answer is probably no, you don\'t gain any advantage.
> This is purely a physiologic program that I am pointing out, that this
> is what happens in the natural instance. Giving GnRH at night versus
> during the day probably has no bearing on the pituitary LH production
> provided you have already primed the pituitary sufficiently to get its
> stores of LH and FSH up.
>
> DR. KEEFE: Has it been tested?
>
> DR. LIU: It hasn\'t been tested.
>
> DR. KEEFE: Because you could imagine if this growth hormone peaks at
> night, as well.
>
> DR. LIU: Right, and growth hormone may have an augmenting effect,
> right, I understand, but it hasn\'t been tested. The problem is we
> don\'t have a good handle other than to say that you need about seven
> days of exogenous GnRH priming to get a more robust LH/FSH response.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: Dr. Liu, this may not be a fair question to you, but Dr.
> Layman sort of alluded to this earlier, about data that suggested FSH
> is necessary to making androgens. Are you familiar with what data he
> was referring to?
>
> DR. LIU: Could you repeat the question?
>
> DR. RICE: He alluded in his talk that there is some data out there
> that suggests that FSH is necessary, may be necessary to make
> androgens. Do you know what data he was referring to?
>
> DR. LIU: No, I don\'t. If we look at the women that have FSH receptor
> defects, there is a Finnish group of women with premature ovarian
> failure. They have normal FSH, actually, extremely high FSH levels,
> but don\'t respond at the ovarian level. They do make androgens, but
> the FSH receptor functionality is not totally ablated in those
> individuals, so I don\'t know if that answers your question. It is not
> a black and white issue.
>
> DR. GIUDICE: Dr. Macones.
>
> DR. MACONES: Dr. Liu, just in follow-up to Dr. Hager\'s question, you
> mentioned an LH cutoff of perhaps 5 to differentiate functional from
> idiopathic, from IHH, and it sounded like there is still going to be
> some overlap even with that cutoff.
>
> I was wondering if there are any clinical criteria or additional
> criteria that you could use to further refine that distinction between
> the two groups.
>
> DR. LIU: We did not use gonadotropins as the criteria for classifying
> people with functional hypothalamic amenorrhea for those studies, and
> I don\'t think people have used it since then either.
>
> It is primarily a stereotypic where they meet certain lifestyle
> criteria associated with amenorrhea, so amenorrhea really is the
> initial screening point, and then we went through to investigate
> whether there were any other organic causes for the amenorrhea.
>
> When we found none, we then looked at the history to subclassify what
> other common features were in those individuals, so we did not use
> gonadotropin as our initial cutoff, and we looked at gonadotropins
> obviously as the cause of their amenorrhea, but not as the classifying
> criteria.
>
> DR. GIUDICE: As a follow-up to that, for women who have functional
> hypothalamic amenorrhea where the gonadotropins, at least in the older
> assays, hovered around 8, and most of us wouldn\'t be so shocked at
> the 5.
>
> It is still clear, though, that they need gonadotropin
> supplementation, so there needs to be some additional amounts, and
> having a specific cutoff, I think, is perhaps desirable for trials,
> but clinically, in practice, there is such a range that it is often
> really not ignored, one just goes ahead and does the supplementation.
>
> Any additional questions for Dr. Liu?
>
> DR. LIU: Can I make one more comment?
>
> DR. GIUDICE: I think so.
>
> DR. LIU: What you are measuring really is a moving target because
> it\'s a pulsatile FSH and LH secretion, so if you happen to draw the
> blood sample at the peak, that may change, and if you draw it at the
> trough, it may change, so you have a huge\--because the amplitudes are
> 4 to 8 mIUs, so you can have various time points on that curve when
> you draw the LH. That is why it is so hard to establish a clear
> gonadotropin threshold.
>
> DR. GIUDICE: Yes, Dr. Crockett.
>
> DR. CROCKETT: I just have a clarification question. Right now in
> patients with FHA, it is very common for us to treat their symptoms
> with oral contraceptives to replace the estrogen that they don\'t
> have.
>
> I am wondering if you remove the need to cause them to ovulate for
> pregnancy, is there other benefit to giving the LH or FSH, or could
> you comment on just the difference between substituting GnRH versus
> the pituitary level versus the end organ level?
>
> DR. LIU: The physiologic replacement would be ultimately the best
> thing, however, we have no way of giving that decapeptide
> physiologically without either an IV mode or some other drug delivery
> means.
>
> So giving the target tissue the steroid, which is what is the
> downstream event is the most appropriate, so for long-term
> replacement, I would treat these individuals very similar to what you
> might do for IHH.
>
> DR. GIUDICE: Dr. Keefe and then Dr. Stanford.
>
> DR. KEEFE: As you can figure out, we are trying to get at this issue
> of the diagnosis, the diagnostic criteria, even though there are not
> explicit criteria available.
>
> In your clinical practice, when do you decide to give a trial of
> clomiphene citrate versus exogenous gonadotropins for somebody is at
> the borderline range, what criteria do you use besides the
> gonadotropins, which you have pointed out are kind of tricky?
>
> DR. LIU: I am a cheapskate, so because of cost issues, I always go
> with a challenge of low dose clomiphene citrate\--and there is no
> clinical data published, I can say that upfront\--I use a half a
> tablet of clomiphene citrate based on my knowledge base that in a low
> estrogen environment, clomiphene acts as an estrogen agonist, so I
> don\'t want to give a very high dose of clomiphene because it may end
> up suppressing.
>
> So, I would use a low dose for one to two cycles to see if there is
> any response. If there is no response, then, I move to gonadotropins,
> so it\'s just a clinical trial.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: It seems like you mentioned a variability of baseline LH
> measurements. It seems like one way to address that might be to draw a
> level and then routinely draw another level 30 to 45 minutes later.
>
> I am just wondering if that has been done and how that worked out.
>
> DR. LIU: It has been proposed and I am sure it has been done for some
> studies, but I don\'t recall the levels that they got. There have been
> some protocols in which three serial samples and then they were
> pooled, and then you measured the pooled specimen.
>
> DR. GIUDICE: Dr. Liu, I would like to get back to Dr. Keefe\'s
> question about your clomiphene challenge. Can you give us some idea of
> how frequently you actually have a positive response to that?
>
> DR. LIU: In my experience, it is about 30 percent will respond to very
> low dose clomiphene citrate, and it is really truly not a clomiphene
> challenge as we use in routine IVF, so it\'s a very low dose, about a
> half-tablet for five days, and we just measure either follicular
> response or LH surge depending upon the individual\'s ability to
> measure.
>
> DR. GIUDICE: And \"follicular response,\" you mean size of follicles
> and estradiol level?
>
> DR. LIU: Correct.
>
> DR. GIUDICE: Thank you.
>
> Any other additional questions? Dr. Keefe.
>
> DR. KEEFE: Have you ever had occasion to look at the ovaries of these
> patients that have severe hypothalamic amenorrhea? What stage, are
> they at the non-growing stage or are some committed?
>
> DR. LIU: You will actually see antral follicles in them, but you will
> not see follicles probably above 7 millimeters if they are truly
> quiescent and their amenorrhea has been more than about six months, so
> the volume will be reduced compared to someone who is in the normal
> cycling category in the early follicular phase.
>
> DR. GIUDICE: Any additional questions from the committee?
>
> If not, I would like to thank Dr. Liu for his presentation and
> participation.
>
> Before we go on, in our flurry to have Dr. Layman finish his talk
> before he had to leave, I actually inadvertently passed over Dr.
> Shames\' opening remarks, so if you have any opening remarks, would
> you please share them with us now.
>
> **Opening Remarks**
>
> DR. SHAMES: I just had some brief remarks, first, to thank you for
> yesterday\'s session. I think we will find it very useful in
> formulating a guidance which hopefully will make development of these
> drugs more efficient.
>
> Secondly, since I find I am answering a lot of questions about process
> and regulations, I just wanted to very briefly give an overview of
> what is going on today, which is that we reviewed the application that
> you are all seeing, this particular NDA.
>
> We reviewed the information and data from the trials that were
> presented and found that it did not provide, in our jargon, as will be
> explained, substantial evidence to be approved.
>
> The Division found that it was not substantial evidence. When that
> happens, the sponsor is given the opportunity for various forms of
> appeal of our decision, and in this case, they can appeal above our
> level, to higher levels in the Center for Drugs, or they have the
> option of presenting their information to an advisory committee.
>
> So, what is happening here is they are going to present their view of
> the information and we are going to present our view of the
> information, and then we are going to ask you for your input regarding
> that.
>
> I just wanted to give a little background about what exactly we are
> doing here today.
>
> Thank you.
>
> DR. GIUDICE: Thank you.
>
> **Committee Discussion**
>
> DR. GIUDICE: There was some discussion sort of post hoc yesterday by
> some of the committee members, and then this morning at breakfast,
> regarding some of the recommendations that we have made for the
> guidance document.
>
> In particular is the issue\--and I hate to raise this again, but since
> it has been very much under discussion\--the issue of pregnancy as the
> outcome for gonadotropins and the issue of the indications.
>
> Some committee members have expressed the desire to have a brief
> discussion this morning about this. The issue of pregnancy, just to
> cut to the chase, has to do with certainly that is the goal of
> gonadotropin therapy for infertility.
>
> We, and many members of the committee, felt it important that this
> message be sent to the FDA that if there is no flexibility in outcome,
> and pregnancy becomes the gold standard, that the n that is required
> for most pharmaceutical trials is going to be so large, and the
> expense so high, that we may actually end up with few, if any, trials
> at all, which of course would be counterproductive to the goals of the
> physicians and the patients.
>
> So, I would like to devote maybe about five minutes to this
> discussion, and for those of you who bent my ear last night and this
> morning, I would invite you to please turn on your microphones and
> begin a brief set of comments.
>
> Dr. Crockett.
>
> DR. CROCKETT: I would just like to address this question to Dr.
> Shames. I was wondering if you could please, for the benefit of the
> committee, explain how the indications are decided, how your breakdown
> for the indications are done, and why it is important that it is done
> the way it is.
>
> DR. SHAMES: Well, I can answer that in a general sense. First of all,
> the guidances are only recommendations as we have been saying here.
> The guidances are often general, there is a lot of wiggle room in the
> guidances, that is just the way they are.
>
> These are not regulations or rules or legally binding. The purpose of
> these guidances is merely to increase the efficiency of the
> development of the products, so that sponsors have some general idea
> of how to develop drugs in a general sense, for the bulk of the drugs,
> say, in this situation.
>
> We always are aware that there are exceptions and especially when
> there are small populations, we understand. Small populations or
> outcomes that are very long, and we recognize that, so if there are
> small populations or outcomes that will be long or burdensome, we
> understand that we don\'t want to make the development so costly that
> it will be essentially impossible to develop the drug.
>
> So, I think I am trying to assuage your fears of this in that what we
> asked for yesterday are sort of general guidelines, because we
> haven\'t done that really in a long period of time, certainly since
> Shelley and I have been here.
>
> We do welcome exceptions. I mean we are flexible, you know, it\'s a
> flexible thing, because these are not set in stone, and they are not
> regulations, they are just merely recommendations that we give as
> guidances, and people can come before they even start developing the
> drugs and talk to us about exceptions.
>
> As far as the indications, generally, it is best, it makes the most
> sense to formulate the trials, so that the endpoints for the trials
> correlate with the indications, but that can be changed also. I mean
> we can look at individual cases and have individual indications.
>
> Part of the reason we try to make these standardized is because we
> have some obligation not to be arbitrary and capricious in a sense,
> which sponsors call \"unfair.\" We try to be as standard as possible,
> so we are not accused of treating people or sponsors differently, so
> that is why we have to have some standardization in these situations.
>
> DR. CROCKETT: I guess what I hear you saying is instead of having a
> general indication, say, for ovulation induction and augmentation,
> it\'s advantageous when they are acting with sponsors to have the
> indications broken down into more specific categories, because it
> offers them an opportunity to better target their research.
>
> DR. SHAMES: As we discussed, we do have to take into account what is
> going on at the moment in the particular area, what the science is in
> the particular area, so that goes into what the indications are also.
>
> This can be altered, these guidances, even if we have a guidance that
> is not draft, is actually a final guidance, still, if the science
> changes, we can alter the indication at that point.
>
> DR. GIUDICE: Dr. Stanford and then Dr. Keefe and Dr. Toner.
>
> DR. STANFORD: It just seems to me that the indications ought to match
> the main outcome, and in this particular case, if the outcome is
> accepted of follicular development, which is another discussion, and
> if it is effective for that, which is another discussion, but if that
> were all the case, then, it seems to me the indication should not be
> for the induction of ovulation, but for the induction of follicular
> development.
>
> I mean it should just reflect what the output was. That would be my
> take on it.
>
> DR. GIUDICE: Thank you.
>
> Dr. Keefe.
>
> DR. KEEFE: We are kind of picking up where we left off yesterday. Both
> of the presentations that Jim and I made emphasized the disconnect
> between follicular development and outcome, that there are is so many
> factors that are egg-specific, embryo-specific, and that to target the
> pregnancy outcome would compromise the development of novel drugs that
> may well be equally good and spur competition and open options that
> have other advantages, convenience, and other factors.
>
> So, I think the proposal we left with was that we are recommending the
> indication be multifollicular development for pregnancy instead of and
> pregnancy, leaving that wiggle room overt and clear.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: I think the issue is really one of trade-offs. Clearly, a
> pregnancy endpoint is closer to the desired goal of the therapy, but
> as a practical matter, we it would probably increase sample size for
> most studies about 10-fold, from 100 to 1,000.
>
> The precedence has been in this country for sponsors to pay for such
> cycles of novel therapies, which in this country are typically
> \$10,000 a crack. So, 10,000 times 1,000 is 10 million as a study, and
> I am not paying that bill, and I don\'t mean to be facetious, but in
> the end, our patients are paying that bill.
>
> So, as one of the considerations here, I think you have to recognize
> that this will make drugs more expensive, and to the extent that you
> believe using the pregnancy endpoint is worth that extra cost, then,
> you stick with the pregnancy endpoint, but I think you have to at the
> same time admit that there is a cost to the patients for that
> endpoint.
>
> DR. GIUDICE: Thank you.
>
> Dr. Slaughter.
>
> DR. SLAUGHTER: I just wanted to comment a little further what Dr.
> Shames and also Dr. Keefe have said. We take into consideration the
> clinical relevance of the indication. In other words, the indication
> should mean something clinically.
>
> With respect to follicular development, I think Dr. Keefe has said we
> don\'t know what that means for pregnancy or there are some questions
> about the distal relevance to pregnancy, so therefore, if you use that
> as a surrogate, the ultimate outcome is to look for pregnancy, the
> surrogate or the reflection of the surrogate in the indication ought
> to have direct clinical relevance.
>
> We do have some flexibility. I think we heard very clearly yesterday
> that you think there should be some flexibility in the outcome or the
> indication of pregnancy as it relates to women with Group I.
>
> So, I think as far as both Dr. Shames and I can persuade you, putting
> this in a guidance document is not law, there is some flexibility. We
> are able to look at some things on the case presented to us and make
> appropriate or relevant adjustments in the ultimate indication.
>
> DR. GIUDICE: Thank you.
>
> Dr. Emerson, Dr. Brzyski, and then Dr. Rice.
>
> DR. EMERSON: I think that if we are going to invoke economics in this,
> we also should invoke the economic cost of approving a drug that is
> not really effective for what people want it for, and that you are
> paying for whether you like it or not, and that is a much greater
> economic cost to society than the cost of mounting a clinical trial
> where per-patient costs of \$10,000 is really quite routine.
>
> DR. GIUDICE: Dr. Brzyski.
>
> DR. BRZYSKI: I was trying to think of examples from other situations
> to try and enlighten myself. I don\'t know if it is relevant, but I
> just thought of the issue of say there is experience with fluoride
> self-limitation for increasing bone density, so if that is the
> indication, then, I think that could be approved to increase bone
> density, but when patients start getting prescribed fluoride and they
> have more osteoporotic fractures in that setting, then, is that a good
> thing?
>
> Well, it did what it was supposed to do, it increased bone density,
> but clinically, it had a negative effect on the patient quality of
> care, and is that a situation that the FDA and that the committee
> would feel comfortable with setting a precedent for.
>
> Now, I can\'t say, I mean there has not been any experience with
> ovulation induction drugs, for instance, that would make people
> ovulate or stimulate follicular development, but actually impair the
> opportunity for pregnancy, but you could imagine that those types of
> drugs could come along.
>
> DR. GIUDICE: Thank you.
>
> Dr. Rice and then Dr. Lewis.
>
> DR. RICE: Yesterday, we were presented with some I think very clear
> evidence from our two presentations that showed us that follicular
> development does not lead to pregnancy in different subgroups of
> patients, and there are several variables that impact that.
>
> So, if we are trying to advance or improve our ability to assist
> patients with their end goal, and that is pregnancy, then, it would
> seem appropriate for us to re-evaluate the criteria under which we are
> approving medications that can go beyond follicular development, and
> that is to pregnancy, because we all know that when those patients
> come in to see us as clinicians, yes, they may be excited they develop
> a follicle, but what they really want to know if this is going to
> assist them in achieving their long-term goal, and that is pregnancy.
>
> The second comment that I will make, and I hope this does not offend
> the committee members, but I think that we must be very careful about
> our subgroup conversations and that this is the forum in which to have
> conversations in which we discuss the issues that are relevant to
> making these guidelines to the committee\--or the FDA, excuse me.
>
> DR. GIUDICE: I think perhaps the reason there were subgroup
> conversations is because there was an element of uncertainty at the
> conclusion of yesterday, and I agree with you, it should have been
> brought up in this forum, but I am glad that we are having this
> discussion today, so that there will not be subsequent subgroup
> conversations.
>
> Dr. Lewis.
>
> DR. LEWIS: Thank you. Yes, we did visit much of this terrain
> yesterday, but clearly, pregnancy is the bottom line, that is what the
> patients want, it is not follicular development, and if you have a
> sufficient sample size, I think issues about individual egg quality
> should be taken care of with randomization.
>
> I would also remind the committee that these are all international
> companies producing these medications, they operate in a variety of
> countries where it may not be so expensive to run clinical trials, and
> clearly, the drugs are much cheaper in other countries. The reason for
> that\--I mean there are a lot of reasons for that.
>
> So, I do think our patients pay the cost if we approve ineffective
> drugs, and I think we ought to stick with pregnancy as the standard
> except as we agreed yesterday, in cases of Type 1 anovulation where it
> is rare and it\'s unrealistic to expect that we are going to get a
> large n to prove efficacy.
>
> DR. GIUDICE: Dr. Hager.
>
> DR. HAGER: It was my impression yesterday that a great deal of
> latitude was offered in our suggestions. I felt that it was very broad
> and reiterating the WHO-I category where follicular development was
> certainly an option for those studies.
>
> But I just want to remind us that we also reviewed not only follicular
> genesis, but we reviewed ovulation, chemical pregnancy tests,
> progressing on to gestational sac with fetal heart motion, so I
> believe what we were saying was that in WHO-I category, the
> development of follicles is certainly a way to evaluate the efficacy
> of therapy, but there are steps higher related to ovulation that would
> fall into that same category, that what we are really looking at for
> an ultimate endpoint in the other categories, assisted reproductive
> technologies, is a gestational sac with fetal heart motion.
>
> DR. GIUDICE: Thank you. I am assuming there are no more hands, that
> everyone has gotten whatever they have had on their chests now off
> their chests.
>
> Dr. Emmi, you have one more comment.
>
> DR. EMMI: I believe that when everybody leaves the table with a little
> bit of thought about what they felt should have happened, it usually
> means that you have compromised, and I feel that the clinical
> pregnancy rate was a compromise amongst the two groups for the
> appropriate endpoint, which is actually pregnancy.
>
> DR. GIUDICE: Thank you.
>
> We are running a little ahead of time, so what we would like to do is
> take break now and return at 10:30, so the sponsor can begin their
> presentation at 10:30. Thank you.
>
> \[Break.\]
>
> DR. GIUDICE: The next series of presentations will be the sponsor
> presentation by Serono, Inc.
>
> The first speaker is Pamela Williamson Joyce, who is the Vice
> President of Regulatory Affairs and Quality Assurance in Serono in the
> United States.
>
> Her topic is Introduction and Regulatory History.
>
> **Sponsor Presentations (Serono, Inc.)**
>
> **Introduction and Regulatory History**
>
> MS. WILLIAMSON JOYCE: Good morning. My name is Pamela Williamson Joyce
> and I am Vice President of Regulatory Affairs and Quality Assurance
> for Serono.
>
> I would like to thank Dr. Guidice and the members of the Advisory
> Committee, as well as the members of the Food and Drug Administration,
> for the opportunity to be here today to share the clinical development
> results for our program in Luveris, a recombinant luteinizing hormone.
>
> \[Slide.\]
>
> The proposed indication for Luveris is as follows. Luveris (lutropin
> alfa for injection) administered with follitropin alfa for injection,
> is indicated for the stimulation of follicular development in
> infertile hypogonadotropic hypogonadal women with a profound LH
> deficiency as defined by a level of LH of less than 1.2 IU/L.
>
> Given the earlier discussion, I would like to take this opportunity to
> clarify the indication. In August of 2003, Serono proceeded to submit
> an amendment. We thought this might be good for two reasons.
>
> First of all, this indication is consistent with the clinical
> development program over the last 10 years in studying LH and
> stimulation of follicular development. Additionally, it is important
> to note that this is also consistent with the indication that is
> currently approved in 46 other countries outside of the United States.
>
> \[Slide.\]
>
> A brief overview of our presentation follows. After my introduction
> and overview of the regulatory history, I will invite Dr. Jerome
> Strauss from the University of Pennsylvania to speak on the need for
> and the rule of LH in HH women with a profound gonadotropin
> deficiency.
>
> Following Dr. Strauss, Dr. Paul Lammers, Chief Medical Officer for
> Serono, will share the clinical development results in terms of
> efficacy and safety of Luveris.
>
> Following Dr. Lammers, Dr. Nanette Santoro from Albert Einstein
> College of Medicine in New York will present the clinical perspective
> and benefit/risk of luteinizing hormone in these women.
>
> Finally, I will conclude the presentation.
>
> \[Slide.\]
>
> Luveris is a luteinizing hormone produced by recombinant DNA
> technology. It is presented in lyophilized 75 IU vials and can be
> self-administered by subcutaneous injection.
>
> \[Slide.\]
>
> Luveris is currently approved in 46 countries outside of the United
> States including the European Union.
>
> \[Slide.\]
>
> It is important to note for several reasons that FDA\'s Office of
> Orphan Product Development has designated Luveris to be an orphan
> drug. Specifically, in the United States, the orphan drug regulations
> provide incentives to sponsors for the development of drugs which are
> intended to treat rare diseases and conditions.
>
> In the United States, that is defined by a prevalence of less than
> 200,000 patients. In this case, the prevalence of hypogonadotropic
> hypogonadal women is estimated to be between 2,800 and 5,600 women.
>
> Furthermore, in terms of profound LH deficient patients, the number of
> women is indeed even smaller. This further points to the challenges in
> developing drugs for rare conditions.
>
> \[Slide.\]
>
> Back in the early 1990s, Serono recognized that for many women, FSH
> alone was sufficient in their gonadotropin treatment regimen, however,
> we also believed that there was a role for LH specifically in the
> hypogonadotropic hypogonadal population. Therefore, we requested a
> meeting with the Food and Drug Administration\--this was a pre-IND
> meeting\--in order to seek advice on a clinical development program of
> using luteinizing hormone in treatment of HH women.
>
> The clinical development program was agreed to be two, Phase II/III
> studies that were intended to be essentially the same in clinical
> design. The endpoint for those studies in terms of registration was
> agreed to be follicular development.
>
> The first study, Study 6253, was conducted in Europe and Israel. This
> study, as Dr. Lammers will share, was of the truly profoundly
> LH-deficient patient population.
>
> Study 6905, which was conducted in the United States, and also
> therefore filed to the IND, was intend to reflect essentially the same
> patient population, however, given the rarity of the condition, it was
> difficult to enroll and therefore a decision was made to broaden the
> inclusion criteria for the U.S. Study.
>
> In hindsight, this was not the best decision because in the end,
> therefore, the population studied in the two clinical trials were no
> longer the same.
>
> In March of 1999, both clinical trials were completed and the data
> were shared with the Food and Drug Administration, who at that time
> had pointed out that given the fact that the two patient populations
> were no longer identical, they would like us to perform a confirmatory
> Phase III trial.
>
> This confirmatory Phase III trial was our Study 21008, which will
> serve as the basis of registration, and Dr. Lammers will share that
> with you.
>
> It is important to note that there were a considerable amount of
> discussions during the time that we presented the initial data and
> then, therefore, agreed to conduct that Phase III trial.
>
> Following completion of the trial, we requested another meeting with
> the FDA, and we met with the Division in December of 2000. This was a
> pre-NDA meeting where the results of the safety and efficacy of
> Luveris were shared.
>
> At that point in time, there were no concerns expressed to us by the
> Division and, in fact, a comment was made that we had indeed conducted
> the trial as had been requested, and that would be viewed favorably.
>
> Given that, we proceeded to submit the NDA in April of 2001.
>
> \[Slide.\]
>
> In March of 2002, we received a Not Approvable letter, which indicated
> that we had not provided sufficient evidence to support the efficacy
> of the 75 IU/day dose, and the Division had requested that we conduct
> another Phase III confirmatory trial.
>
> In this instance, the request was that the trial again be efficacy
> versus placebo, as in the previous trial, that the indication be for
> ovulation induction using P4, and that this also be a dose-ranging
> study which would include a placebo arm, the proposed 75 IU/day dose,
> and another dose, lower dose, either 50 or 25 IU/day.
>
> Following the receipt of the Not Approvable letter, Serono requested a
> Type A meeting in order to hear from the agency the concerns with
> regard to approvability, and one of the concerns which we will speak
> to today, although prospectively defined in the protocol, was told the
> fact that cycle cancellation due to risk of OHSS should be considered
> an efficacy failure.
>
> In January of 2003, we met with the agency again to talk about what
> possibilities there were for us to provide any additional information
> to help clarify the concerns. At that point in time, the Division
> agreed and we agreed, mutually agreed that it would be prudent to
> bring the information for Luveris before an Advisory Committee.
>
> \[Slide.\]
>
> One thing I would like to take note of, which happened subsequent to
> the review, is that in April of 2003, as discussed with the agency, we
> amended our NDA to include additional results from an extension study.
>
> The extension study, 21415, was a follow-on to the original pivotal
> trial, and this was intended to provide an additional three cycles of
> treatment to patients in order to allow them the opportunity to become
> pregnant and to gather additional data in terms of safety, efficacy,
> and pregnancy.
>
> \[Slide.\]
>
> A few of the topics that we would like you to consider in your
> discussions today.
>
> Is there a need for recombinant luteinizing hormone? We believe that
> some of the speakers that presented yesterday, as well as speakers
> that will present in just a moment, will clearly indicate that there
> indeed is a need for recombinant luteinizing hormone in treatment of
> these patients.
>
> Has the appropriate patient population been defined? Some initial
> discussion has taken place earlier today on that.
>
> Has a safe and effective dose been identified? Specifically, the 75
> IU/day dose. Dr. Lammers will share that we indeed believe that the 75
> IU/day dose is the effective and appropriate dose for these patients.
>
> Is the composite primary endpoint of follicular development an
> appropriate endpoint to assess efficacy in this specific patient
> population?
>
> \[Slide.\]
>
> Further, to consideration of the efficacy endpoint, again, how should
> one consider in terms of analyses cancellation of cycles and also
> pregnancy?
>
> Finally, do the data that will be shared with you today in terms of
> safety and efficacy support Luveris to be approved in this proposed
> indication, and should another Phase III, double-blind
> placebo-controlled clinical trial be required in order to grant
> approval of Luveris?
>
> Certainly, although not first and foremost in these considerations, it
> is important to note specifically with regard to this patient, given
> the rarity of the condition and the amount of time that each of our
> previous clinical trials have taken to conduct, that we would estimate
> that to do a trial as requested, using ovulation rates and the three
> arms double-blinded, placebo-controlled, is estimated to take an
> additional 195 patients.
>
> We estimate it would take at least five years to complete that trial.
>
> \[Slide.\]
>
> As I close, I would like to share with you the names of some of our
> external consultants who are here with us today. Although some of
> those folks may not be speaking, they are available to respond to
> questions that you may have.
>
> First, Dr. Sarah Berga from Emory University School of Medicine.
> Michael Diamond from Wayne State University in Detroit, Michigan. Dr.
> Gary Koch, who is our statistical consultant.
>
> \[Slide.\]
>
> Dr. Bert Spilker. Dr. Bert Spilker is co-founder and former President
> of Orphan Medical, and has extensive experience in the development and
> commercialization of drugs intended to treat rare conditions and
> diseases.
>
> Dr. Nanette Santoro, Professor and Director, Division of Reproductive
> Endocrinology at Albert Einstein College of Medicine.
>
> Jerome Strauss from the University of Pennsylvania.
>
> I would also like to take this opportunity to note that both Drs.
> Berga and Santoro were clinical investigators during our clinical
> development program for Luveris. Both have extensive experience in
> treatment of HH women including those who are profoundly LH deficient.
>
> With that, I would like to invite Dr. Strauss.
>
> **Need for and Role of LH in HH Women**
>
> **with Profound Gonadotropin Deficiency**
>
> DR. STRAUSS: Thank you.
>
> We heard two excellent presentations this morning that are relevant to
> the issue of the patient population for which the sponsor is seeking
> approval of its drug, and I would like to share some additional
> thoughts regarding the role of LH in follicular development and why it
> is needed in the treatment of infertility with women who have profound
> gonadotropin deficiency.
>
> \[Slide.\]
>
> I want to touch on the heterogeneity, the pathophysiology of this
> disorder, and the significance of that to clinical management, the
> consequences of profound LH deficiency, briefly on our current
> therapeutic options, and then some comments on the unmet medical need.
>
> \[Slide.\]
>
> As we heard this morning, HH can be caused by disorders in the central
> nervous system, hypothalamus, pituitary, or both the hypothalamus and
> the pituitary gland.
>
> \[Slide.\]
>
> It was mentioned that this is a very rare disorder and it\'s
> heterogeneous. Let me share a vignette with you that relates to the
> rarity of the condition.
>
> The University of Pennsylvania was a participant in the sponsor\'s
> confirmatory trial 21008. We have nine reproductive endocrinologists
> on staff who have 18- to 20,000 patient contacts per year, and even
> with that volume, we were only able to identify a single patient to
> participate in that trial. It basically says these individuals are as
> rare as hen\'s teeth.
>
> I would also like to point that Dr. Layman, in his excellent
> discussion of HH, didn\'t specifically point out that there is a
> significant sex difference in the occurrence of this disorder. He
> talked about some significant numbers of patients, but you have to
> recognize that HH is five times more common in males than females.
>
> Heterogeneity was touched upon by the two previous speakers, and that
> is important with respect to clinical management. It can span from
> pan-hypopituitarism, and those individuals may require gonadotropins
> and additional treatment, such as growth hormone, to achieve
> follicular development and to pregnancy.
>
> There is the isolated severe gonadotropin deficiency, which we are
> going to discuss a little bit later in greater detail, and moderate
> impairment, which may be treated with, for example, FSH alone.
>
> But it is the severe gonadotropin-deficient patient which is the topic
> of today.
>
> \[Slide.\]
>
> How do we identify these patients? That has been touched on earlier.
> First of all, we have to recognize that these patients have very low
> gonadotropin levels, low FSH, very low LH, and they are also
> chronically hypoestrogenemic.
>
> So, to capture the diagnosis, we have to use clinical judgment and
> oftentimes the history and physical examination is terribly
> informative, but there are some biochemical and functional tests that
> can be used to identify the patients who will indeed benefit from LH
> in addition to FSH in their therapy.
>
> One mechanism to do that is to measure LH, and as was mentioned
> earlier today, an LH level of less than 1.2 IU/liter it a very
> reasonable index of the patients who will require LH in their
> treatment. That comes from literature.
>
> One citation, which was in your briefing document from Shoham et al.,
> demonstrated that patients whose LH levels are 1.2 IU/liter or less do
> benefit from the addition of an LH activity in their follicular
> development stimulation protocol.
>
> There are other papers with smaller numbers of patients that also
> confirm this, and indeed the sponsor has used that cutoff value in
> their clinical trials and confirmed the value of LH, as they will show
> you, in that patient population with that LH level.
>
> I should also point out that these different studies that I have just
> mentioned relied upon different LH assays, so there is some robustness
> in the cutoff value.
>
> The hypoestrogenemia can be identified by an endocrine measurement,
> and I would suggest an estradiol level of less than 30 picograms/ml,
> or a functional test, the progestin withdrawal test, and Dr.
> Montgomery Rice appropriately pointed out that that functional test
> has some warts, particularly when it is used as a primary diagnostic
> criteria, for example, the old WHO group I definition, but in the
> context of a patient with low LH levels, it does document chronic
> hypoestrogenemic state.
>
> Now, I don\'t think this is news to anyone in this room who practices
> reproductive endocrinology, indeed, if we look at the ASRM Technical
> Bulletin on Follicular Development and Ovulation Induction, it is
> recommended that patients with low gonadotropin levels be treated with
> a preparation that contains LH activity.
>
> I should point out that the citation that is used to support that
> suggestion was a paper that I wrote with Michael Steinkampf \[ph\],
> and at the time when that paper was written, we were basing that
> concept recommendation on experience and the existing clinical
> literature at the time, because there were no randomized,
> placebo-controlled trials to establish that point.
>
> As you will hear today, we now have that information which does
> indicate that in those individuals who are severely gonadotropin
> deficient, the addition of LH is indeed beneficial.
>
> \[Slide.\]
>
> Now, what are the consequences of profound LH deficiency, why is LH
> needed? To answer that question, we have to address, first, what are
> the roles of LH in follicular development, follicular function.
>
> As Dr. Liu mentioned to you, LH is important for stimulating
> follicular steroidogenesis. It promotes the production of androgens,
> which are then aromatized in the granulosa cells to estradiol, and
> that estradiol has important effects, not only on the central nervous
> system, as we heard today, it is critical for programming the
> reproductive tract, and that is important because you need to have an
> appropriately developed endometrium if you are going to achieve a
> pregnancy.
>
> LH also synergizes with FSH in follicular development, as was
> mentioned, and indeed it can support the terminal differentiation of
> the follicle even in the absence of FSH. FSH is the main driver, but
> LH is clearly synergistic.
>
> LH also promoted ovulation, which involves several steps. It is the
> resumption of meiosis, the actual release of the egg, and, of course,
> luteinization of the granulosa cells and the theca cells in the
> formation of a corpus luteum, and LH is necessary for the maintenance
> of corpus luteum function.
>
> \[Slide.\]
>
> Now, in thinking about endpoints for assessing the action of LH, one
> would like to capture all of the activities of LH in the follicular
> development process, and indeed clinically that is done. We measure
> estradiol levels, an assessment of the steroidogenic activity, we
> monitor follicular growth by ultrasound, and we assess progesterone as
> an index of ovulation.
>
> I should point out, however, that in the HH population that is
> severely gonadotropin deficient, exogenous progesterone is clinically,
> usually administered soon after the administration of hCG because
> those individuals will not be able to sustain appropriate luteal phase
> progesterone levels in the absence of either some gonadotropic factor
> or exogenous progesterone.
>
> \[Slide.\]
>
> Let me just briefly go over some of the important roles of LH and
> follicular function. Jim Liu showed us this, that LH acts on theca
> cells to stimulate androgen production, androstenedione, a touch of
> testosterone, goes into the granulosa cell compartment where FSH is
> acted on granulosa cells to stimulate the aromatase expression, which
> converts that androgen into estradiol.
>
> \[Slide.\]
>
> Now, there are several prismatic examples that I can show you of the
> essential role of LH in this process. One way of look at this is to
> take a look at ovaries that cannot respond to LH, and that has been
> studied in a mouse model. Indeed, there are humans who share mutations
> in the LH receptor, who have a similar phenotype, but this is
> dramatically shown here.
>
> Here we have a mouse who has no LH receptor, so it cannot recognize LH
> action on the ovary. This is the uterus, it\'s hypoplastic, and it\'s
> hypoplastic because of the absence of estrogen compared to the Wild
> Type animal.
>
> If we look at the ovaries of this animal, there is some follicular
> development, but only to the early antral stage, and indeed if we look
> at higher power, we see these antral follicles, but no corpora lutea,
> the animals can\'t ovulate, they can\'t luteinize. Here, in the Wild
> Type, we see multiple corpora lutea.
>
> \[Slide.\]
>
> Now, as I mentioned, this is a phenotype that is also seen in humans,
> the rare humans with homozygous mutations in the LH receptor.
>
> Clinical experimentation validates, which I have just shown you, in
> animals and humans. Here we have a severely gonadotropic-deficient
> patient who has been treated with recombinant FSH alone, each one of
> these green bars representing a 75 IU vial.
>
> What you see here is that exogenous FSH accumulates in the patient\'s
> blood, and there is follicular expansion, follicular growth, because
> that is the primary action of FSH, and the ovals here show the
> follicular size by ultrasound, and you can see that you get a follicle
> or follicles that reach the pre-ovulatory size.
>
> However, in the absence of LH in these individuals, estradiol levels
> remain virtually unchanged. Importantly, they are below the threshold
> level that we know that is essential for stimulating endometrial
> proliferation. That is about 100 picograms of estradiol per ml.
>
> Indeed, if you look at the endometrial thickness by ultrasound, it
> doesn\'t change, and it remains below about 6 millimeters in diameter,
> and that is a threshold level which one wants to achieve to have a
> permissive, a receptive uterine environment.
>
> \[Slide.\]
>
> I am going to take the same type of patient and do the experiment now,
> not only with recombinant FSH, but adding back recombinant LH, and
> what you see here is yes, FSH levels increase, there is follicular
> growth, follicular expansion, but more importantly, we now have
> estrogen production, a consequence of adding LH to the stimulation
> protocol.
>
> More importantly, now we have an appropriate endometrial response,
> endometrial proliferation that would be consistent with an environment
> that could support implantation. Indeed, if one wants to achieve
> pregnancy, one has to consider that, as well, in addition to the
> growth of the follicle.
>
> \[Slide.\]
>
> Now, there are some subtleties to the actions of LH, and Dr. Toner
> referred to this as the \"Goldilock\'s Principle\" yesterday. I prefer
> to think about this in terms of a window, but we are talking about the
> same thing.
>
> There is a level of LH that supports normal follicular growth, normal
> androgen production and therefore normal estrogen production, and
> normal oocyte maturation.
>
> If the LH level is below that threshold, and I think that is clearly
> characteristic of those patients who are apulsatile in terms of their
> LH secretion, 1.2 IU or less LH, there is impaired follicular growth,
> inadequate estrogen production, therefore, inadequate support for the
> endometrium, and also there is evidence for impaired oocyte
> maturation.
>
> There may be a ceiling, and Dr. Toner mentioned this, over which
> additional LH does you no good and may, in fact, do some harm. That is
> a result of suppression of granulosa cell proliferation because LH
> causes granulosa cells to differentiate.
>
> There may be promotion of follicular atresia of non-dominant
> follicles, and that actually could turn out to be a good thing, but
> premature luteinization of the pre-ovulatory follicular, an impairment
> of oocyte development are not good.
>
> So, we want to be in the right zone in terms of the therapeutic window
> for LH administration.
>
> \[Slide.\]
>
> What are our current options for the treatment of HH? That was touched
> upon earlier today. We talked about gonadotropin-releasing hormone can
> be used in women with an intact pituitary. Unfortunately, it is not
> available.
>
> Gonadotropins. Gonadotropins containing both FSH and LH activity,
> human menopausal gonadotropins have been used to treat these women in
> mostly very small and uncontrolled studies. The virtue of gonadotropin
> therapy is that it can be used in women with lesions either in the
> hypothalamus or the pituitary gland, but as we have heard yesterday,
> gonadotropin therapies do have some drawbacks.
>
> In the case of hMG, there is a fixed ratio of LH and FSH activity in a
> single file. What that does is it compromises the capacity of the
> treating physician to individualize or titrate gonadotropin treatments
> in these patients, and I know Dr. Santoro is going to touch on this
> when she speaks to you.
>
> There are some risks of gonadotropin therapy, were mentioned
> yesterday - ovarian hyperstimulation syndrome, but I would just leave
> you with the thought, and this is an important one from my
> perspective, that in treating women with HH, if you get a response
> even though it\'s an exuberant response and may cause you to cancel a
> cycle, you know that that patient is capable of responding to your
> therapy, and you can use that information to readjust your protocol in
> a subsequent cycle.
>
> Multiple gestations, a concern. Hopefully, with improved titration of
> gonadotropin therapy, that can be avoided.
>
> \[Slide.\]
>
> Now, what are the unmet medical needs? As you know, in the United
> States, there is no FDA-approved LH-only treatment for the profoundly
> LH-deficient patient, and what that does is compromise treatment, I
> believe, in terms of the individualization, the titration of
> gonadotropins, which is important to the success of the outcome.
>
> The product before you today is a recombinant product that has some
> distinct advantages to both the clinician and the patient, first of
> all, with respect to purity and consistency, one is not dosing
> patients with material that has been assayed by a bioassay with a
> significant coefficient of variation.
>
> There is great assurance that each vial contains the same activity,
> and, of course, these gonadotropin preparations could be administered
> subcutaneously, which as we heard yesterday, is a distinct advantage
> to the patient.
>
> \[Slide.\]
>
> So, in conclusion, I think there is compelling evidence that LH is
> required for follicular competency, some threshold level with LH.
>
> We talked about HH as a very rare disorder and it is heterogeneous and
> it is appropriate to identify the subgroups of patients within the HH
> broad category who are going to require a specific therapy and, in
> this case, combined gonadotropin therapy.
>
> The evidence that you will hear today and that I have presented
> briefly is that the profoundly HH-deficient woman will required
> exogenous LH for normal follicular function, and again, for the
> benefit of both the clinician and the patient, the ability to optimize
> therapy by individualization and titration of gonadotropins is
> paramount for successful treatment of these individuals.
>
> I will now turn the podium over to Dr. Paul Lammers, who is the Chief
> Medical Officer of Serono, to discuss the clinical development program
> with you.
>
> **Luveris Clinical Development Program**
>
> DR. LAMMERS: Thank you, Dr. Strauss.
>
> Madam Chairman, members of the committee, I appreciate the opportunity
> to me today to provide with you an overview of the most pertinent data
> that we have assembled at Serono over the past 10 years on recombinant
> LH or Luveris.
>
> \[Slide.\]
>
> What I would like to do for you is provide you a brief overview of the
> clinical development program and go over some of the considerations
> that went into the study design and in the treatment, and also explain
> how we came to our definition of treatment effect and the study
> endpoints that we used in our studies.
>
> Then, discuss the results on the dose finding study on the efficacy
> confirmatory trial 21008 with its extension study 21415.
>
> Finally, provide a real brief, one-slide summary of safety, and then
> end with some overall conclusions.
>
> \[Slide.\]
>
> This table is also provided in the briefing package that you have
> received, summarizes the six studies that are totally included in this
> development program.
>
> They are summarized here in two different groups. The top four
> basically identify those studies that included the profoundly
> LH-deficient patients that are defined by an LH level of below 1.2.
>
> The two bottom ones, 6905 and 8297, are two studies with a more
> broader hypo/hypo population, and therefore present a different
> patient population.
>
> I just want to bring your attention to this column here, Number of
> Patients. If you look in the literature on hypo/hypo, most case
> series, or the few that have been published, perhaps include eight or
> nine patients.
>
> Here, you can see that Serono truly has assembled the largest database
> so far on women with hypo/hypo.
>
> \[Slide.\]
>
> Now, when I show you results, we are back in time, but I would like to
> take you back at the beginning of this program and just briefly
> mention the challenges that any company has when you embark on a new
> clinical development program for a new product, especially in such a
> rare orphan population as hypo/hypo.
>
> The issues at hand were that what we were faced with had an impact
> both on our study design and also how these patients were going to be
> treated as part of the study protocols.
>
> First of all, our intent was to try to identify a clear dose response
> in our study. Obviously, since these products are given together, so
> we have LH that has been added to FSH, which means you have two active
> products, however, we wanted to focus on the effect of LH alone.
>
> That is why we fixed the dose of FSH in these cycles, which is
> contrary to what clinicians do in practice where they tailor the dose
> of FSH to the individual patient\'s response, but we did want to have
> the potential confounding effect of a change in FSH dose. That is why
> we fixed the dose.
>
> At the time that we started, there was very limited information on
> these patient populations, so we didn\'t quite know how these patients
> would respond to treatment. We did want to ensure that we had adequate
> follicular growth and therefore we fixed the dose of FSH at 150
> IU/day.
>
> However, because of the fact that we had this fixed dose of FSH,
> without the possibility of down titrate in case a patient showed an
> exaggerated response, the investigators supposed the fact that we
> would put more conservative criteria in place in the protocols to
> cancel a cycle in case there was an over-response and there was a risk
> of potentially developing OHSS if treatment would continue.
>
> \[Slide.\]
>
> The primary endpoint that we used in our study is a composite endpoint
> that truly captures, as Dr. Strauss showed you, the different actions
> of LH on the growing follicle. It works with FSH and follicle growth.
> We use a cutoff for a normal pre-ovulatory size lead follicle of 17 mm
> or greater. It works to support steroidogenesis and therefore we
> measure E~2~.
>
> We used a cutoff of 400 pmol/L in the European study, which we then
> consistently also used in the U.S. studies, but now it was converted
> back to picograms/ml, which gives you this somewhat odd number of 109
> pg/ml, but it stems from the conversion.
>
> This level represents the lower limit of normal and it is adequate for
> endometrial growth, as Dr. Strauss just mentioned.
>
> Finally, the contribution of LH to corpus luteum competence after
> administration of hCG. We used 25 nmol/L in Study 6253, the European
> study, which was similarly converted back to U.S. standard of 7.9
> ng/ml.
>
> FDA indicated to us they like to see the 10 ng/ml cutoff, however,
> since none of the patients in any of our studies had a level in
> between the two, whether we take the 7.9 or the 10 ng/ml doesn\'t
> change the outcome of our results and clearly both of those, the 7.9
> and the 10 are clearly above the threshold for normal ovulating women
> of 6 ng/mL.
>
> \[Slide.\]
>
> The way we defined success in our protocols is really critical and
> pertinent to the discussion today. I just showed you the three
> parameters of our composite endpoint of follicular development,
> however, if the patient did not meet all three criteria, as an
> example, if hCG was withheld, but she went on, then, pregnancy was
> always considered an important endpoint.
>
> So, if she didn\'t meet all three, however, if the patient became
> pregnant, that obviously was a success because ultimately, that is the
> ultimate outcome of these studies.
>
> If the cycle was canceled for risk of potentially developing OHSS, it
> also was considered a success since, as Dr. Strauss mentioned, an
> ovarian response in these women, especially women with primary
> amenorrhea who may never have had any ovarian response, it is a
> positive sign, and, in fact, provides a measure of titrating the dose
> in subsequent cycles of treatment, so this is a good sign for
> clinicians and for the patients because it may set the tone for the
> next cycle.
>
> Looking here at the cutoff values, Dr. Keefe presented yesterday an
> E~2~ in a controlled ovarian hyperstimulation scenario of 3,500 pg/ml.
> Obviously, for ovulation induction is lower. In clinical practice,
> people use 2,000 or 2,500 as a cutoff.
>
> We were more conservative and set at 1,100. Again, the reason is that
> we had a fixed dose of FSH that could not be down-titrated.
>
> \[Slide.\]
>
> The key secondary efficacy endpoints that were used in the study were
> estradiol level per se, endometrial thickness, and pregnancy rate.
>
> \[Slide.\]
>
> Turning then to the results of our dose finding studies.
>
> \[Slide.\]
>
> Study 6253 was the first study conducted as part of this development
> program. It was a controlled, parallel-designed, open-label,
> randomized, 3-cycle, dose-finding study conducted in Europe and Israel
> between 1993 and 1995, an enrolled 36 subjects in four countries.
>
> We used a standard dose-finding approach. As I mentioned, we fixed the
> dose of FSH at 150 IU/day to which we added either no, 25, 75, or 225
> IU of Luveris per day, randomized equally across the first cycle.
>
> The protocol pre-specified that Armitage trend test to detect a
> relationship between the LH dose and follicular development in the
> first cycle, and was adequately powered at 85 percent.
>
> \[Slide.\]
>
> The clinical entry criteria used for Study 6253 was the patients
> needed to have clinic amenorrhea of six months or longer, combined
> with low gonadotropin levels as indicated by an LH below 1.2, an FSH
> below 5 IU/L, truly profoundly gonadotropin-deficient patients.
>
> Also, they needed to have a negative progestin challenge test as an
> indication of chronic low estrogenic status.
>
> Treatment duration was up to 14 days with the proviso if at day 14,
> there was signs of follicular development, treatment was allowed to
> continue.
>
> We analyzed our primary and secondary endpoints based on Cycle 1
> information, however, pregnancy was evaluated across all three cycles.
>
> \[Slide.\]
>
> It is important again to realize, going back to Dr. Layman and Dr.
> Liu\'s presentations this morning, the sometimes severe pathologies
> and underlying deficiencies in these patients.
>
> The 38 patients included in 6253, as you can see here, the breakdown
> into either primary or secondary amenorrhea, there were 28 patients
> with primary and 10 patients with secondary amenorrhea included in the
> study, and again the underlying deficiencies clearly showed that these
> deficiencies truly block these patients\' ability to achieve their
> goal of pregnancy.
>
> \[Slide.\]
>
> If we look at the results for 6253, at first glance you see a clear
> dose-response curve. This trend was high statistically significant. If
> you take a linear trend or any other reasonable trend, the statistical
> significance is maintained which shows the robustness of this data.
>
> If we look at the individual dose group results, 1 out of 9 patients
> responded to the FSH alone, which is in line with what is reported in
> the literature that about 10 percent of patients could respond to FSH
> treatment alone.
>
> If we look at the 25 IU dose group, 2 out of 8 or 25 percent response,
> which is as you can see about twice as high as the placebo response,
> however, it is not clinically nor statistically different from the
> placebo response.
>
> The steep rise, however, in the dose-response curve occurs at the 75
> IU dose where now 7 out of 11 or 63 percent of patients respond to
> this treatment with the 75. This is four to five times high response
> than placebo and two to three times higher than observed for the 25 IU
> dose.
>
> Tripling the dose from 75 to 225 IU of Luveris only adds a marginal
> incremental benefit in terms of follicular development. So, it seems
> almost that we are topping off here in terms of the dose-response
> curve.
>
> \[Slide.\]
>
> The design of 6253 allowed us to also look at the individual dose
> groups, at how patients individually responded if they were treated
> with different levels of Luveris.
>
> This slide gives an example of this. There were 10 patients who, in
> Cycle 1, participated in the 225 IU dose group. Out of these 10
> patients, 2 patients showed no follicular development, 5 out of 10 had
> adequate follicular development and went on to receive hCG, 3 patients
> had an over-response, therefore, their cycles were canceled due to
> risk of potentially developing OHSS.
>
> These 5 responders, adequate response, were then in Cycle 2 treated
> with the 25 IU dose, and then only 1 out of these same 5 patients
> responded. Out of these 4 who didn\'t respond, 3 went on to
> participate in Cycle 3, were given the 75 IU dose, and now all 3
> patients responded.
>
> So, it clearly shows that in order to have an adequate follicular
> development, they need to be at the 75 or 225 IU dose, however, as I
> showed you in the previous slide, the 225 doesn\'t add that much more.
>
> Also, it is important to know that in the first cycle, 1 out of 5
> patients respond on 25, here again we see the same thing on the 25 IU
> dose. Only 1 out of 5 patients responded.
>
> \[Slide.\]
>
> If we look at the secondary efficacy parameters in the study, if we
> look at the estradiol levels, you can see again a clear dose response
> where both the 75 and 225 IU dose clearly surpass the important mark
> of 109 to 100 pg/ml that Dr. Strauss indicated that is required for
> endometrial growth.
>
> Again, here we see no difference between the 25 and the placebo dose
> groups.
>
> This is then translated in an adequate endometrial response on the 75
> and 225 IU dose groups, with 75 showing numerically the highest
> response in endometrial thickness. Both of those, however, are above
> the 6 mm endometrial thickness that Dr. Strauss indicated is required,
> is ideal for early embryo implantation of pregnancy.
>
> \[Slide.\]
>
> Moving then to our second study, Study 6905. This was a controlled,
> parallel-designed, open-label, randomized, 3-cycle, dose-finding study
> conducted in the U.S. between 1994 and 1997, and included 40 subjects
> enrolled at 14 centers.
>
> Dose groups, again, we used 150 fixed dose of FSH combined again with
> 0, 25, 75, and 225 IU dose of Luveris again randomized equally across
> the first cycle.
>
> \[Slide.\]
>
> Apart from the fact that the clinical criterion of amenorrhea was
> similar, there are some major differences with the design compared to
> Study 6253.
>
> First of all, as Ms. Williamson already indicated, the entry criteria
> for the LH and FSH were relaxed to try to facilitate patient
> enrollment, and we ended up with an LH cutoff of below 13 IU/L instead
> of 1.2, and FSH lower than 11 instead of lower than 5.
>
> Also, there was no requirement for a progestin challenge test, so
> therefore, there was no real indication whether these patients truly
> had a chronic low estrogenic status.
>
> Finally, treatment duration was allowed to be up to 21 days instead of
> 14 days, with the same proviso if at day 21 there were signs of
> development, she was allowed to continue the treatment.
>
> \[Slide.\]
>
> If we look at the results of 6905, it is obvious at first glance there
> is no dose response across the studies, also, there is no different
> change between the four different dose groups, and the only conclusion
> we can take from this study, there is no benefit of adding Luveris to
> this broader hypo/hypo patient population.
>
> \[Slide.\]
>
> So, at this point in our development program for Luveris, we had
> completed two dose-finding studies. Study 6253, in the profoundly
> LH-deficient patient population, where we have shown a benefit of LH,
> and Study 6905, broad hypo/hypo population, LH above 1.2, no
> additional benefit.
>
> The results of these two studies were not contradictory, but truly we
> have shown what we have included two different patient populations
> with two different responses.
>
> After meeting with the agency, as was mentioned already, agency
> requested for us to conduct a confirmatory Phase III trial in which we
> decided to include the same cutoff level for LH because we have shown,
> in 6253, that that is the patient population that truly benefits from
> Luveris.
>
> The reason that we selected the 75 IU dose therefore was based on our
> Study 6253, where we had shown that the 25 IU dose was not clinically
> nor statistically different from the zero IU, and we had shown the 75
> percent non-response in this dose group.
>
> The 75 IU dose had shown a clinically and statistically different
> response from the zero IU in primary endpoint with a more than 5-fold
> increase in patient response and a primary endpoint of follicular
> development. Also, we saw very clinically meaningful differences in
> secondary endpoints in terms of estradiol response and endometrial
> response.
>
> Finally, the 225 IU dose did not provide additional benefit in
> efficacy compared to the 75 IU dose. So, basically, we can conclude
> that the 75 IU dose is the minimum effective dose that provides the
> maximum therapeutic benefit to these profoundly LH-deficient patients.
>
> \[Slide.\]
>
> Study 21008 was then followed by a rollover study 21415. This was
> designed as a two-phased approach, was already intended from the
> beginning, so we had a placebo, double-blind, placebo-controlled
> trial, one cycle, after which patients were allowed to roll over in
> Study 21415.
>
> \[Slide.\]
>
> Turning then to the results of our confirmatory study 21008.
>
> \[Slide.\]
>
> This is a double-blind, randomized, placebo-controlled, multinational
> study in patients seeking pregnancy. In fact, to date it is the only
> double-blind, placebo-controlled study in hypo/hypo.
>
> We compared placebo, which is now a true placebo, and 75 IU of
> Luveris, again combined with 150 IU of FSH. Again, we want to keep the
> protocol as similar to Study 6253 which would enable us also to look
> for result across studies.
>
> Patients were randomized in a 1 to 2 fashion and again the fixed dose
> of LH and FSH.
>
> \[Slide.\]
>
> The clinical entry criteria were identical as those used for Study
> 6253 and as I mentioned, it was a single cycle of treatment to focus
> on the primary endpoint of follicular development with the possibility
> of rollover in the extension study.
>
> \[Slide.\]
>
> Again, as shown for Study 6253, in the 39 patients enrolled, there was
> a breakdown of about 20 patients in primary amenorrhea and 10 patients
> with\--or it\'s just the other way around\--I think it\'s 20 and 20
> with primary and secondary amenorrhea.
>
> \[Slide.\]
>
> If we looked under results of our primary endpoint of follicular
> development, you can see we get a very consistent response. We see
> again a 4 to 5 times higher response between the 75 and the placebo
> group, which difference is both clinically and also highly
> statistically significant.
>
> We had 2 out of 13 patients responding on placebo compared to 17 out
> of 26 on the 75 IU dose group, and the 65 percent is very close to the
> 63 percent in 6253, and the 15 percent of placebo is very similar to
> the 11 percent on the zero IU dose in 6253.
>
> \[Slide.\]
>
> Now, after submission of the NDA, FDA indicated to us they felt it was
> inappropriate to count cycles that were canceled due to the risk of
> potentially developing OHSS as successes, and therefore they should
> have been excluded and counted as failures.
>
> If you do that analysis, you get the following results. We still have
> a 3- to 4-fold difference in response between the 75 IU dose group and
> the placebo dose group. This difference maintains a statistical and
> clinical significant difference.
>
> It is important to realize that you see that because of the cycles
> canceled, you see a bit of a drop in the 75 IU dose group, whereas,
> you hardly see a drop\--well, it only goes from 2 patients to 1
> patient on placebo, but this truly indicates if patients do not have
> an ovarian response, there is no reason to cancel their cycle, so that
> is why we see the difference here in the 75 IU dose group, but we
> don\'t see the difference in the placebo dose group, however, it is
> important to realize that the clinical and statistically significant
> difference is maintained.
>
> Now, you may have observed that in the two briefing packages that you
> received, there are differences in how the calculations are done in
> terms of success or failure, and also that translates then to
> different p-values between our analysis and FDA\'s analysis.
>
> I just want to use these next two to three slides to highlight the
> differences.
>
> \[Slide.\]
>
> On the left side you see Serono analysis, on the right side you see
> the agency\'s analysis. The numbers I have just shown you are on the
> left side what we see, but whether we take the cycles canceled as
> success or cycles canceled as failure, we maintain a statistical
> significance.
>
> You see on the agency side, the numbers are slightly different. Here,
> in Dr. Meaker\'s statistical section, she shows this p value, which is
> almost consistent with ours, however, if we look at the cycles
> canceled, the agency has a p value of 0.06, which is just above the
> 0.05 cutoff, but still borderline significant, the difference,
> however, being the fact that the agency did not include a patient who
> achieved pregnancy and therefore should have been included as a
> success.
>
> \[Slide.\]
>
> I just want to bring you back briefly to the protocol definition of
> treatment success. This is an exact quote out of the protocol for
> Study 21008 and 21415. Again, we had the three parameters of
> follicular development. I just want to point your attention to the
> underlined sentence that says, \"Should any patient achieve pregnancy,
> that patient will be counted as having achieved follicular
> development.\"
>
> \[Slide.\]
>
> The patient in the underlined part of this discussion, it was a
> patient who had an adequate follicular development in terms of a lead
> follicle of 20 mm. She easily cleared 7.9 or 10 ng/mL cutoff for P~4~,
> however, E~2~ was just below the 109 pg/mL, therefore, because of
> this, she was not counted as a success on the primary endpoint of
> follicular development.
>
> However, she was given hCG because again it is up to the investigator,
> these E~2~ levels come in later, so if the investigator feels with a
> lead follicle like this, that it was appropriate to give her hCG, and
> a month later she had a positive pregnancy test, which was again
> repeated two days later and again it was clearly positive.
>
> Now, the ultimate outcome of the pregnancies doesn\'t take away from
> the fact that this patient did achieve a positive pregnancy test,
> therefore, she did have clear signs of follicular development and
> ovulation, otherwise, she cannot achieve these levels of hCG and of
> serum pregnancy test. Therefore, she should be included as a success.
>
> \[Slide.\]
>
> Turning then to our rollover study 21415.
>
> \[Slide.\]
>
> If patients participated in 21008 in this one-cycle treatment, and if
> they did not have a serious adverse event, did not have actual ovarian
> hyperstimulation, and did not become pregnant, they were eligible to
> participate in a rollover study.
>
> Here, they were given up to three additional cycles of treatment to
> truly try to achieve their goal of achieving pregnancy. We used a
> consistent primary endpoint, important, however, difference here, they
> were given 75, but now an individualized dose of FSH.
>
> This is really how the drug will be used in clinical practice where
> the dose of FSH will be tailored to the patient\'s individual
> response.
>
> \[Slide.\]
>
> Out of 39 patients who participated in Study 21008, 31 elected to
> participate in the rollover study. These 31 can be broken into two
> separate groups, 11 had been treated in 21008 with placebo, 20 had
> already been treated in 21008 with the 75 IU dose.
>
> \[Slide.\]
>
> If we look at the response in terms of follicular development, this
> graph shows you if you take cycles canceled due to risk of OHSS as
> success, you see that in the first cycle, they have a 67.7 percent
> response, again very consistent with 6253 and 21008.
>
> This goes up, it\'s a cumulative rate, in the second and third cycles
> to 83.9 and 87.1 percent follicular development overall. However, as I
> mentioned, now these patients were allowed, the physicians were
> allowed to titrate the dose of FSH based on their previous cycle
> response, and it is truly shown here that whether you take the cycle
> canceled with risk of OHSS as a success or a failure, there is no
> difference in outcome in the second and third cycles, the numbers are
> identical.
>
> \[Slide.\]
>
> So, allowing individualization of the dose, titrating the dose of FSH
> downwards allows you to mitigate this risk of potentially canceling a
> cycle. So, cycle cancellation due to the risk of OHSS is a normal
> precaution in clinical practice. Ovarian over-response is a treatment
> effect and provides guidance for the next cycle of treatment.
>
> It is important to note that out of 11 patients whose cycles were
> canceled either in the first cycle of 21008 or in the first cycle of
> 21415, 4 out of these patients went on\--because patients can still go
> on in subsequent cycles\--and 4 out of these 11 patients did achieve
> pregnancy.
>
> \[Slide.\]
>
> I mentioned 11 patients that were treated with placebo in 21008 and
> now in 21415 were given 75 IU dose of Luveris for the first time. They
> can be considered what we call the LH-naive patient group.
>
> If you look at their different responses in 21008, only 1 out of these
> 11 had follicular development, she did not become pregnant in Study
> 21008, however, if they were then treated with the 75 IU dose of
> Luveris, 7 out of these same 11 had a response of 63 percent, and 4
> out of these 11 achieved pregnancy.
>
> \[Slide.\]
>
> I know pregnancy is a big part of the discussions yesterday and today,
> and I just want to highlight the pregnancy results that we have
> achieved in this rollover extension study.
>
> Thirty-one patients participated, of which 27 continued to receive
> hCG. In Cycle 1, 11 of these patients achieved pregnancy and 9 in the
> second cycle, overall, for 20 patients out of 27 who received hCG,
> which is a pregnancy rate of 74.1 percent.
>
> \[Slide.\]
>
> If we are looking at clinical pregnancies per se, the numbers are 11
> pregnancies in Cycle 1, 5 in Cycle 2, overall, 16 out of 27 for a 59
> percent clinical pregnancy rate, which is an excellent rate in these
> difficult-to-treat patients.
>
> \[Slide.\]
>
> Looking overall the pregnancy results in our studies, this slide
> summarizes the three studies that are really pertinent to this
> discussion of the profoundly LH-deficient, 6253, 21008, and 21415.
>
> If we look at the results here, you see that out of 22 patients
> treated with placebo or FSH alone, 2 patients achieve a pregnancy, of
> which one was a clinical pregnancy. The 75 IU dose out of 48 patients
> included here, 24 or 50 percent achieved pregnancy, of which 19 or
> 39.6 percent a clinical pregnancy.
>
> \[Slide.\]
>
> In terms of pregnancy outcome, this table summarizes the results. Let
> me just focus on the largest patient group, which is basically the 75
> IU dose group. There were 111 patients in total included in our
> program that were seeking pregnancy treated with the 75 IU dose of
> Luveris.
>
> Out of those 111, 51 achieved a pregnancy, of which 44 were clinical
> pregnancies. These 44 resulted in 35 live births that resulted in 22
> singletons, 12 twins, and 1 triplet, and 1 stillbirth.
>
> \[Slide.\]
>
> Concluding then on efficacy.
>
> \[Slide.\]
>
> Study 6253 provides the rationale for selection of the 75 IU dose of
> Luveris as the appropriate dose for hypo/hypo patients with profound
> LH deficiency as defined with a cutoff of below 1.2.
>
> We have shown there is no benefit of the 25 IU dose, and there is no
> additional benefit for 225 IU dose over the 75 IU dose of Luveris.
>
> Study 21008 is the only double-blind, placebo-controlled study
> conducted in this patient population, which confirmed the efficacy of
> the 75 IU does in this profoundly LH-deficient patient population.
>
> \[Slide.\]
>
> The rollover study 21415 supports the efficacy of the 75 IU dose as
> used in standard clinical practice with individualization of the
> dosing.
>
> We saw a cumulative follicular development rate of 87 percent and a
> cumulative pregnancy rate of 74 percent.
>
> Overall, we had a 50 percent pregnancy rate in profoundly LH-deficient
> women treated with the 75 IU dose of Luveris.
>
> As I mentioned at the beginning, I would only have one slide on safety
> as the Medical Review Officer at the agency indicated in their
> briefing documents the FDA has no concern regarding the safety of
> Luveris, so I just want to summarize this in one slide. However, we
> have also provided in our briefing package quite a bit of information
> on safety and I will be more than happy in the Q and A session should
> you desire to answer any questions about safety.
>
> \[Slide.\]
>
> Basically, as I said in the beginning, Serono has assembled the
> largest safety database in female hypo/hypo patients, 170 patients in
> total, of which 152 received Luveris in a total of 283 cycles.
>
> There was no increase in adverse events when Luveris is
> co-administered with recombinant FSH, compared to recombinant FSH
> alone.
>
> We have seen similar rates of actual OHSS across all dose groups
> including recombinant FSH alone.
>
> Overall, the safety profile of Luveris is comparable to currently
> marketed gonadotropins.
>
> \[Slide.\]
>
> Concluding then overall on our Luveris clinical development program,
> among women with hypo/hypo, a cutoff value of 1.2 IU/L differentiates
> between LH dependence and LH independence.
>
> Follicular development is an appropriate endpoint in this population
> and correlates with pregnancy as is clearly shown in Study 21415, 87
> percent follicular development rate, a 74 percent pregnancy rate.
>
> Canceling a cycle is prudent clinical practice in an over-responding
> patient with follicular development.
>
> Women with profound LH deficiency clearly benefit from the 75 IU dose
> of Luveris.
>
> The safety profile of Luveris is similar to other gonadotropins and is
> not different from treatment with FSH alone.
>
> With that, I would like to invite Dr. Santoro to provide an overview
> of clinical perspective and risk/benefit assessment.
>
> **Clinical Perspective and Risk/Benefit Assessment**
>
> DR. SANTORO: Good morning, Dr. Guidice, and good morning to the panel.
>
> What I would like to do is provide some of the clinical perspective on
> the use of recombinant LH as someone who has been treating patients
> with hypo/hypo and probably has a case series of about 30 such
> patients over 20 years in practice.
>
> \[Slide.\]
>
> Hypogonadotropic hypogonadism, the typical clinical patient that comes
> into the office when it is a severe disorder has primary amenorrhea,
> she is in her teens, she comes in accompanied with her mother, and she
> has a complete absence of pubertal development and amenorrhea.
>
> Both mother and daughter are very worried because they feel that
> something is severely wrong that needs to be addressed and that
> perhaps multiple treatments are needed. It is sort of a white knuckle
> affair in the office.
>
> When I get to tell them on the basis of my history and physical and
> biochemical testing that it\'s a single endocrine factor and that in
> most cases they are solely deficient in gonadotropin-releasing
> hormone, there is quite a bit of relief.
>
> Then, when I tell them their potential to be highly fertile when
> ovarian responsiveness is restored, usually, since my patient is
> teenager, she is not that worried about that, but her mother starts to
> weep with relief that this is the case.
>
> As you saw from Dr. Lammers\' data, the very high fertility rate in
> these patients seems to be a general finding clinically. We do know
> that both gonadotropins, as Dr. Strauss has pointed out, LH in
> addition to FSH are needed to optimally grow follicles in these women,
> and the induction of follicular development is a prelude to fertility,
> and is the therapeutic goal, as a clinician, I cannot guarantee
> pregnancy to my patients, but I can induce follicular development, you
> must have follicular development, it\'s an obligatory step on the way
> to pregnancy.
>
> \[Slide.\]
>
> In follicular maturation, FSH induces early growth of follicles as we
> have seen, and controls the follicle number, and that is an important
> point that has not been emphasized, and I will emphasize that in the
> next slide.
>
> LH provides the estrogen precursors and therefore allows for estradiol
> to be secreted, and is needed for the latter stages of follicle
> growth.
>
> \[Slide.\]
>
> When one gives recombinant FSH only to women with profound LH
> deficiency in hypo/hypo, one sees follicle growth, but no estradiol,
> so with escalating doses of FSH, serum FSH goes up, nothing happens to
> estradiol, as Dr. Strauss showed, but look at what happens to
> follicles.
>
> This is a cohort of growing ovarian follicles, and the follicular size
> and number is large, and that is influenced by FSH. In my training, we
> used to say that FSH loads the gun, because it makes all these
> follicles.
>
> This is important in the evolution of these studies because a
> prospective criterion was to cancel cycles at risk for ovarian
> hyperstimulation syndrome because we had to fix the dose of FSH and we
> knew in advance that some women might get too much.
>
> What you see here is the ovary of a woman who has been stimulated, she
> has three follicles in her single ovary. If she has got three in the
> other ovary, she has already met my criteria to cancel her cycle
> because she would then have a total of six and would be at an
> excessive risk of ovarian hyperstimulation syndrome, which you can see
> a picture of on the right.
>
> This is a smaller ultrasound picture than the one here. These ovaries
> are probably 10 to 15 centimeters in size. There is probably quite a
> bit of acidic fluid in this patient, she is hurting, and she is sick.
> She may be hospitalized and is at risk for even more dreadful problems
> like a pulmonary embolus.
>
> As a clinician involved in a study like this, I would not want to give
> a patient like this hCG because I might create this sort of a problem.
> If I gave hCG, could I obtain a progesterone level of 10? I am pretty
> confident that I would.
>
> Might this patient get pregnant? She might, at a very high pregnancy
> rate, but she might wind up with this, and therefore, ethically, we
> needed to make conservative criteria to withhold hCG under such
> circumstances.
>
> \[Slide.\]
>
> In HH patients, we have to have no gonadotropins, so you have to give
> back what is missing. Since most of these women are solely deficient
> in gonadotropin-releasing hormone, that has been shown in the past to
> be highly effective when the pituitary gland is intact, but, alas, is
> not available in the United States.
>
> Alternatively, exogenous gonadotropins can be given in the form of
> hMG, but there is a fixed ratio in the combination medication. Almost
> all except for one of these has to be given as an IM drug, and that is
> a limitation to treatment.
>
> My patients overwhelmingly prefer sub-Q medications that they can give
> themselves, and our current strategies do not allow for the
> circumstance in which I can fix the dose of LH at 75 IUs, but I might
> have to give less than 75 IUs of FSH. There is currently not a way to
> do that unless both medications were split.
>
> So, the optimal strategy for patients clearly is to have stand-alone
> recombinants that allow the titration and individualization of
> medication that happens in real life reproductive endocrine practice.
>
> \[Slide.\]
>
> LH is permissive and is obligatory for follicle growth in profoundly
> LH-deficient women. I know clinically that I must tailor the FSH dose
> that I give to my patients in a gonadotropin cycle. In fact, my brain
> is the sole source of feedback to my patients\' ovaries when I get the
> estradiol results every day, and once a day is a little too slow
> sometimes.
>
> I may have to go down and I may have to go up. So, I need to be sure
> that I am only changing one thing at a time. It would make it
> impractical to be fiddling with both FSH and LH.
>
> So, in fact, in practice, we do the opposite of what was done in the
> clinical trials. We move the FSH, and I would like to keep that LH
> fixed at an effective dose, so I don\'t have to worry about it, and I
> think Dr. Lammers has shown you enough evidence that the 75 IU dose is
> an adequate one.
>
> This strategy then maximizes the return on the investment that a
> patient and clinician makes in a cycle, which is expensive, which
> involves a great deal of effort, and which sometimes involves a
> learning curve.
>
> \[Slide.\]
>
> The risks and benefits have been briefly touched upon, but the risks
> of LH are those that are the known complications of gonadotropins in
> infertility treatment, and these include ovarian hyperstimulation
> syndrome, which is to be avoided and can in many, but not all, cases
> be avoided by withholding hCG, and the risks of multiple births.
>
> There were other minimal or transient treatment-related adverse
> effects that were generally minor, and the general risks of
> gonadotropins can be mitigated with proper diagnosis and attention to
> dosing and very careful observation of the patient.
>
> \[Slide.\]
>
> The benefits of a stand-alone LH is that optimal folliculogenesis and
> an optimal endocrine profile can be based on individualized treatment.
>
> The convenience of a sub-Q preparation, particularly if it can be
> mixed with the FSH, is that patients can give themselves a single
> daily shot of meds that they can control themselves.
>
> The safety profile of LH is comparable to other gonadotropins that are
> currently on the market, and they are associated with a high pregnancy
> rate particularly in this patient population.
>
> \[Slide.\]
>
> So, to summarize, this is a rare patient group, but in this patient
> group, it is critical to give them LH during the process of
> folliculogenesis.
>
> The provision of recombinant LH to recombinant FSH allows the maximum
> flexibility in the treatment of these patients, which is what we, as
> clinicians, need, and will be much more convenient for patients.
>
> The benefit-to-risk profile is therefore in favor of approving this
> product and making it available to women who have hypo/hypo.
>
> Thank you. I would like to turn over to Ms. Williamson to conclude.
>
> **Summary and Conclusions**
>
> MS. WILLIAMSON JOYCE: Thank you, Dr. Santoro.
>
> \[Slide.\]
>
> As we close our presentation today, I would just like to touch on a
> few of the points that we have shared with you and hoping that we have
> been able to provide some clarifications and have provided some
> additional information.
>
> First and foremost, I believe that the presentations that were made
> both yesterday and then again by Drs. Strauss and Santoro have clearly
> indicated that there is a need for LH in treatment of patients with
> the rare condition of HH, and in particular, those patients that are
> considered to be profoundly LH deficient.
>
> We also believe that based on these data, that the appropriate patient
> population has been identified. Through our clinical trial results as
> shared by Dr. Lammers, we believe that we have identified and studied,
> and have proposed the optimal dose of treatment for these women, which
> is 75 IU/day, and that that dose is both safe and effective.
>
> Importantly, we continue to believe that follicular development is an
> important endpoint in treatment of these patients. This endpoint was
> prospectively defined in our double-blind, placebo-controlled clinical
> trial and is consistent with the endpoints as studied in our earlier
> trials.
>
> We believe that follicular development is the appropriate endpoint and
> provides more information than any other single endpoint because it
> allows you to determine the appropriate action of the drug under
> study, which in this case is LH.
>
> Serono, as Dr. Lammers has indicated, has compiled now the most
> extensive database in studying a recombinant luteinizing hormone in
> hypo/hypo women. These studies have now totaled 170 women overall
> during the last 10 years.
>
> \[Slide.\]
>
> As also mentioned, we have also conducted the largest double-blind,
> placebo-controlled trial in these patients with this rare condition as
> prospectively defined in the protocol that we submitted to the agency.
>
> We believe that this pivotal trial is positive irrespective of whether
> cycle cancellation due to the risk of OHSS is analyzed as an efficacy
> success or as an efficacy failure.
>
> Since the original action, we have also provided additional supportive
> data in our follow-on Study No. 21415, which provided those initial
> patients an additional opportunity to achieve pregnancy in three
> subsequent cycles. We believe that this study has also provided
> important additional supportive evidence in terms of safety, efficacy,
> and pregnancy.
>
> \[Slide.\]
>
> Finally, there is no increase in adverse events compared to placebo
> when administering LH versus FSH alone, and the safety profile is
> similar to that of other gonadotropin drug products which are
> currently approved and on the U.S. market today.
>
> We believe and we hope that we have provided sufficient evidence to
> demonstrate that Luveris is effective in the treatment of these
> infertile women with a profound LH deficiency, and provides for a very
> positive benefit-to-risk profile in support of approving this product.
>
> I would like to thank you very much for your attention today. Our
> presentation went over just for a few minutes, and we would be happy
> to answer any questions that you may have.
>
> DR. GIUDICE: Thank you very much. I would like to thank all of the
> presenters for their very clear presentations. I will now open up the
> discussion for questions from the committee, please.
>
> Dr. Hager.
>
> **Questions from the Committee**
>
> DR. HAGER: For Dr. Lammers. You stated that you have shown
> emphatically, in your own words, that the 75 IU dose was the effective
> dose. Might I just ask how do you not know that 50 IUs is an effective
> dose?
>
> MS. WILLIAMSON JOYCE: Dr. Lammers.
>
> DR. LAMMERS: The selection of 75 IU dose as the dose that provides the
> maximum therapeutic benefit was based on 6253 and then confirmed by
> Study 21008. Although it is true that we have not studied the 50 IU
> dose, Dr. Hager, I think that in our dose-finding Study 6253, we have
> clearly shown that the difference in response between the 25 IU dose
> and the 75 IU dose truly supports the 75 IU as the maximum responding
> dose, also because it really is that part of the curve where you see
> the maximum therapeutic benefit and increase.
>
> Also, I think it is important to realize there is no safety concern
> with Luveris, so therefore, I think it is important to provide the
> patient right away with the maximum or the optimum dose of Luveris,
> which we clearly think have shown this at 75 IU dose.
>
> DR. SANTORO: I just want to point out that dose reductions, the
> difference between 25 and 75 IUs is 50 IUs, which is a fraction of an
> ampule, and those are dose increments that are rarely employed.
>
> So, whether the needle needs to be moved in either direction, I would
> strongly argue in favor of keeping it simple and leaving it at 1 amp
> because we know that worked well, because when one is clinically given
> the medication, I know I have to move my FSH, I want to keep my LH
> fixed.
>
> DR. GIUDICE: Dr. Rice and then Dr. Keefe.
>
> DR. RICE: You didn\'t spend a lot of time on looking at the patients
> in 6905, these patients, that subpopulation who had the LH less than
> 1.2, and believe me, it\'s difficult to look at the data that you all
> submitted versus what the FDA submitted, and make sure we are looking
> at the same tables, so I am trying to make sure of that.
>
> But when I look at the data, if I pull those patients out of 6905, who
> had an LH of less than 1.2, of those five patients, 100 percent of
> them actually have follicular development. It took them on average 20
> days to get to that follicular development with 25 versus an average
> of 10 days of the patients who were given 75, but they still got
> there.
>
> Now, my concern is that the incidence of OHSS, though, in those
> patients receiving 75 IUs was 21.7 percent, and I assume that is using
> your definition of three follicles greater than 15 and/or that
> estradiol level, but when the patients with 25 IUs was, it was only
> 11.8 percent. That seems like a significant jump in my opinion for an
> additional 10 days of treatment.
>
> So, I guess I am not convinced that there is not room in there where
> you could have 25 IU of LH as the dose, and then you increase that
> appropriately, because you clearly show that even when you maintained
> 150 IU of FSH, that you got adequate follicular development at 75 IU
> and some at the 25 IU, so you could titrate up the LH and perhaps be,
> quote, unquote, \"safer,\" as you define OHSS.
>
> MS. WILLIAMSON JOYCE: I think I would like to have Dr. Michael Diamond
> comment on that, but, first, I would just like to clarify. In terms of
> OHSS, are you referring specifically to the risk of OHSS or actual
> OHSS?
>
> DR. RICE: From what I see from the data here, it says 21.7 percent, 20
> of 92 patients across all the population receiving 75 IU experienced
> OHSS as defined in the clinical.
>
> MS. WILLIAMSON JOYCE: Thank you. We will clarify those numbers.
>
> Dr. Diamond.
>
> DR. DIAMOND: I think it\'s important not to confuse the issue of risk
> of ovarian hyperstimulation syndrome with just an exaggerated response
> with actual occurrence of ovarian hyperstimulation syndrome. In fact,
> the incidence of ovarian hyperstimulation syndrome in the patients who
> were treated with Luveris was actually no different than what is
> available for other gonadotropin formulations which have been
> approved.
>
> So, that is I think part of response to your question. The other issue
> is about the patients within 6905 who had the low LH levels. As you
> have correctly identified, there are a subgroup of those patients who
> did respond, but required much longer duration of therapy.
>
> Normally, when we give gonadotropins, as you know, normal duration of
> therapy is going to be 9 days, 10 days, 12 days. Twenty days is much
> longer than we would conventionally give for patients. It requires
> them to come to the office many times for monitoring first thing in
> the morning, disrupting their normal activities, taking them away from
> their work, and so there are lots of patient inconveniences for that.
>
> The other component of that to keep in mind is that among those
> patients, if you had limited it to 14 days of therapy, which is what
> was done in the pivotal trial and which is a more conventional length
> of therapy, among those patients who received 25 IUs of LH in
> combination with the FSH, only 4 out of 5 of them would have gotten
> actually to a point where they had follicular development.
>
> MS. WILLIAMSON JOYCE: We do have that data for you, and I do want to
> clarify that the numbers to which you were referring are not the
> actual OHSS patients. They are the ones that were at risk.
>
> DR. RICE: I am looking at your information now on page 49, and you
> have three patients who had OHSS at 75, and zero patients who
> experienced OHSS at 25. So, there is still a difference, zero compared
> to 4.7 percent, or if you look at it as the FDA looked at it, I guess
> they looked at it by risk, 20-some percent versus 11 percent.
>
> So, the question that comes to mind to me, are we comfortable with the
> fact that we may eliminate our significantly decreased OHSS by using a
> lower dose for a longer period of time versus having a risk of OHSS by
> starting with that higher dose.
>
> DR. LAMMERS: Again, I just want to go back to the fact what Ms.
> Williamson just pointed out. I think we clearly need to differentiate
> between actual occurrence of OHSS, which I can show you in a minute is
> not different between the dose groups, that is one thing, but compared
> to cycle cancellation, again, we had to imply very conservative
> criteria because of the fixed dose of FSH in these studies.
>
> So, therefore, I think we clearly need to differentiate between the
> cycle that was canceled for the risk of potentially developing OHSS,
> it didn\'t mean, as Dr. Santoro said, that she would go on and develop
> OHSS compared to the actual cases.
>
> \[Slide.\]
>
> This slide summarizes the actual cases of OHSS across our studies. As
> you can see here, the number of patients in the top row, out of 118
> patients, 75, if you look at the percentage patients, because, of
> course, we had the highest number of patients and cycles in the 75, if
> you on a percent patient basis or percent of cycles, you can see here
> there is no dose-related increase in their response of actual OHSS.
> This number of 5.9 percent is very much in line what is known for
> other marketed gonadotropins.
>
> So, in terms of OHSS risk, that risk is no different.
>
> DR. RICE: These are people who actually had it.
>
> DR. LAMMERS: Right.
>
> DR. RICE: So, that\'s not risk.
>
> DR. LAMMERS: These are actual. You see in our overall 10-year program,
> there were 11 cases of OHSS, of which there were 7 on the 75 dose, but
> given the number of patients and cycles, this translates in an
> incidence rate, either percentage or cycle, this is very comparable to
> the other dose groups.
>
> DR. RICE: But I want to make clear that what you are showing me is
> incidence of actual occurrence.
>
> DR. LAMMERS: Right.
>
> DR. RICE: And what they are reporting is actual risk, I assume, and I
> am sure they will clarify that with their presentation.
>
> DR. GIUDICE: I would like to also point out that with zero LH and 150
> IUs of FSH, there was a case of severe OHSS, so in thinking of whether
> it is the actual occurrence or the risk of the occurrence, as I read
> the data, we are really looking more towards the fixed FSH as
> problematic for the risks for OHSS.
>
> Are there other questions from the committee? Dr. Keefe and then Dr.
> Emerson.
>
> DR. KEEFE: Just to put this OHSS story in context, I have a question
> for Dr. Santoro.
>
> It seems to me the absence of significant amounts of endogenous LH,
> when you see it coming down the pike, it is pretty easy to manage,
> right, you just don\'t trigger, they don\'t get pregnant and it sort
> of probably melts away? It is probably easier to manage these
> impending OHSS situations than it would be in normal circumstances
> with these patients.
>
> Was that your experience? As long as you saw the gun overloaded, you
> didn\'t pull the trigger?
>
> DR. SANTORO: Exactly. My clinical training was FSH loads the gun, hCG
> pulls the trigger. So, if you have got the loaded gun, you can still
> avoid pulling the trigger, but once you have given that, you can\'t
> take it back.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: Two questions. One, I don\'t know the doses of any of
> these preparations, but is it possible using hMG to titrate this, such
> that hMG, in combination with FSH, would get the appropriate ratio of
> LH and FSH?
>
> If you gave hMG at the appropriate dose for LH, that would be too much
> FSH?
>
> MS. WILLIAMSON JOYCE: Dr. Santoro.
>
> DR. SANTORO: It can be in the following circumstance. HH women, in
> general, are very sensitive to gonadotropins to FSH. They are often
> petite, and you can overdose them with 1 ampule.
>
> So, if I have someone who needs less than 75 IUs, and I can\'t give
> her less than 75 IUs of LH with any currently available
> preparation\--I mean I can\'t give her the 75 IUs, I am sorry. So, if
> I need to give her the 75 IUs of LH on the basis of these studies, but
> she needs a half or 37.5 of FSH, there isn\'t a way for me to do that
> now.
>
> DR. EMERSON: And then the other thing that I would like to return to
> is you presented some data about pregnancy rates in the extension
> trial, and they were not really broken down the way that would be most
> appropriate, which would be by randomization, that we could evaluate
> that entirely by randomization since the people went there, that we
> could still look at those effects and, you know, just some things I
> was trying to pick up was what was the cumulative pregnancy rate by
> randomization group for the extension trial or for both trials
> combined.
>
> Then, I couldn\'t also figure out was this pregnancy rate chemical,
> clinical, live birth, could it be broken down by that.
>
> MS. WILLIAMSON JOYCE: So, as I understand your question, you would be
> interested in understanding the breakdown of the pregnancy rate in the
> extension study based on randomization, and you would also like to
> know specifically whether the pregnancies were early pregnancies,
> clinical, and what the outcome was.
>
> DR. EMERSON: And actually not just the extension study, I would like
> it combined with the original study, as well, per cycle.
>
> MS. WILLIAMSON JOYCE: Fine. I would like to invite Dr. Susan Kenley,
> who is our worldwide director of biostatistics to answer your
> question.
>
> DR. KENLEY: Good morning. There was no randomization in the extension
> study.
>
> DR. EMERSON: Excuse me, there was randomization in the first study,
> and that randomization still holds.
>
> DR. KENLEY: Okay. So, you are interested in the pregnancy rate for the
> 11 patients that were randomized to placebo in the first study and how
> many of them got pregnant in 21415 compared to those randomized to 75.
>
> DR. EMERSON: That\'s correct.
>
> DR. KENLEY: Do we have those numbers? Just to mention\--
>
> DR. EMERSON: I guess another question that I would like to ask is also
> has the FDA reviewed that data.
>
> DR. KENLEY: No, we have not provided a summary of that data. I don\'t
> know if they have done that on their own.
>
> DR. GIUDICE: On page 54 of the gray briefing document from Serono,
> there is a table. Dr. Emerson, does this answer over here?
>
> DR. EMERSON: I don\'t know.
>
> DR. SHAMES: As a point of information, the original application did
> not have this.
>
> DR. KENLEY: Can I make one comment while we are working on that? Dr.
> Lammers showed that in 21415, 4 out of the 11 patient randomized to
> placebo got pregnant in 21415. Since there were 31 patients in that
> study, that means that 20 randomized to 75 went on the 21415, so that
> means that 16 of those obtained pregnancy, and that is a total
> pregnancy rate.
>
> DR. EMERSON: And that is chemical pregnancy, clinical pregnancy, live
> birth?
>
> DR. KENLEY: A total pregnancy rate whether it be early pregnancy or
> later pregnancy.
>
> DR. EMERSON: So, that\'s chemical.
>
> DR. GIUDICE: It sounds like it\'s at least chemical
>
> DR. EMERSON: You don\'t have live births without chemical pregnancy,
> isn\'t that true? Okay. I just wanted to make certain that these were
> hierarchical.
>
> DR. LAMMERS: Dr. Emerson, perhaps I can summarize this.
>
> \[Slide.\]
>
> This table summarizes for Study 21415, the cumulative total and
> clinical pregnancy rate that is mostly determined by a positive
> ultrasound of fetal sac with or without heartbeat. You can see here,
> in Cycle 1, there were 11 out of 31 cumulative became pregnant, and
> they were cumulative basis, and out of these total pregnancies, the
> clinical pregnancy, all 11 were clinical pregnancies.
>
> In the second cycle, 20 out of 31 totals, 16 out of 31 clinical, so
> there were basically 4 biochemicals in here in the second cycle.
>
> In the third cycle, again, we stated that there were no additional
> pregnancies in the third cycle, so basically, you can see here, the
> majority of these pregnancies were clinical pregnancies.
>
> DR. EMERSON: So, there were 4 who were initially randomized to
> placebo\--
>
> DR. LAMMERS: Correct.
>
> DR. EMERSON: \--who in the second or third cycle, I guess first,
> second, or third, were any of those the same? I believe there was one
> pregnancy in the placebo group in the first cycle?
>
> DR. LAMMERS: That is correct.
>
> DR. EMERSON: Were any of those the same patients?
>
> DR. LAMMERS: No.
>
> DR. EMERSON: So, there were a total of 5 in the placebo group.
>
> DR. LAMMERS: Correct.
>
> DR. EMERSON: And then the remainder must be then 16.
>
> DR. LAMMERS: Correct.
>
> DR. EMERSON: And what about the one person in the other group?
>
> DR. LAMMERS: We only had the placebo group and the 75 IU dose group.
>
> DR. EMERSON: But in the first cycle under the randomized trial, there
> was one patient in each group who\--
>
> DR. LAMMERS: No, there were two pregnancies in the 75 IU dose group.
> One was an early, one was a clinical, and there was one pregnancy in
> the placebo group.
>
> DR. EMERSON: So, are those two in addition to the 16 that are in
> 21415?
>
> DR. LAMMERS: Yes, they are.
>
> DR. EMERSON: The point I am trying to make here, for the committee,
> this is exactly the point I was trying to say yesterday, about how to
> analyze these data. Once you have randomized, that randomization
> holds, and so long as you are treating all the rest of the patients
> the same after that point.
>
> I don\'t when the blinding stopped and if the placebo patients were
> unblinded in that second trial, but I am going to act as if they had
> done this in the fashion.
>
> DR. LAMMERS: Right.
>
> DR. EMERSON: It would be perfectly legit to design the study in which
> you did randomized, placebo versus drug, and then after that, took
> everybody and put them on active, and if you saw a difference at that
> point, the only thing that explains it is that absence of therapy in
> that first cycle.
>
> So, if we are seeing differences between the placebo group and the
> treatment group as randomized, as the trial progresses, and if we can
> trust this, you know, lack of blinding and other elements like that,
> that is where there might be any evidence here.
>
> This lack of randomized trial in this extension treatment, if I could
> have three wishes, one of them certainly would be to convince people
> that they are hurting themselves in these extension trials if they
> don\'t continue to gather information about the randomization that
> went forward and that the best way to present this data would be to
> look at that.
>
> We are looking at\--and you already know that I am in favor of live
> births as an endpoint instead of these earlier ones\--but there is
> some evidence of this. It hasn\'t been reviewed by the FDA, I am
> gathering, so, you know, it\'s not there, but this is an important
> point here, and the non-randomized issues are\--
>
> DR. LAMMERS: Dr. Emerson, I just want to point out that, of course, we
> look at the data overall, and I think it is important to note whether
> you look, we see there were far more clinical pregnancies than early
> pregnancies or biochemical pregnancies.
>
> But overall, I think that out of the 111 patients on the 75 IU dose,
> there were more than 50 pregnancies, of which 44 became live birth
> pregnancies, so that live birth rate is an excellent rate in these
> profoundly LH-deficient patients.
>
> DR. EMERSON: Live birth rate is which?
>
> DR. LAMMERS: Out of 44 clinical pregnancies that were established, 35
> became live births.
>
> DR. EMERSON: I am just bringing this up as this is an issue that needs
> to be addressed. I don\'t think that the presentation of the data here
> is, you know, my back of the envelope analysis, I don\'t think is
> adequate. I am just saying that there are these points that need to be
> addressed.
>
> The other issue that I would like to address, though, is\--I said if I
> had three wishes, that that would be one\--the second would be that
> nobody use the word \"clearly\" for any of these data, and that will
> hold on both sides.
>
> This finding the dose, some data was presented that showed in the one
> study where you started out with 10 patients at the 75 dose, and then
> you basically challenged them at 25. I would have to look at this. I
> am sorry, this was of your Cycle 225, where you took the five patients
> who had what you called \"adequate follicular development,\" and then
> dropped them down to 25, and then raised them up to 75. This is Slide
> 44 in your presentation.
>
> Many statements were made about this conclusively shows something. Let
> me put this data in its proper framework. Let\'s just imagine this was
> randomized data, so it\'s not randomized data, there was a lot of
> selection going on here, but we basically had three samples, 5 out of
> 10, 1 out of 5, and 3 out of 3, and all of those are compatible with
> the exact same success rate.
>
> This data is just completely inadequate to make the statements about
> whether the cycle had changed. Do we have any other data that you are
> using to support these statements that reducing the 75 was bad?
>
> MS. WILLIAMSON JOYCE: We didn\'t prospectively design the study to
> demonstrate that.
>
> DR. EMERSON: Thank you.
>
> DR. LAMMERS: I just want to add, Dr. Emerson, that obviously, our
> primary analysis falls in Cycle 1, which I have shown basically in
> Cycle 43, however, if you present this data, clinicians always ask, by
> the way, what happens if you take the patients who didn\'t respond to
> this, and look at the other, if you put them through the other data,
> so this was an example to show if the patients who respond at 225, if
> you bring them to a low dose, only 4 out of these 5 patients did not
> respond.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: I had really just one question regarding the criteria for
> cancellation. The third element allows cancellation for this risk of
> OHSS category, but patients with or without LH treatment could end up
> in that category by virtue of follicle numbers.
>
> You also had an estradiol criterion and I would hope that at least in
> those treated with LH, that you also saw estradiol production, because
> follicle growth per se in any of these groups tells you nothing about
> LH effect, in my opinion. It presents really the FSH component.
>
> I guess I would like confirmation back that, by and large, those who
> got the LH had high estrogens, and those who didn\'t often had low
> estrogens. I mean you still may have one or two in that non-treated
> group, non-supplemented group who had it because their own endogenous
> happened to be high enough.
>
> But I would like sort of a dichotomization of estradiol levels in
> those two groups.
>
> MS. WILLIAMSON JOYCE: Dr. Lammers.
>
> DR. LAMMERS: Dr. Toner, out of the seven cycles that were canceled due
> to risk of potential OHSS, there were four patients who had an E~2~
> above the cutoff. The other three patients were excluded because of
> the number of follicles.
>
> DR. TONER: What groups were they in?
>
> DR. LAMMERS: That was in the Study 21008. That was in the 75 IU dose.
> There were seven cycles canceled in the 75 IU dose, and that is the
> ones I am referring to, so 4 for E~2~, 3 for follicles.
>
> DR. TONER: I understand that, but I wanted to know how that
> intersected with whether they received LH or not. So, you may have to
> look back through your papers.
>
> DR. LAMMERS: There was one patient in the placebo whose cycle was
> canceled, and that was due to the follicle numbers.
>
> DR. TONER: I guess I would have an objection to including them as
> successes if they got LH, but were canceled only because of a number
> of follicles. If they had five follicles, but had no estrogen
> production, and you were calling that a success, I would argue with
> that.
>
> DR. LAMMERS: Okay. Dr. Santoro, would you like to comment on that?
>
> Could you rephrase your question, Dr. Toner, for Dr. Santoro?
>
> DR. TONER: Sure. The thing that drives the cancellation risk for this
> study can be number of follicle only, so you can see that in both the
> LH treated and the LH not treated group.
>
> If we are really asking the question of whether the LH is working like
> we hope it would work, we would expect always to see adequate
> estradiol production in those high-response cycles who were treated
> with LH. I would just like to know that those cycles that got canceled
> on LH treatment also had good estrogen production.
>
> DR. SANTORO: What I can show you, if you can put the previous one on
> with the graph from 6253, I mean I was a 6905 investigator, and I was
> very conservative about canceling people for risk because I think that
> is what you have to do in a clinical trial like this, so we wanted to
> be conservative. So, I would probably have canceled them regardless of
> their E~2~, but there is evidence.
>
> Can I have the slide on.
>
> \[Slide.\]
>
> This slide that Dr. Lammers showed before just shows you there is a
> big difference in the E~2~ levels in the women, and this includes
> women who were canceled for OHSS risk. So, this slide includes all of
> those, and the median, not exactly pre-ovulatory because some of them
> never got hCG, but there is a big difference, it\'s over 10-fold.
>
> So, it is what you would expect physiologically. At time these studies
> were being done, we were sort of learning this, so it was all
> happening at the same time. Prospectively, we were not sure. We
> expected that the cycles without LH would do exactly what you said,
> they would make follicles, but no E~2~, but weren\'t positive that was
> going to happen.
>
> So, just let me put it back in a time capsule into perspective.
>
> DR. TONER: Right. I don\'t know if there is understanding of my
> question and I am having maybe a hard time phrasing it correctly.
>
> I would consider success for this LH product to have been met if a
> cycle was canceled because of large follicle numbers, but only if they
> were also making estrogen. If they were growing follicles and not
> making estrogen, then, I would not want to consider that particular
> effort a success.
>
> MS. WILLIAMSON JOYCE: Given the fact that our endpoint was a composite
> endpoint, and we did not break down those prospectively, what we can
> do is show\--Dr. Kenley can actually share some information with you.
>
> DR. KENLEY: I think I am understanding your question. You are saying
> that you consider some of these ladies that were canceled because of
> risk of OHSS to potentially be successes, others to be failures, and
> the ones that would be successes would have the high estrogen.
>
> We have not analyzed them as such, but we did do a sensitivity
> analysis, and I think it will help to show you that the significance
> is still there when you consider those patients who were canceled due
> to risk of OHSS as a 50 percent chance of responding or 40 percent
> chance, et cetera. We could get the actual analysis for you later on
> today.
>
> Let me just point out that in the distribution of the data, the one
> patient on placebo was canceled because of large follicles. The 6
> people on 75, 2 of them were canceled because of large follicles, 4
> due to high estrogen levels, so let\'s bring this one up.
>
> \[Slide.\]
>
> In that summary, you had 2 of the patients on 75 canceled because of
> follicles, 4 canceled because of estrogen, and 1 on placebo canceled
> because of follicles.
>
> Now, when you look at this, this is where we looked at the risk of
> OHSS as a nebulous type area, not all successes, not all failures, and
> in this analysis, what you see in the middle is when the 1, when it
> says, \"weight of risk of OHSS,\" and it\'s given a weight of 1, that
> means that they are all successes. The 1 means they are all successes,
> and that is where our p value came at 0.006.
>
> The zero means they are all failures, and that is where the p value is
> 0.034 although, say, you give them the 50 percent chance of being a
> success, the p value drops to 0.0064, 25 percent chance of being a
> success. It goes down to 0.01, and then a 10 percent chance of
> actually being a success, we go down to 0.011.
>
> So, given the distribution, I think you can see the study would still
> remain significant if you included half or less of these patients as
> successes.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: It is always easier to look at study designs in
> retrospect than prospectively, and recognizing that, I am not
> convinced that fixing the dose of FSH was the best way to do the
> pivotal study.
>
> Given Dr. Strauss\' physiologic rationale that he mentioned that LH is
> critical regardless of the level of FSH, and given Dr. Santoro\'s
> clinical rationale that the way this is actually going to be used in
> clinical practice is by fixing the dose of LH and then varying your
> dose of FSH, couldn\'t you design a protocol where you have a blinded
> dose, fixed dose of LH or placebo, and then you allow the clinicians
> to titrate the FSH, you should be able to demonstrate your response,
> and that would mirror actually how it is going to be used in practice
> and be more convincing.
>
> So, I guess my question is in a way maybe not fair retrospectively,
> but if you were to do the pivotal study again, wouldn\'t you design it
> that way rather than with the fixed dose of FSH?
>
> MS. WILLIAMSON JOYCE: I would like to have one of our clinicians
> comment on that, but I think it is important to note that in addition
> to the design considerations, the number of patients available to be
> studied in this clinical trial are indeed rare, so I suspect that a
> clinical trial designed in that manner would require a significantly
> larger number of patients in that study.
>
> Dr. Strauss, would you care to comment on that, please?
>
> DR. STRAUSS: The issue here is establishing the efficacy of the active
> agent, and the decision to fix the dose of FSH provided a clear
> opportunity to establish whether the LH dose indeed was biologically
> effective and clinically effective.
>
> The sponsor did do the rollover study which did provide information
> regarding how these drugs would be used in clinical practice, as Dr.
> Santoro pointed out, so, in essence, the combination of 21008 and
> 21415 provides the data that you want, again with the limitations of
> the small sample size that would be available for evaluation.
>
> DR. STANFORD: I guess I would echo Dr. Emerson\'s comment that if the
> rollover had maintained the randomization, that would be a more
> convincing extension, but I guess what I am saying is that that kind
> of design could have avoided this conundrum of risk of OHSS
> cancellation and do you call it a success or a failure, or at least
> minimize it.
>
> I don\'t know if Dr. Emerson has any comments on whether it would
> actually require a larger sample size with a varying FSH. It doesn\'t
> seem to me that it would, but I am not a statistician.
>
> DR. EMERSON: I don\'t see that a different treatment suddenly changes
> what the sample size requirements are to determine an effect, I would
> do the same calculations no matter which. So, if you are saying that
> what was going to be done and what would be more efficacious, would be
> titrating that dose, then, that is what you should be testing.
>
> MS. WILLIAMSON JOYCE: I would suggest that given the fact that that
> would provide for an additional confounding factor, it could lead to a
> different series\--
>
> DR. EMERSON: Again, confounding is protected for by randomization. It
> is not a confounding issue, it\'s a precision issue, that you might
> get more precision by having a very, very controlled population if you
> could manage to do that, but if you can\'t do that, then, you have the
> randomization that is protecting you for everything that happens
> afterwards.
>
> DR. KENLEY: I just want to make sure that this is clarified. Your
> optimal design would be to have patients randomized to placebo in 75
> IU, and stay on those two doses for multiple cycles, stay on placebo
> or stay on 75?
>
> DR. EMERSON: It need not be, to tell you the truth, but that is where
> you would have the most power. You are going to get some attenuation
> of your effect if you allow the crossover, but when you do allow the
> crossover, that doesn\'t change the fact that you are now testing the
> difference between, if you will, delayed administration of the drug
> versus taking it right from the very first cycle.
>
> Again, any difference, and this is dependent upon trusting that there
> wasn\'t selection on who went forward and things like that. Again,
> without the FDA having reviewed the data in this way, I am not saying
> that I can make a judgment on that, but if we pretended that all of
> this went forward, you can design a trial that is delayed
> administration of a treatment, and that is what you are testing.
>
> DR. KENLEY: It is already difficult to recruit for these trials, and I
> think to recruit for a trial where the patient was going to take
> placebo for multiple cycles would make it much more difficult.
>
> DR. GIUDICE: Dr. Santoro. As the hour is coming to a close for
> discussion, we will take a few more questions, and then we will modify
> the program this afternoon, so that the sponsor will have some
> additional time for additional questions from the committee.
>
> Your comments?
>
> DR. SANTORO: There is a saying that the retrospector scope always sees
> 20/20, and while the trial was being constructed, which was a while
> ago, the options seemed to be much more limited in what could be done
> with these patients.
>
> So, patients are improperly named there, inpatient when they have HH
> and they want to get pregnant, and keeping someone in a study,
> maintaining them on a placebo dose of LH, I think would have run into
> issues of feasibility that would have probably made the study undoable
> in my opinion, but you have others on the panel who I think can
> comment on that.
>
> DR. GIUDICE: Yes, Dr. Lipshultz.
>
> DR. LIPSHULTZ: I may have missed this data, but Dr. Santoro was
> talking about how much you like the ability to vary your FSH and keep
> your LH steady.
>
> In the rollover group, I am assuming then that the LH was kept at 75
> and the FSH varied. What was the dose that you needed then to achieve
> those pregnancies with your FSH? Do we have that?
>
> MS. WILLIAMSON JOYCE: Yes, we do, and your first assumption is
> correct, the LH dose was kept constant and the FSH dose was allowed to
> vary.
>
> DR. LIPSHULTZ: What were the doses that achieved efficacy, were they
> down to 25, because Dr. Santoro suggested that she often has to go
> down as low as 25 in these women?
>
> MS. WILLIAMSON JOYCE: I am sorry, I want to clarify that. I am quite
> certain that what Dr. Santoro was saying, that the desire was to
> reduce the FSH dose.
>
> DR. LIPSHULTZ: Right, the FSH.
>
> MS. WILLIAMSON JOYCE: Yes.
>
> DR. LIPSHULTZ: So, what was the FSH used in that rollover group?
>
> MS. WILLIAMSON JOYCE: Dr. Lammers.
>
> DR. LAMMERS: You are correct that the dose of FSH changed. It was part
> of the design of the study.
>
> If I can have the slide on, please.
>
> \[Slide.\]
>
> This table summarizes the FSH dosing, as you requested, Dr. Lipshultz,
> in the 54 cycles included in this rollover study, and you can look
> here.
>
> The average daily dose, if we divide it into 150 or even lower than
> 150, more than 150, you can see the number of cycles, that 30 percent
> that had a lower dose of 150, 68 percent had follicular development,
> and 37 or 6 out of 60 of these patients achieved pregnancy.
>
> In the 150 is 30 percent pregnancy rate, 3 out of 10 patients
> responding. More than 150 dose of FSH, we had a 75 percent follicular
> development with a 39 percent pregnancy rate, or 11 out of 28.
>
> DR. LIPSHULTZ: Yes, but in that less than 150, that you have to go
> below 75, because Dr. Santoro was indicating that her problem with the
> urinary product was that she is stuck with the 75. So, did you go
> below 75 in this less than 150?
>
> DR. LAMMERS: I think we have that data, but it is not summarized. We
> have the data, however, we can provide it to you later.
>
> DR. GIUDICE: Dr. Lewis.
>
> DR. LEWIS: Two things. One, it is very difficult to design a trial to
> treat these patients, and, of course, the way we use gonadotropin in
> clinical practice is to tailor the dose as much as we can to the
> individual patient, so I can respect that it is very tough to design a
> trial to look at what an effective dose would be.
>
> But looking at these data where you do get a delayed response with 25
> in some patients, it does beg the question of whether 50 would work. I
> mean I understand it is hard and these are rare patients, and this is
> expensive, but it is also hard to make a judgment about what the
> effective dose is.
>
> The second comment I would make is that there is another way to
> titrate the LH dosage, and that is with hCG. Clearly, that would be
> off-label, but there are some trials using fixed doses of FSH and then
> small, very small doses of hCG, which acts just like LH and has a
> longer half-life, much less expensive, and, of course, there is a
> recombinant formulation available.
>
> DR. GIUDICE: Does the sponsor want to reply to either of those
> comments?
>
> MS. WILLIAMSON JOYCE: I wasn\'t sure if you had a question for us or
> if you were just commenting on behalf of the committee.
>
> DR. GIUDICE: It has certainly been very instructive to think of
> alternative strategies for alternative protocols, but I would like to
> remind the committee that our responsibility today is to look at the
> protocol and the protocols that have already been conducted and to
> analyze the data that have been provided.
>
> Before we break, there are two burning questions over here from Dr.
> Macones and Dr. Crockett, so please go ahead.
>
> DR. MACONES: This is really more of a comment than a question, and it
> is following up Dr. Toner\'s questions earlier.
>
> Dr. Lammers presented I think a very pivotal slide which compared the
> FDA analysis to the Serono analysis. In the analysis after removing
> the people who were at risk for OHSS, the difference really came down
> to one patient who Serono defined as being a success because she
> achieved a pregnancy, FDA did not.
>
> I think what is interesting, at least as I saw that slide quickly, was
> that the estradiol level in that patient was low, and that is why FDA
> suggested that that was a failure. I think that is consistent with
> what Dr. Toner was saying, that we think that the LH is really working
> based on at least partially through an estradiol level, so whether or
> not you can really count that as a success, again, a chemical
> pregnancy that is implanting into an endometrium that is not ready, I
> really question.
>
> So, it is just a comment more than a question.
>
> MS. WILLIAMSON JOYCE: I just want to note again that that was
> prospectively defined in the protocol and never an issue in our
> discussions with the agency until after the NDA was filed.
>
> DR. GIUDICE: I think it is also important to point out that we should
> be careful about drawing conclusions for the reason why that may not
> have been a successful pregnancy.
>
> Yes, Dr. Crockett.
>
> DR. CROCKETT: Yes, I have a question concerning the health of the
> pregnancies. Yesterday, we heard a lot of discussion about aneuploidy
> and the risk of genetic defects when we superovulate women.
>
> I haven\'t seen any data in my review on the genetic health of the
> pregnancies in this trial, any of these trials, so I would like to
> know from the company about the genetic outcomes, whether they were
> live births, terminations, or fetal losses, what the genetic
> abnormality rates were.
>
> MS. WILLIAMSON JOYCE: Yes, we have those data. What would you like to
> see, the studies specifically, the pivotal trial?
>
> DR. CROCKETT: I would like to see it all.
>
> MS. WILLIAMSON JOYCE: Okay.
>
> DR. GIUDICE: Slide 71, I have been told has the table in it. Then, Dr.
> Lammers, if you would like to make a comment.
>
> DR. LAMMERS: Have we got Slide 71 on?
>
> \[Slide.l\]
>
> DR. LAMMERS: This table summarizes, presented the results of all
> studies included in our Luveris development program, looking at
> patients seeking pregnancy, going on to clinical pregnancy, going on
> to live birth, the number of miscarriages, lost to follow-up, and
> stillbirths.
>
> We do have information, we have tried to obtain information\--I will
> try to show you that in a minute\--on the patients who went on to
> deliver live babies, either the singletons, twins, and triplets that
> you were referring to.
>
> Can I have the next slide on, please.
>
> \[Slide.\]
>
> Again, later, it is always difficult to acquire information, however,
> this is in 6253, where we looked at a patient who had a pregnancy in
> the 225 IU dose group, and basically, the mother confirmed\--this is
> last available data in May of 2000\--that daughter is doing well.
>
> Here, on the 75 IU dose in 6253, also, this patient delivered twins,
> male and female, and mother confirmed that the children are healthy.
>
> Next slide on, please.
>
> \[Slide.\]
>
> If you look at Study 21008, we had the placebo in the 75 dose group,
> we had twins in the placebo, and basically, she delivered two babies,
> small for age, 25 weeks, and they were small weight and birth weight,
> and the 75 was a singleton at 38 weeks, a boy, and also relatively
> lower birth weight.
>
> The next slide.
>
> \[Slide.\]
>
> We are looking at our bigger study 21415, you can see here that most
> of these were delivered at the appropriate time. There was a variation
> between 30 weeks and the highest I think of 42 weeks of pregnancy,
> most, you can see the weights here. There are a few low for birth
> weights babies, but it fits with the gestational age, also here with
> the 30 weeks.
>
> However, the majority of these children are doing well as far as we
> have\--we have tried to obtain follow-up information as we discussed
> yesterday, but it provides issues of lost to follow-up, and people
> also are not willing to provide that kind of information after they
> concluded the study.
>
> Does that answer your question? We didn\'t do any genetic studies that
> you are particularly referring to, as we discussed this morning,
> because we didn\'t do any, you know. Most of the information was not
> available at the time that we did the studies.
>
> DR. CROCKETT: So, am I to assume that in all of the live births that
> you had in your studies, you don\'t have any Down\'s syndrome children
> that you know about or any other genetic defects that happen in the
> normal population?
>
> DR. LAMMERS: No, we do not.
>
> DR. GIUDICE: Thank you.
>
> For the committee, you can leave your books here, and the room in the
> restaurant is still reserved for today, as well. Please, let\'s
> reconvene to keep on schedule at 1 o\'clock when Dr. Slaughter will
> give her presentation.
>
> Thank you.
>
> \[Whereupon, at 12:35 p.m., the proceedings were recessed, to be
> resumed at 1:00 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> \[1:10 p.m.\]
>
> DR. GIUDICE: Since the afternoon agenda is quite tight, we are not
> going to have a formal break, so if people get up to use the
> facilities, please be aware that no one else is going to be offended
> by your exit.
>
> I would like to begin right now with introducing Dr. Slaughter, who is
> the Reproductive Team Leader for the Division of Reproductive and
> Urologic Drug Products at the FDA. She will be speaking on Luveris:
> The FDA Perspective.
>
> **FDA Presentations**
>
> **Luveris: The FDA Perspective**
>
> DR. SLAUGHTER: Good afternoon. I hope you all had a good lunch even
> though it was somewhat rushed. As Dr. Guidice said, I, along with Dr.
> Meaker, will be presenting the FDA perspective on the Luveris Drug
> Development Program.
>
> \[Slide.\]
>
> The NDA indication for Luveris was for concomitant administration with
> recombinant FSH for the induction of ovulation in infertile women with
> severe LH and FSH deficiency.
>
> This, I might mention was actually a second change in the indication
> with the original one being for women with LH and FSH deficiency, and
> as you hear today, the sponsor has now proposed a third indication,
> that we might change to a third indication.
>
> \[Slide.\]
>
> The object of the population is women with hypogonadotropic
> hypogonadism or hypothalamic pituitary failure. The criteria for
> enrollment in the NDA studies has defined subpopulations of
> hypogonadotropic hypogonadal women requiring therapy based on serum
> LH, FSH, and estradiol levels with or without functional evidence of
> endogenous estrogen.
>
> \[Slide.\]
>
> Luveris was granted orphan drug designation on October 7, 1994.
>
> \[Slide.\]
>
> The Orphan Drug Act of 1983 refers to orphan drugs as rare diseases or
> conditions affecting less than 200,000 persons in the United States.
> It confers certain marketing exclusivity.
>
> Orphan products receive no preferential treatment in terms of testing
> and submission requirements, and face the same safety and
> effectiveness criteria and review processes as undesignated products.
>
> \[Slide.\]
>
> As mentioned earlier, the FDA has no concerns with the ultimate safety
> profile as presented in the NDA, so the presentation today will
> discuss efficacy only, focusing on population, endpoints, and how
> these things have changed throughout the drug development process or
> program, and the power of the Phase III study and the dose.
>
> \[Slide.\]
>
> My overview of efficacy will cover the primary studies proposed to
> establish efficacy, FDA requirements to establish efficacy. I will
> examine the regulatory evaluation of Luveris, focusing on the strength
> of the evidence, and will summarize the concerns of the FDA, and
> finally, we will come to the committee with our questions.
>
> \[Slide.\]
>
> Two identical Phase II dose-finding studies were proposed to the FDA
> in 1992, when the company met with the FDA in a pre-IND meeting.
>
> One of those proposed studies, U.S. Study 6905, was submitted to the
> FDA in an IND in 1993. Annual reports to the IND, beginning in 1996,
> identified U.S. Study 6905 as the proposed primary study to support an
> NDA. Remember, initially, there were two identical Phase II
> dose-finding studies proposed.
>
> Study 6253, the study conducted in Europe, the European Phase II
> study, was not submitted to the FDA, and, in fact, the FDA was not
> aware of the data from Study 6253 until we were at the discussions
> just prior to submission of an NDA.
>
> In 1998, this study, 6253, was proposed as the primary study to
> support the NDA.
>
> \[Slide.\]
>
> These studies had different patient populations and efficacy criteria.
> The U.S. Phase II study submitted to the IND, Study 6905, was
> open-label. It enrollment criterion was for an LH less than 5, an FSH
> less than 5, and a negative progesterone challenge test.
>
> This protocol was amended prior to conduct of the study and it changed
> the population to an LH less than 13.3, the progesterone challenge was
> replaced with an estradiol less than 60, and there was a change in the
> FSH requirement.
>
> This, the sponsor did, as you heard before, based on recommendations
> from their own consultants.
>
> Finally, the European Phase II Study was also an open-label study. The
> LH requirement was for a less than 1.2, a negative progesterone
> challenge test was required, an estradiol level was not required.
>
> Additionally, this European trial enrolled volunteers, not necessarily
> seeking to become pregnant. The efficacy criterion that were put forth
> on these Phase II trials was a combined efficacy endpoint taking into
> consideration follicle size, estradiol on the day of hCG, a mid-luteal
> progesterone level.
>
> As you see, these efficacy criteria also varied. In Study 6905, an
> estradiol was to be greater than 200 pg/ml and a mid-luteal
> progesterone greater than 10 ng/ml. This was changed when the study
> was amended to make it greater than 160 pg/ml and greater than 7.9
> ng/ml, and the European study was 109 pg/ml with the estradiol
> criterion of the combined endpoint, and a progesterone of 7.9 ng/ml.
>
> \[Slide.\]
>
> The briefing document for the proposed NDA was submitted in 1998, and
> over a period of 1998 to 1999, the FDA reviewed these documents and
> had numerous discussions with the sponsor.
>
> Two non-identical Phase II studies, 6905 and 6253, were proposed. No
> statistical hypothesis was set forth for these studies at the outset.
> These studies were not powered for efficacy.
>
> They used trend tests as confirmatory statistical tools for efficacy
> assessment. FDA considered at that time, and considers now, that trend
> tests are exploratory, and not to be used as confirmatory statistical
> tools.
>
> The result of the European study was significantly different from that
> of the U.S. study 6905.
>
> \[Slide.\]
>
> As a result of the FDA sharing its concerns, Serono proposed then to
> support an NDA with Study 6253, the European Phase II, as primary as
> opposed to what was identified to us in 1996 and 1997 as 6905 being
> primary.
>
> \[Slide.\]
>
> The FDA\'s conclusion on Study 6253 was that the database was
> insufficient for filing an NDA. It was composed of 11 patients on 75
> IU dose of Luveris versus 9 patients on placebo.
>
> \[Slide.\]
>
> The FDA presented two options to the sponsor. One was that we could
> discuss with an Advisory Committee whether the database for Luveris
> was sufficient to support an NDA.
>
> \[Slide.\]
>
> The second option was that the sponsor could conduct a Phase III
> study. A further recommendation for such a Phase III study was that
> the sponsor enroll patients with an LH less than 5 and a significant
> subset with an LH less than 1.2.
>
> The reason for making a recommendation of enrolling subjects with an
> LH greater than 1.2 was that the labeling could reflect both the
> population showing efficacy and that for which the product was
> ineffective if the data did indeed turn out that way.
>
> We have had several discussions on pregnancy in subjects with WHO Type
> I, and the agency did suggest that it was really interested in
> pregnancy, however, if the study could not be powered to demonstrate a
> difference in pregnancy rate, then, ovulation rate, the proposed label
> indication, should be the primary clinical outcome.
>
> We said that a single treatment cycle, as proposed by the sponsor,
> would be adequate to demonstrate efficacy regarding ovulation rate.
>
> \[Slide.\]
>
> In 1999, the sponsor submitted its Phase III protocol. The population
> in that Phase III protocol was an LH less than 1.2, the same as Study
> 6253, with an E~2~ less than 60 pg/ml. It was proposed to be a single
> dose study and study follicular development as the primary clinical
> outcome.
>
> Serono\'s cover letter stated that a review of Serono data indicates
> that use of ovulation rates as a primary endpoint would be burdensome
> since some patients would be canceled for the risk of OHSS, and will
> not reach ovulation.
>
> \[Slide.\]
>
> The FDA comments to the Phase III protocol were that the drug
> development program to date had not demonstrated dose responsiveness,
> that the protocol proposed only a single 75 IU dose. It included a
> historical control, and the population studied was different from the
> previous FDA recommendation to include a population with an LH less
> than 5 with a significant subset less than 1.2.
>
> \[Slide.\]
>
> FDA\'s recommendation on that protocol was that the sponsor should
> demonstrate dose responsiveness, should determine the lowest effective
> dose in Phase III, or alternatively, conduct a separate Phase II
> trial.
>
> FDA further stated that a single dose may be an issue that affects the
> outcome of the review recommendation and that we might not have
> determined the lowest effective dose.
>
> We further recommended a placebo arm, and not historical data as the
> control.
>
> \[Slide.\]
>
> Further recommendations were that the ultrasonographer and patient be
> blinded, and if the sponsor was not going to take our recommendation
> to use ovulation rate as determined only by the progesterone, then, we
> had some comments on the criteria for their combination primary
> endpoint. We suggested an estradiol of 200 pg/ml and a progesterone
> level of 10 ng/ml.
>
> We felt that that was more in keeping with estradiol levels attained
> by a mature follicle in a normal menstrual cycle.
>
> \[Slide.\]
>
> The NDA was received on May 1st, 2001. As I said, the indication was
> for concomitant administration with recombinant human FSH for the
> induction of ovulation in infertile women with severe LH and FSH
> deficiency.
>
> The NDA was supported by one Phase III trial, Study 21008, and two,
> non-identical Phase II does-finding studies.
>
> \[Slide.\]
>
> On March 1st, 2002, the NDA received a non-approvable decision by the
> Division of Reproductive and Urologic Drug Products.
>
> \[Slide.\]
>
> I am going to give an overview, a little more in depth, of the three
> studies supporting the NDA, as well as the extension study 21008.
> Again, some of this will be a repeat of what Serono has already shown
> you.
>
> \[Slide.\]
>
> U.S. Phase II Study 6905 and European Phase II Study 6253 had
> objectives to determine the need for LH and the minimum effective dose
> for ovulation induction. The FDA review determined that the lowest
> effective dose had not been determined.
>
> U.S. Phase III had an objective to confirm the efficacy and safety of
> the 75 IU dose of Luveris. The FDA review was that the 75 IU dose of
> Luveris was not effective.
>
> \[Slide.\]
>
> This slide now is just an extension of the previous slide that I
> showed to include the U.S. Phase III trial, and just so that it is
> very clear the Study 6905, the U.S. Phase II open-label, the European
> Phase II open label, and finally, the Phase III double-blind study had
> different enrollment criteria.
>
> The European Phase II and the U.S. Phase II were the same. The
> efficacy criteria did differ between the U.S. Phase II studies and the
> European Phase II and the U.S. Phase III trial.
>
> \[Slide.\]
>
> Whereas you have already heard, one of the major discrepant point of
> views that significantly influenced the outcome of the review was the
> issue of how to account for cycles canceled to avoid ovarian
> overstimulation syndrome.
>
> The FDA believe that cycles should not be considered as a treatment
> success for the purpose of evaluating the efficacy for ovulation
> induction and pregnancy.
>
> We believe that cycles canceled to avoid the risk of OHSS, a
> pharmacologic adverse event, is not a surrogate for pregnancy.
>
> \[Slide.\]
>
> I won\'t go over this again because I think this was presented by
> Serono, but FDA believes that the appropriate way to account for cycle
> cancellations is to plan for and prospectively adjust the sample size.
>
> \[Slide.\]
>
> Study 21415, the extension study, was a non-randomized, open-label
> extension of Study 21008 that included 31 patients with an LH of 1.2,
> who are treated in Study 21008, who had not conceived.
>
> The primary objective was provide additional data on follicular
> development and safety of the treatment with the 75 IU dose of
> Luveris.
>
> \[Slide.\]
>
> Next, I would like to say a little bit about what the FDA considers as
> substantial evidence.
>
> \[Slide.\]
>
> Congress, in the Federal Food, Drug, and Cosmetic Act of 1962, put
> forth that the term \"substantial evidence\" means evidence consisting
> of adequate and well-controlled investigations. Historically, these
> were interpreted by the FDA to mean more than one.
>
> The Modernization Act of 1997 stated the data from one adequate and
> well-controlled clinical investigation and confirmatory evidence are
> sufficient to establish effectiveness and FDA may consider such data
> and evidence to constitute substantial evidence.
>
> \[Slide.\]
>
> Working on these statutes, the FDA put forth a guidance for industry.
> That guidance says reliance on a single study \"whether alone or with
> substantiation from related trial data leaves little room for study
> imperfections or contradictory nonsupportive information.\"
>
> The results of the two, Phase II trials are contradictory. The results
> of the Phase III trial is not robust. It relies on the results of a
> single patient.
>
> Also, the guidance puts forth that a single study should be limited to
> where confirmation would be practically or ethically impossible.
>
> It is both practical with an extended use of patient accrual and
> ethical to provide substantial evidence for Luveris in the treatment
> of women with hypogonadotropic hypogonadism.
>
> Next, I will turn the mike over to Ms. Meaker, who will present the
> statistics.
>
> MS. MEAKER: Hi. My name is Kate Meaker and I am the statistical
> reviewer for this NDA.
>
> \[Slide.\]
>
> First, I will be presenting the FDA\'s re-analysis of the three main
> clinical trials, and then I will discuss the agency\'s conclusion that
> these trials lack sufficient evidence for efficacy.
>
> \[Slide.\]
>
> The main issues, as Dr. Slaughter already explained, are the
> classification of subjects whose cycles were canceled due to risk of
> OHSS, and secondly, the concerns that the results of these studies are
> not robust.
>
> \[Slide.\]
>
> I will be covering the same three main studies that Dr. Slaughter has
> already described.
>
> \[Slide.\]
>
> Some background on the Phase II studies. The planned analyses for
> these studies were trend tests. This type of test is appropriate for
> dose-finding studies, which was the goal of the two, Phase II trials.
>
> Weights are assigned to each dose group prior to unblinding, and
> typically, the weights will reflect the anticipated dose response,
> such as a linear response.
>
> \[Slide.\]
>
> Our concerns about the sponsor\'s trend test analyses are these
> weights were not pre-specified, and when the results were first
> presented to the agency, we were told that the weights were selected
> after unblinding. This creates bias in choosing weights which show the
> greatest support.
>
> \[Slide.\]
>
> An additional concern was that the 75 IU dose group and the 225 IU
> dose group received the same weights, and the actual weights applied
> were placebo received minus 2, 25 IU dose received a weight of zero,
> and then the 75 and 225 IU dose received the weight of 1. So, in
> essence, this test treats anyone who received 75 or higher as having
> the same dose.
>
> \[Slide.\]
>
> Now, the results of these studies, and for each of the three main
> studies, I will be presenting the same analysis table. The first line
> will be the sponsor\'s analysis as presented in the NDA, and this
> includes OHSS, risk for OHSS as a treatment success for follicular
> development, and then the second line will be my re-analysis, which
> will include risk of OHSS as a treatment failure.
>
> Here, the endpoint that we are looking at is percent success on
> follicular development.
>
> \[Slide.\]
>
> So, in Study 6905, the sponsor\'s analysis, as they already presented,
> the trend test was not significant. One other point, in the process of
> my review, of the agency\'s review of this NDA, the question came up
> can any of these studies stand alone to support the efficacy of the 75
> IU dose.
>
> \[Slide.\]
>
> So, to address that question, in my re-analysis, I did a direct
> comparison of the 75 IU dose group to the placebo group, and in doing
> that, I used a Fisher\'s Exact Test.
>
> For this study, comparing the 7 out of 11 to the 5 out of 11,
> Fisher\'s Exact Test is not statistically significantly different. So,
> in conclusion, when OHSS risk is a treatment failure, actually, in
> both of these analyses for 6905, there was no statistical difference.
>
> \[Slide.\]
>
> Moving on to the second Phase II study 6253, again, sponsor\'s
> analysis. This was presented this morning. The trend test had a
> significant p value of 0.004. The other thing that was presented this
> morning was the sponsor compared this 7 out of 11 to the 1 out of 9 in
> head-to-head comparison, and showed a p value of 0.02. Again, that was
> with OHSS risk as a treatment success.
>
> \[Slide.\]
>
> When this is reclassified in my analysis, the comparison of the 75 IU
> group to placebo shows no statistically significant difference.
>
> \[Slide.\]
>
> Finally, moving on to the Phase III trial, this is a single Phase III
> trial. It had just two groups, Luveris and placebo. The plan
> comparison was a head-to-head comparison using a Fisher\'s Exact Test.
>
> Just to clarify, this was the analysis that was presented in the NDA.
> The sponsor did an evaluable analysis, they excluded three subjects
> from their analysis.
>
> Now, what was presented this morning, just to clarify the differences
> in what you are seeing in the package, this morning the sponsor
> presented an intent-to-treat. So, their denominators this morning were
> 26 in Luveris and 13 in placebo. That is the same intent-to-treat
> population that I used in mine.
>
> \[Slide.\]
>
> In doing a Fisher\'s Exact Test comparison, the p value for mine is
> 0.063, and as you have heard, there is a single subject in the Luveris
> group. The sponsor\'s analysis will show 11 out of 26 as being a
> treatment success here. There is a single subject where there is
> disagreement between the agency and the sponsor about the clinical, I
> guess it\'s the chemical pregnancy.
>
> So, this raises additional concerns about the robustness if the
> interpretation of this single Phase III study hinges on the
> classification of a single subject.
>
> So, again, when OHSS risk is considered a treatment failure, the
> single Phase III study does not have sufficient evidence to show
> efficacy for the 75 IU dose.
>
> \[Slide.\]
>
> This slide is to summarize the results of these three individual
> trials, and what I am showing you is the odds ratio and the 95 percent
> confidence interval. Now, the odds ratio shows the chance of having
> success, chance of follicular development in the 75 IU dose group
> versus the placebo group. The 95 percent confidence interval
> corresponds to the test at alpha .05.
>
> Now, the vertical line at the value of 1 here represents the odds
> ratio where the chance of treatment success in the placebo group is
> the same as treatment success in the Luveris group. All three of these
> confidence intervals, the lower bound is less than 1, so none of these
> trials can rule out the possibility of equal chance of getting
> pregnant or equal chance of follicular development on placebo as on
> Luveris.
>
> \[Slide.\]
>
> Of interest to the agency\'s medical officers was ovulation rate. This
> was the desired indication was ovulation induction. FDA requested that
> the sponsor use this as a primary endpoint, as Dr. Slaughter already
> discussed, and ovulation rate was to be determined by progesterone
> levels.
>
> The sponsor chose to use follicular development instead as the primary
> endpoint, and this was shown as the secondary endpoint.
>
> \[Slide.\]
>
> This slide shows the results of ovulation rate for each of the three
> studies. Now, you will notice in the 6905, the progesterone level was
> slightly higher than in the other two to be classified as a success
> for ovulation, but in all three studies, a head-to-head comparison,
> there is no statistically significant difference between Luveris 75
> and placebo for ovulation rate.
>
> \[Slide.\]
>
> So, in summary, these three studies, when we try to answer the
> question can any of them stand alone, looking at the primary endpoints
> with OHSS risk as the treatment failure, there is insufficient
> evidence and also looking at the additional endpoint that was of
> interest to the medical officers, ovulation rate, the same conclusion.
> None of these studies can stand alone to support that efficacy.
>
> Now, I will return it to Dr. Slaughter.
>
> DR. SLAUGHTER: Let me say that FDA agrees that in some population of
> hypogonadotropic hypogonadal women, LH will be necessary.
>
> \[Slide.\]
>
> Our concerns have been that we were left with, at the end of this
> review, were the appropriate subpopulation of hypogonadotropic
> hypogonadal women that would benefit from therapy with exogenous LH;
> that the correct surrogate for pregnancy was not chosen in this
> instance.
>
> \[Slide.\]
>
> Finally, in the appropriate population, the lowest effective dose.
>
> \[Slide.\]
>
> As you have heard earlier, there are alternative treatments,
> intravenous gonadotropin hormone releasing hormone is not currently
> marketed, and the menotropins have never been presented to the agency
> for this indication, so they would be used off label.
>
> I will proceed with our questions for the committee.
>
> No. 1. Can subpopulations of hypogonadotropic hypogonadal women be
> identified solely by serum hormone including LH, FSH, and estradiol
> levels? This is in addition to the physical examination, et cetera.
>
> If you do not agree, what additional markers should be attained?
> Should it be demonstration of withdrawal bleeding upon progestin
> challenge, DNA markers, or other clinically significant markers?
>
> If you agree that subpopulations can be identified on the basis of
> hormone levels, were the appropriate subpopulations studied in 6905,
> 6253, and 21008?
>
> No. 2. Was a placebo-controlled trial the appropriate trial design to
> demonstrate efficacy? If you disagree, should an active comparator
> trial be considered?
>
> No. 3. Should multiple cycles be considered for evaluation? Is there a
> priming effect of the first treatment cycle?
>
> No. 4. Was it appropriate to use a surrogate endpoint for pregnancy?
> We have talked this over several times. In this case, follicular
> development, however, in this study of hypogonadotropic hypogonadal
> women seeking pregnancy?
>
> If you do not agree, should the studies have evaluated clinical
> pregnancy or live birth?
>
> If you agree, which surrogate endpoints should have been used? A
> single mid-luteal progesterone? Multiple mid-luteal progesterone
> levels? Or other surrogates?
>
> Should cycle cancellation to avoid OHSS be used as a surrogate for
> pregnancy?
>
> No. 5. Is the data sufficient to establish efficacy for ovulation
> induction?
>
> No. 6. If additional clinical studies are to be recommended, what type
> of study should the Division request in order to provide sufficient
> evidence of efficacy?
>
> Should additional studies evaluate doses lower than 75 IU?
>
> Finally, I would like to close in thanking the committee for your
> deliberations over the two days. These are very important issues that
> the Division has struggled with, and we very much appreciate all of
> your input.
>
> I would also like to thank the following people: Dr. Ridgely Bennett,
> who is in the audience. He is the medical officer who has worked on
> the drug products for infertility for over the last 30 years, and we
> owe him a tremendous debt.
>
> I would also like to thank Dr. Audrey Gassman, Dr. Barbara Wesley, and
> Ms. Dornette Spell-Lesane for all of their help in putting together
> this presentation.
>
> I would like to thank Drs. Griebel, Shames, Houn, and Jenkins for all
> of their valuable comments during this process of presenting before
> the committee.
>
> Thank you.
>
> DR. GIUDICE: Thank you, Dr. Slaughter.
>
> I would like to open this discussion for some questions from the
> committee to Dr. Slaughter specifically about the issues that she has
> discussed, and I would like to begin the questioning by at least
> recounting as someone who was naive to these data and a first time
> around, and I would like to hear comments also from other committee
> members.
>
> We seem to have essentially two sides of the story. There are two
> different statistical analyses, there are comments that the FDA gave
> favorable views and yet within a few months there was an unfavorable
> letter.
>
> There is an issue that has been made of not having identical trials
> from the beginning or Phase II studies from the beginning. What that
> exactly means to the committee or to the FDA, I for one am not
> completely clear.
>
> There is a Phase II trial that was conducted in Europe that\--and
> pardon me for using the word \"clearly,\" Dr. Emerson\--but it seemed
> pretty clear to my eye that there was a dose-dependent, statistically
> significant change with recombinant LH.
>
> There are comments about the 6905 study not being equivalent and both
> trials not being equivalent to the 6253. Very little discussion has
> been addressed to the subset of severely LH-deficient patients in the
> 6905, the data of which again to my eye in reviewing the data seemed
> very comparable to the 6253.
>
> I can go and on. These are the issues that when I have gone through
> the data head-on, came to my pen to paper. An additional issue was
> brought up today, and that has to do with the pivotal patient of an
> estradiol of 106 versus 109, and again no discussion has been made
> with regard to had we re-assayed that patient sample, or had drawn her
> blood within five minutes, would we have gotten 110 nanograms per ml
> for an E~2~ or perhaps a 100.
>
> At least as I understand biology, you don\'t usually get pregnant
> unless you have follicle development. So, these are very serious
> issues that, as I have gone through the data, these have come to my
> mind, and as a group, I would like for you to let me know if these are
> on target with your thinking and how we can advise the FDA with regard
> to this particular product proposed by this sponsor.
>
> With that as a background, because I do want people\'s juices to be
> flowing here, I really want the brains to be thinking especially
> postprandially. There are a number of questions, and as we look at the
> subquestions, we need sufficient time to be able to discuss these,
> because some of them are very subtle and some of them I think are
> going to require a lot more attention.
>
> With that as a background, I would like to open the discussion for
> questions for Dr. Slaughter.
>
> Yes, Dr. Tulman.
>
> **Questions from the Committee**
>
> DR. TULMAN: I am asking this and it might be a bit broader rather than
> narrow. When the sponsor applied for orphan status because of the
> rarity of the condition, and has spent, and the FDA has spent, a
> considerable amount of time looking at a drug that, by all accounts is
> for the very rare patient, the 1 in 18,000 perhaps a tertiary care
> center.
>
> Clearly, there is in the background another agenda that may be at
> operation here that I think must be put on the table, and that is the
> FDA approves a drug for a very set purpose, for a set population that
> you have the evidence or may or may not have the evidence as we are
> discussing.
>
> The reality is if a drug were to be approved and it goes out to market
> and it\'s available for prescription by licensed people who can
> prescribe, and we all know there is much off-label use, which is not
> what the FDA approved it for, and in this particular case, there is
> the potential that the off-label use may outweigh the on-label use by
> a ratio of 18,000 to 1, which I am not sure how it works out with all
> our other medications out there, but it seems to me that is a pretty
> big off-label use potential.
>
> Of all of the trials that have been shown to us, the only one that
> might give us a hint were this drug to be approved and were this drug
> to be then used off label, is the 6905, the one that was done in the
> United States, of which several of the women in that study were not
> meeting the LH requirement of less than 1.2, but did go up to the
> median level, essentially a normal FSH and LH.
>
> There was no breakdown, but doing some calculations on my own, trying
> to capture that population that was greater than 1.2 in that trial,
> when you looked at the differences in pregnancy rates, in clinical
> pregnancy rates, it came out to, for a sample of those 25 women, it
> came out to 4 in the 75 or 225 dosage, and 5 in the zero or 25, or
> essentially no difference by any statistical means one could imagine
> doing.
>
> I know that we are a very focused hearing, and we are focused on this
> particular population, and somehow we have a gigantic elephant in the
> room. We have the 17,999 other women as opposed to the other 1 woman
> with this condition being discussed, and I guess I would like to hear
> some comments about how we can make a decision for something that the
> reality in the future may turn out to be very different on the use of
> this drug.
>
> I guess it wasn\'t just directed to the FDA.
>
> DR. SLAUGHTER: Thank you.
>
> DR. TULMAN: It was directed to all of my other colleagues in the room.
>
> DR. SLAUGHTER: I think that I cannot comment about any future or other
> indications for this drug, so I guess I would like to throw it out to
> the committee to discuss.
>
> DR. GIUDICE: I would like to comment. When we look at the
> indication\--and I will read it if I can find it amongst all this
> paper\--it is indicated for stimulation of follicular development in
> infertile hypogonadotropic hypogonadal women with profound LH
> deficiency defined by less than 1.2 IUs per liter.
>
> The purpose of this committee is to evaluate the data at hand for the
> indication proposed. So, I believe that we should focus our\--because
> we don\'t know, just as many other drugs are used off label\--we
> don\'t know other applications at this point for the use of this drug,
> nor really is that our charge to address that.
>
> My understanding of our charge is to advise the committee regarding
> this particular indication for this particular NDA. Unless someone
> wants to have some additional comment, Dr. Stanford, and I would
> appreciate it if we can keep this brief because we have a number of
> other very important questions that the FDA has requested that we
> address.
>
> DR. STANFORD: All I wanted to say is I want to clarify what is the
> indication we are asked to consider. There have been three different
> indications. There was one presented in the packets and then the one
> presented here is different.
>
> The ones you are asking us in the question, I think that is a pivotal
> question and may affect our vote, it may affect which way we vote.
>
> Is the indication\--you asked No. 5\--are the data sufficient to
> establish efficacy for ovulation induction, whereas, the presentation
> from Serono this morning is proposing an indication for follicular
> development. Those are different things.
>
> So, what are we being asked to consider?
>
> DR. SLAUGHTER: I think Serono is offering up an alternative
> indication. The indication in the NDA was for induction of ovulation.
>
> DR. STANFORD: Are we sort of open to say we will vote no on one and
> yes on one, are you just asking us to vote on this one? I am just
> trying to establish the parameters of what we are being asked to
> address.
>
> DR. SHAMES: We can certainly discuss everything, but technically, it
> was the ovulation induction indication that we ultimately did not
> approve, and that is what we need the help on. You can discuss the
> other issues also, but technically, it\'s that particular NDA having
> to do with ovulation induction that we need the answer.
>
> Question 5 is the actual question regarding that.
>
> DR. STANFORD: So, we would vote on Question 5 and then make any other
> comments that you might take into advisement for anything else.
>
> DR. SHAMES: Right. I want to make one other comment about the off
> label, et cetera. The other way to look at it is we are looking at
> this, the information before us, and if reproductive endocrinologists
> think it would be really nice to have, you know, some LH to fool
> around with, and we were really nice and we said, okay, we could have
> this, the truth is we are, by law and by regulation, required to
> approve a drug based on what Dr. Slaughter showed you, substantial
> evidence.
>
> It is fairly well defined as what is substantial evidence, and it has
> to do with the number of trials and the supportive evidence. So, the
> other way to look at this, you have to sort of take your way, in a
> sense, out of the total big picture and focus on not only the clinical
> evidence or the trial evidence, which you would look at as
> academicians or practitioners, but also on our regulatory charge,
> which is a certain legal standard of having substantial evidence which
> has a real meaning to it.
>
> So, that is why Dr. Slaughter reviewed with you what that was.
>
> DR. GIUDICE: Dr. Keefe.
>
> DR. KEEFE: We are going to be making decisions based on whether or not
> there is or is not substantial evidence to support the IND, and I am
> wondering if, from the perspective of the FDA, does the fact that this
> is a deficiency syndrome, that this is as close as you can get to the
> natural product, way into it, for example, if this was a new form of
> insulin, does it change the weight of the evidence required to tip the
> balance in one direction or another.
>
> DR. SLAUGHTER: I think that I put this on the slide. It really
> doesn\'t influence the weight of the evidence. We have to consider
> these drugs for these orphan indications in the same manner that we
> would consider other drugs.
>
> DR. SHAMES: There is a reason we are replacing this, and we have to
> decide. The endpoint here is the reason we are replacing it to attain
> pregnancy. I mean there may be a lot of things that people are
> deficient in as you get older, whatever it is, but to approve
> something, there has to be an endpoint that has clinical meaning, not
> just replacing the particular deficiency.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: I guess I am just not clear because what Serono presented us
> this morning, the second slide says they are looking for indication
> for stimulation of follicular development, and apparently they amended
> their NDA on August the 21st, 2003, which you present to us is an NDA
> indication for ovulation induction.
>
> So, which endpoint are we going to make a decision on, ovulation
> induction or follicular development? In other words, do they get to
> change midstream their decision or amend the NDA and was that accepted
> by the FDA?
>
> DR. SLAUGHTER: Our decision was based on ovulation induction. We did
> not accept the amendment to change it to follicular development.
>
> DR. RICE: So, today, we are making a decision based on ovulation
> induction, not follicular development?
>
> DR. SLAUGHTER: Yes.
>
> MS. WILLIAMSON JOYCE: Excuse me. May I comment on that? I want to make
> it clear that the NDA amendment, the proposal to create an indication
> that was more clearly closely aligned to the clinical development
> program, starting back more than 10 years, and also to make it
> consistent with the indication that is currently approved in over 46
> countries.
>
> Now, that indication, the proposal to amend that indication was
> provided to the agency in a document in December of 2002 with hopes
> that we could get to the part of our discussion where it might be
> possible, however, given the fact that the matter was being brought
> before an advisory committee, we have not to date entered into any
> discussions concerning the label.
>
> We are proposing this indication because we feel it is appropriate
> based on the clinical studies that we have conducted, and today was
> the first moment that we were told that the amended indication was not
> accepted.
>
> DR. GIUDICE: Dr. Hager.
>
> DR. HAGER: That was my question.
>
> DR. GIUDICE: Dr. Lipshultz.
>
> DR. LIPSHULTZ: I have a question for Dr. Slaughter. We are talking
> about this one patient, and Dr. Guidice mentioned, well, if we drew
> the blood again, perhaps it would be different.
>
> I mean if that one patient is so significant in this decisionmaking,
> then, I am concerned about the depth of the data that we are
> discussing. How important is this one patient?
>
> DR. SLAUGHTER: If you eliminate women, if you do not count as
> successes women whose cycles were canceled for the risk of OHSS, the
> data is swayed from a significant p value to a non-significant p value
> on the basis of that one patient. So, the one patient really
> influences the outcome of this study.
>
> DR. LIPSHULTZ: Because the sponsor has said that either way you look
> at the data, with or without the canceled cycles, it still is
> statistically significant, but you are saying that if we cancel the
> one patient out, then, it does change the data.
>
> DR. SLAUGHTER: If you take that one patient along with patients whose
> cycles were canceled for the risk of OHSS, then, yes, it does
> influence the data.
>
> I just wanted to respond to some of the points that you raised
> initially. One is that I presented the business about which studies
> were to support the NDA only to give you some historical perspective
> and that things were not clear-cut from the onset, that we were
> presented with the proposal for different studies to support the NDA
> over the 10-year review process.
>
> I think we did discuss the single patient. I just wanted to make a
> little comment about the favorable response, and it\'s not to get into
> a he said-she said situation, but I just want to put that in
> perspective.
>
> The comment that Serono has put forth about the favorability of the
> study was made by me, and I was commenting at the level of the pre-NDA
> meeting, that the sponsor had done the type of study, meaning
> double-blinded, placebo-controlled study that I had asked for, and
> that was favorable.
>
> However, left out of that comment was that we could not even tell them
> at that time whether we would accept that NDA for filing. That comment
> was in no way made to suggest that they would ultimately receive a
> favorable outcome after the review of their NDA.
>
> DR. GIUDICE: Thank you. I would like to have two quick comments and
> then we need to go to the open public hearing, and then we will go
> directly to the questions.
>
> Dr. Crockett and then Dr. Rice.
>
> DR. CROCKETT: I actually have a question to address to Dr. Emerson,
> our statistician. In reviewing Dr. Meaker\'s statistical analysis,
> there seems to be significant difference regarding the statistical
> analyses applied to the data both on the follicular development and
> the ovulation rates.
>
> In her presentation of the data, neither the follicular development
> nor the ovulation rates were statistically different between the
> Luveris and the placebo, and I just wondered if you had a comment
> concerning the correct application of the statistical methods used.
>
> DR. EMERSON: There were differences in the statistics being presented,
> the types of things that you are looking for. So, first, the issue is
> doing a test for trends versus the pairwise comparison, and obviously,
> there is a multiple comparison issue, if you let me do enough
> statistics, I will eventually find out something that is significant.
>
> So, this prespecification question is very, very important when you
> are doing a test for trend, prespecifying the weights is very, very
> important, so there is a lot of issues there that you can say sure,
> they plugged it into the computer, and the computer gave it the
> correct p values subject to the differences in the definition of
> failures and dealing with the one patient.
>
> But the issues of the weighting and whether it is prespecified and
> whether that would be then the credible evidence is one that has to go
> in the study design, because you have to be very certain that you
> aren\'t given too many chances to be right.
>
> I would say that everything looks like it is appropriate if there
> wasn\'t an element of dredging through the data until you got the
> result that you wanted.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: This is a comment and I guess I may want a response, but I
> am concerned about this history of this changing of the NDA indication
> and I just want to know is there some precedent for this, that before
> a pharmaceutical company comes before us that they can have changed
> the indication, the endpoint that was going to be evaluated, is there
> any history of that, and I guess I am concerned about what you just
> said was that you changed the indication after you looked at the data.
>
> Did I misunderstand that, after it has been approved in the European
> study, what did you say?
>
> MS. WILLIAMSON JOYCE: Yes. First of all, I want to make clear that
> there has been no change in the endpoint, the endpoint has been
> consistently applied in the pivotal study and in the previous studies.
> There has been no change in the endpoint.
>
> DR. RICE: So, ovulation induction versus follicular development?
>
> MS. WILLIAMSON JOYCE: The endpoint has always been follicular
> development as provided by Dr. Lammers and the sharing of our data,
> that has always been set, follicular development. What we did, when
> the NDA went in, the wording of the indication that was submitted was
> broad and similar to that of other products that had been approved in
> gonadotropin treatment therapies for OI.
>
> It was clear as we looked at this that that was an overly broad
> indication.
>
> DR. RICE: Which was an overly broad indication?
>
> MS. WILLIAMSON JOYCE: The initial indication submitted in April of
> 2001, ovulation induction. So, there was a disconnect between the
> indication that was included in the original NDA\--
>
> DR. RICE: Ovulation induction.
>
> MS. WILLIAMSON JOYCE: Ovulation induction\--I want to clarify this, it
> was stimulation of follicular development and ovulation induction. All
> we did was remove the term \"ovulation induction\" because we felt
> follicular development, stimulation of follicular development was what
> we had studied. That was our endpoint, and in changing that
> indication, we combined, we made consistent the endpoint and the
> proposed indication, which is also approved in the other countries in
> the same terminology. So, I hope that clarifies what we did. No?
>
> DR. RICE: No.
>
> DR. SLAUGHTER: Just one comment also. That indication was taken word
> for word from the label that was submitted by Serono with the NDA
> application.
>
> MS. WILLIAMSON JOYCE: Yes, it was, I agree.
>
> DR. GIUDICE: Can we be very clear, rather than using \"it\" or
> \"they,\" so specifically say either follicular development,
> follicular development and ovulation, and ovulation induction as we
> discuss these, because it\'s a very good point.
>
> Dr. Lipshultz, your question was?
>
> DR. LIPSHULTZ: Could you please, as chairperson, restate what was
> said, because I did not understand. Did you understand?
>
> DR. GIUDICE: What I understood was that the original indication was
> for follicular development and ovulation induction, and that the
> outcome was follicular development, and to make the outcome consistent
> with the indication, they dropped the words \"ovulation induction.\"
>
> Is that correct?
>
> MS. WILLIAMSON JOYCE: Yes.
>
> DR. SLAUGHTER: After the NDA, after the NDA was submitted.
>
> DR. RICE: So, they dropped it after they looked at the data, correct,
> which was what I said, you dropped it after\--okay, you didn\'t drop
> it after you looked at the data.
>
> MS. WILLIAMSON JOYCE: I think we are getting into semantics. The words
> ovulation induction were proposed to be removed in the amended
> indication, but follicular development in the indication, which has
> always been in the indication, and has always been the endpoint, are
> consistent. That has not changed.
>
> DR. GIUDICE: I would like to remind the committee that the criteria
> for follicular development, if progesterone, mid-luteal progesterone
> is one of the sub-criteria, that is almost implicit that there has
> been ovulation, so you are correct that there is a bit of an issue of
> semantics here.
>
> Certainly follicular development can occur, and you may not allow
> ovulation to happen, but with the criteria that were used in the
> composite, progesterone was one of the endpoints.
>
> DR. RICE: But I think one thing that is somewhat clear to me is that
> they canceled patients, so you didn\'t get to ovulation induction, so
> you never got a progesterone level. So, it was to their favor to use
> follicular development, because they didn\'t give those patients the
> hCG to ever answer the question of ovulation induction, so that is why
> the semantics makes a difference.
>
> DR. GIUDICE: Well, it does and it doesn\'t, and I will get to you in
> just one second, because if one is looking at the pharmacologic
> endpoint of the action of LH, it is truly not follicular growth, but
> it is steroidogenesis, and that I think has been\--I won\'t say
> clearly shown, but we can discuss that elsewhere\--but the endpoint
> for the action of LH had one not canceled cycles because of the risk
> of OHSS, would have been for ovulation.
>
> It\'s just on an ethical basis and by the criteria for cycle
> cancellation, and that\'s the reason that those patients were not
> included, but had one just decided, well, let\'s take a cutoff of
> 5,000, then, we would have had evidence of ovulation induction.
>
> So, the pharmacologic action of LH was clearly proven in those
> patients who were excluded.
>
> DR. RICE: I will only say this. We are talking semantics, and we are
> talking about one patient making a difference of some statistical
> difference, but that one patient that we are talking about, when Dr.
> Macones asked the question what was that estradiol level in that
> patient who ended up getting pregnant from this \"chemical\"
> pregnancy, my understanding was that estradiol level was low.
>
> DR. GIUDICE: It was 106.
>
> DR. RICE: It was under the threshold, so that is your indication for
> LH action, that estradiol. So, there are some semantics there that
> raise the question. I just think that we need to be clear about what
> we are going to discuss, what we are going to vote on, and that is
> whether or not the drug is looked at for ovulation induction as the
> endpoint versus follicular development, and that is what I would like
> clarification on, and I want to make sure that we all understand as a
> committee, either it\'s acceptable that they could drop the wording of
> the initial indication or they can\'t, so we just need to know what to
> vote on as a committee, because I know I can look at the data and
> assess it for what I think it shows once I know what the question is.
>
> DR. GIUDICE: Dr. Keefe.
>
> DR. KEEFE: It seems to me the pivotal patients are those who had OHSS
> and never got a chance to have a progesterone that is elevated, which
> brings us back to Dr. Toner\'s point earlier, which is whether or not
> they had adequate estradiol levels.
>
> So, from my understanding of the data, if you include all those who
> were canceled for OHSS in the group, they will have significance, but
> if you exclude them, they don\'t, but the question is if you partition
> them into those who had adequate levels of estrogen above the cutoff
> and those that didn\'t, where does that leave us? Does that put that
> one patient who is defined as pregnant as the make or break piece of
> data?
>
> MS. WILLIAMSON JOYCE: Excuse me for just interrupting. I want to make
> it clear that these patients were not canceled due to OHSS.
>
> DR. KEEFE: I am sorry, the potential for OHSS risk.
>
> DR. GIUDICE: I think we need to move on. We will continue this
> discussion essentially as we go through the individual questions, so
> this certainly has provided an excellent base for that.
>
> **Open Public Hearing**
>
> I would like to open the open public hearing and I need to read a
> statement by the FDA.
>
> Both the FDA and the public believe in a transparent process for
> information gathering and decisionmaking. To ensure such transparency
> at the open public hearing session in the Advisory Committee meeting,
> FDA believes that it is important to understand the context of an
> individual\'s presentation.
>
> For this reason, FDA encourages you, the open public hearing speaker,
> at the beginning of your written or oral statement to advise the
> committee of any financial relationship that you may have with any
> company or any group that is likely to be impacted by the topic of
> this meeting. For example, the financial information may include a
> company\'s or a group\'s payment of your travel, lodging, or other
> expenses in connection with your attendance at this meeting.
>
> Likewise, FDA encourages you at the beginning of your statement to
> advise the committee if you do not have any such financial
> relationships. If you choose not to address this issue of financial
> relationships at the beginning of your statement, it will not preclude
> you from speaking.
>
> I understand that we have three individuals who would like to make a
> statement. Would you please raise your hands. May I have the person
> who is walking towards the center come first.
>
> MS. KRAMER: Thank you, Chairwoman Guidice and members of the
> committee. My name is Erin Kramer. I am here to represent Resolve, the
> National Infertility Association, and I am a consultant to Resolve.
>
> Resolve has been for 30 years providing compassionate support and
> information to those individuals who are touched by infertility, and
> Resolve works to increase public awareness of infertility issues and
> the family building options available to those individuals.
>
> Resolve appreciates the important work of the agency and this panel,
> and the careful thought and consideration that must accompany the
> approval of any new drug.
>
> For the sake of disclosure, the corporate sponsor of the product
> discussed here today has been a supporter of Resolve\'s work. I do
> want to also make clear that I do not have a medical or a clinical
> background, so I cannot comment on the specific merits of any new
> product, but I do have an important viewpoint to impart and that is of
> the patient.
>
> Infertility, receiving that diagnosis is devastating. According to the
> American Psychological Association\'s National Task Force on Women and
> Depression, 40 percent of women in one study identified the inability
> to conceive as the most upsetting experience of their lives.
>
> Certainly for individuals for whom treatment is not available, that
> depression would be magnified.
>
> We understand that there is a patient population for whom there is not
> treatment currently available. Of course, those are the individuals we
> have talked about today, those who are profoundly LH deficient, and
> while, of course, this is a rare patient population and certainly one
> very difficult to study, we encourage the panel to think about the
> human toll, of the decisionmaking that goes into the process of
> identifying and looking at the research.
>
> These women deserve to have treatment that is both safe and effective
> in the investigational setting and treatment that is specific to their
> infertility problem. We understand that this treatment is available in
> European markets and that patients are benefitting there.
>
> While there are numerous factors that go into contributing to the
> success of treatment and pregnancy in the end, the passage of time and
> the delay of treatment is a very key component of that success, and 10
> years of investigational study is a long time and too long for many
> patients who are waiting for a family to love and an answer to their
> medical problem.
>
> The research overwhelmingly is paid for by patients. There is very
> little federal funding into infertility research, so it is the
> patients themselves and private companies who are willing to invest
> the time and money into cures.
>
> We encourage the panel to help assure timely availability and access
> to new pharmaceutical products that will be for all infertile
> patients.
>
> Thank you.
>
> DR. GIUDICE: Thank you for your comments.
>
> MS. MADSEN: Hello. Thank you for having me here today and giving me
> some of your time. My name is Pamela Madsen and I am the Executive
> Director and the founder of the American Infertility Association.
>
> I am supposed to disclose. Serono does give the American Infertility
> Association some funding for educational activities, as well as other
> people here in the room, Ferring Pharmaceuticals and Organon, and
> nobody paid for my travel.
>
> I came here today because some patients asked me to come. Those are
> those orphan patients that we have discussed, not those 17,000, for
> which there are products available to treat their infertility, but
> this very, very small group of orphan patients.
>
> While those numbers, 2,000 to 5,000 patients, when you are in the
> medical practice, seem very, very small. When you are a part of that
> couple that is your whole world, so we are talking about somewhere
> between 2,500 worlds, lives, couples, who are looking to have a baby,
> and these hypo/hypo women do not have a product that is designated to
> treat just them.
>
> And how do we measure success? I keep hearing that today over and over
> again. If I am anovulatory, if I can\'t ovulate, if I don\'t get my
> period, I may measure success in the ability to buy a box of tampons,
> that\'s success. If I don\'t ovulate, follicular development is a
> success of that drug. Ultimately, if I want to have a child, this drug
> may help me obtain that final goal.
>
> But there may be lots of different successes for that patient along
> the way outside of that take-home baby, and I don\'t think that we
> should demean that at all, because if you are a woman who doesn\'t
> menstruate, menstruation is a victory.
>
> I hope that you will consider those women who were canceled. Again, I
> am not a doctor, but I know a little bit, and I know lots and lots of
> patients on lots of different medications who get canceled because of
> hyperstimulation. As a patient advocate, that tells me something is
> working, I am ovulating, I am making a lot of eggs. I am doing
> something, and the doctor is concerned that I am going to get sick if
> they don\'t cancel my cycle.
>
> So, some physicians made some very key decisions to protect my health
> as a volunteer or participant in the study, but it was working, and I
> think that patients in the United States should have the same access
> to care as we are hearing this patients have in other countries.
>
> So, again, let\'s look at the measure of success for the infertile
> couple, for the infertile woman, for the woman who is struggling with
> this. I think it sounds like this drug is working.
>
> Thank you.
>
> DR. GIUDICE: Thank you for your comments.
>
> The last person, please.
>
> DR. SHOHAM: Ladies and gentlemen, my name is Dr. Shoham. I am
> practicing medicine in Israel. I am the Director of the Infertility
> Clinic and Kaplan Hospital. I came from Tel Aviv yesterday night in
> order to participate in this discussion, which I think is highly
> interesting.
>
> We gain a lot of interest and we need a lot of research in this unique
> group of patients. Actually, I was involved in Phase I, II, and III of
> the recombinant FSH with Organon and Serono, and Phase I, II, and III
> with recombinant LH of Serono, and I worked with Howard Jacobs in the
> early nineties, and we were the first to inject recombinant FSH to a
> patient with hypogonadotropic hypogonadism.
>
> I remember that we stayed the whole night looking if there will be any
> reaction to this one small injection of recombinant FSH.
>
> But since then we were stimulated to look at this unique disorder and
> we published our first paper in 1993, after extensive research in this
> group of patients. If we look at that old paper before the area of the
> recombinant FSH and LH, we can see that in order to get the patients
> pregnant, it is not the follicle, it\'s not the LH, the FSH, it\'s the
> combination.
>
> We need to create an endocrine environment which will get the patient
> pregnant, and if we look at that old paper, we can always overcome
> with a lecker \[ph\] of LH with FSH. In 10 patients who were treated
> just with FSH, and at that time it was Metrodene, we received
> ovulation in three patients. The progesterone was high, but we felt in
> order to get them pregnant, because the endometrium was too thick,
> although the estrogen was at some lower level.
>
> So, it is not the follicle, it\'s not the progesterone, and it\'s not
> ovulation, it\'s to create the environment to get the patient pregnant
> which I think is the most important. FSH and LH are two gonadotropins
> that interact with each other. They are playing, they are talking with
> each other. It\'s not atroxin and paracetamol, it\'s two gonadotropins
> that influence the development of the follicles in the ovary.
>
> Therefore, I think it is very important to get these two hormones in
> combination, to think about these two hormones as one.
>
> If we look at that old paper, looking at the dose, what would be the
> appropriate dose, and this was before the study which was done with
> Serono. We can just easily calculate and find that the optimal LH dose
> in this group of patients is 100 IU.
>
> We started with all our patients with 75, but we always had to
> increase the dose. You can always overcome the low LH dose with high
> FSH, but then you pay the consequences with these.
>
> If you want to create a safe pregnancy, then, you have to titrate the
> different gonadotropins in order to get the optimal results, and I
> think that 25 units of LH in order to start treatment is too low, 75
> might be optimal although if you ask me how much I start with, I start
> with 75 and gradually increase the dose, but i never start with less
> than 75 units because I think it\'s a waste of time and it\'s waste of
> the drug, and the patients are paying for the drug, which is quite
> important.
>
> I also want to comment about the definition of hypogonadotropic
> hypogonadism. Hypogonadotropic hypogonadism is the clinical syndrome,
> it\'s not a laboratory syndrome, we are not looking for LH and FSH.
>
> We are looking for long-standing amenorrhea, low estrogen, thin
> endometrium with a combination of low LH and FSH in order to define
> this group of patients, for example, for ovarian failure, for
> menopause patients, but it\'s not the LH and the FSH which make the
> whole story, it\'s the low estrogen.
>
> I was listening very carefully to the presentation of Dr. Liu, who
> presented hypothalamic amenorrhea, and it showed that you can have
> hypogonadotropic amenorrhea even if you have high estrogen, and he
> showed that the estrogen might be approximately 140 pmol/L, which I
> think is high.
>
> I think that there is no need in order to establish the definition for
> the progesterone challenge test because if you know how to do the
> ultrasound and how to scan the patients, if you have thin endometrium,
> you don\'t have to look to estrogen, you don\'t have to give the
> patient progesterone, they will not bleed.
>
> In the paper we published long ago, 10 years ago, we showed that the
> mean level of estrogen was 43 pmol/L. If the estrogen level is less
> than 73 pmol/L, the patients will not bleed. If the endometrium level
> is thinner than 4 mm, you give progesterone as much as you want, the
> patient will not bleed.
>
> So, it can be supported by the level of LH and FSH. It is very fine to
> have, it\'s very nice to have low level of LH and FSH, but in the
> paper, actually, we get to the counterpoint that the level of LH was
> 1.2. But if I have the patients with the same criteria with LH level
> of 2, for me they are hypogonadotropic hypogonadism.
>
> The last thing I want to comment to is about endpoint, which I had a
> discussion this morning. I don\'t think that we, as a physician,
> should reach an endpoint of pregnancy. It is very nice to have an
> endpoint of pregnancy, but our role as a physician and clinician is to
> restore physiology.
>
> We have to restore normal physiology in these patients, and they will
> become pregnant, and if our endpoint is pregnancy, and we try to
> overcome the physiology, then, come the consequences. Then, we
> stimulate patients with too many follicles, we replace too many
> embryos because we want them to become pregnant, which is wrong.
>
> I think that we have to restore physiology and the rest will be fine.
>
> Thank you.
>
> DR. GIUDICE: Thank you for your comments, as well.
>
> **Presentation of Questions and Committee Discussion**
>
> DR. GIUDICE: We now have six questions before the committee, and Dr.
> Slaughter had reviewed them. Perhaps we can also have them put up on
> the screen.
>
> I would like to advise the committee that we need a vote on the first
> five questions. The procedure for the vote is that the members of the
> committee\--and we will start over here and go around, or start over
> here and go around\--my understanding is that the members of the FDA
> who are sitting at the table do not vote. Is that correct? Okay.
>
> The first question is\--and this is actually falling right on the
> heels of what you have just heard from Dr. Shoham\--Can subpopulations
> of hypogonadotropic hypogonadal women be identified solely by serum
> hormone, LH, FSH, E~2~ levels?
>
> If you do not agree, what additional markers should be attained?
> Demonstration of withdrawal bleeding upon progestin challenge, DNA
> markers, Others.
>
> If you do agree, were the appropriate subpopulations studied in Study
> 6905, 6253, and 21008?
>
> Dr. Toner.
>
> DR. TONER: I think the appropriate subpopulations were studied. The
> criteria used in those studies were not only these three endocrine
> markers, but also the amenorrhea that Dr. Shoham mentioned as an
> important sign. So, that would be my answer.
>
> DR. GIUDICE: Dr. Dickey.
>
> DR. DICKEY: I think I agree with Dr. Toner that they were. The
> question comes back perhaps though to the question raised in Dr.
> Slaughter\'s remarks, and that is, whether the robustness of the
> numbers in subpopulations were studied in that for some of the
> subgroups, there were very small populations, and I am somewhat
> concerned, keeping in mind the legal obligations I guess of the FDA.
>
> DR. GIUDICE: I think we will get to that as we go down to other
> questions.
>
> The first question is whether subpopulations can be identified by
> serum markers or other means. Dr. Liu presented some data this
> morning. Perhaps you would like to comment.
>
> DR. LIU: The LH/FSH levels, when they are extremely low, the pulsatile
> activity is also concomitantly low, so there is less error in judging
> a subpopulation with extremely low gonadotropin levels.
>
> So, in someone with HH, as opposed to a lesser severe disorder like
> the exercise-associated amenorrheas, it would be much easier to
> distinguish that population.
>
> The estradiol levels, I think are fairly accurate if one does not use
> the rapid assay for estradiol, but a much more sensitive
> radioimmunoassay. A lot of the immunolyte assays that were used for
> IVF are totally inappropriate for determination of estradiol levels in
> this category where you are looking at between 40, 30, or 20 pg/ml, so
> a more sensitive RIA probably would be appropriate in establishing
> that.
>
> Progestin challenge tests, we talked about it recently in an ACOG
> meeting of a variety of REs, and our feeling is that this is a
> bioassay for integrated estradiol exposure, but it does not really
> tell us the particular situation at that point in time when we assess
> the patient.
>
> So, it is more of an integrated measure of estradiol activity, but
> clinicians still use it. Our feeling is it is probably not useful
> because if the patient spots, what does that mean versus having a full
> bleed, what does that mean, so there is a variation in response other
> than amenorrhea with respect to progestin challenge.
>
> So, my feeling is it is not as reliable a tool as the biochemical
> measures we have.
>
> DR. GIUDICE: Thank you.
>
> Dr. Hager.
>
> DR. HAGER: I would agree. I think that the objective evaluation of
> progestin challenge would leave it as a deficient method to evaluate,
> and I think that we are left, as has already been said, with the
> markers that were looked at, being LH, FSH, and estradiol.
>
> I think as more specific assays become available, then, that is
> certainly the direction to go, but I would agree, I think that the
> subpopulations were identified in the only way that we could identify
> them, which was with these particular assays.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: I would agree except that I would point out that 6905
> had different cutoffs, and am not comfortable that that particular
> study had the appropriate population.
>
> DR. GIUDICE: I think also from Dr. Layman\'s discussion this morning,
> that we should all probably tuck in the back of our minds that within
> the near future, there likely will be genetic tests that will more
> clearly define different subpopulations that currently are not
> commercially available and certainly not in large numbers.
>
> So, the question is now\--and I would like to go around the room
> unless there is any further discussion on No. 1\--
>
> DR. HAGER: I do have one question and that is, is the FDA asking for
> specific cutoffs, or is this a generalized question, are you asking
> for less than or equal 1.2 for LH, or is that the purpose?
>
> DR. SLAUGHTER: The purpose was to have a consensus whether or not the
> subpopulations could be identified appropriately to put in a label by
> these markers as the population requiring treatment.
>
> DR. GIUDICE: So, Dr. Slaughter, can you answer the question, do you
> want a cutoff?
>
> DR. SLAUGHTER: If you agree that the markers were appropriate, yes.
>
> DR. GIUDICE: Well, then, the question is different as stated here,
> because the question asks us can you distinguish subpopulations of
> hypogonadotropic hypogonadal women by the markers of LH, FSH, E~2~,
> unless you want to restate the question and ask us\--let\'s answer
> that question first.
>
> We will start on this side of the table for a change.
>
> Dr. Rice.
>
> DR. RICE: Yes.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: Yes. DR. BRZYSKI: Yes.
>
> DR. STANFORD: Yes.
>
> DR. EMMI: Yes.
>
> DR. EMERSON: Yes.
>
> DR. LIPSHULTZ: Yes.
>
> DR. LIU: Yes.
>
> DR. KEEFE: Yes.
>
> DR. GIUDICE: Yes.
>
> DR. DICKEY: Yes.
>
> DR. TULMAN: Yes.
>
> DR. LEWIS: Yes.
>
> DR. MACONES: Yes.
>
> DR. CROCKETT: Yes.
>
> DR. HAGER: Yes.
>
> DR. GIUDICE: Thank you. That is now unanimous. This is quite amazing.
>
> So, then, the 1(a), if you will, we do not need to answer because we
> apparently all agree.
>
> The second part of that question is, if you do agree, were the
> appropriate subpopulations studied\--and let\'s take it study by
> study\--Study 6905? Let\'s go around the room, Valerie, starting with
> you.
>
> DR. RICE: There were five people that met the criteria, so, yes, for
> those five, yes.
>
> DR. GIUDICE: It\'s a subpopulation.
>
> DR. RICE: Subpopulation of that study? So, the LH less than 1.2 group?
> What do you mean? A subpopulation of the population, of hypo/hypo.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: One of the issues would be that if you were to regard
> this study and trying to use the ideal or randomized, but then
> disregard part of the randomized therapy, that is somewhat problematic
> statistically, so I would interpret the question as do you believe the
> whole study is appropriate or not.
>
> \[All voted no.\]
>
> DR. GIUDICE: Next one is 6253. This is for the severely deficient, LH
> deficient, less than 1.2.
>
> \[All voted yes.\]
>
> DR. GIUDICE: Finally, 21008.
>
> \[All voted yes.\]
>
> DR. GIUDICE: I am almost afraid to ask the question. Since we have not
> truly been asked for a cutoff, we could go through the rest, and that
> may surface.
>
> Let\'s go to No. 2. Was a placebo-controlled trial the appropriate
> trial design to demonstrate efficacy? If you disagree, should an
> active comparator trial have been considered?
>
> Let\'s start on this side of the table now, Dr. Hager.
>
> DR. HAGER: Are we discussing or yes or no here?
>
> DR. GIUDICE: Yes, let\'s discuss this. I assume this is 21008 that you
> are referring to. Okay. So, this is the Phase III trial.
>
> DR. HAGER: I think we have already discussed that for the initial
> trial, that the use of a placebo is the ideal way to go in a
> randomized, blinded trial.
>
> I personally believe that as the data accumulate, that a comparator
> trial certainly has to be considered, so that colors my view on that.
> The initial trial, as stated, as a placebo-controlled trial, I believe
> is adequate. I do believe there is need for a comparator trial.
>
> DR. GIUDICE: Other discussion on this? Dr. Keefe.
>
> DR. KEEFE: Since there is no FDA-approved treatment for the condition,
> I think the placebo-controlled was the only viable one at this point.
>
> DR. GIUDICE: Anyone else want to make a comment? Dr. Crockett.
>
> DR. CROCKETT: For the sake of future studies that may come up, when we
> may have an FDA-approved drug for this indication, I think the placebo
> is a standard that we should try to meet, but as we discussed
> yesterday, when we are taking care of this population of infertile
> patients, it can be difficult to always provide studies with a
> placebo.
>
> I like the idea of having an active comparator or the crossover study
> that we discussed at length yesterday, and I think those should be
> viable options for this type of study.
>
> DR. GIUDICE: Thank you.
>
> DR. LIU: I really think the FDA ought to make some guidelines if you
> are going to do a placebo followed by a crossover, so that the drug
> companies will know what standards they have to meet, and I don\'t
> think that is clear.
>
> DR. GIUDICE: Thank you. Any other comments before we vote on No. 2?
>
> Okay, we are going to start on this side of this table then. Dr.
> Hager.
>
> \[All voted yes.\]
>
> DR. GIUDICE: Once again unanimous.
>
> The third question is: Should multiple cycles be considered for
> evaluation? Is there a priming effect of the first treatment cycle?
>
> Dr. Slaughter, is the question under No. 3, is that an explanation of
> what the question is?
>
> DR. SLAUGHTER: That\'s one of the explanations. Do you feel that
> exposure to the recombinant in the first cycle affected the subsequent
> cycles, and even to a gonadotropin at all in the first cycle affected
> subsequent cycles, and should we be using only the single cycle or
> multiple cycles?
>
> DR. GIUDICE: Dr. Liu.
>
> DR. LIU: Based on our observations with the GnRH patients, in general,
> the responsiveness in the second cycle on a variety of target tissues
> from the estrogen production from the first cycle does affect your
> second cycle response.
>
> This includes an increase in the size of the uterus gradually with
> estrogen priming and also the pituitary and/or cohort of follicles may
> be affected by the higher estrogen levels that are generated from the
> first cycle assuming the first cycle is not a placebo cycle.
>
> So, there are really a variety of effects from the first cycle
> priming, and it may be difficult to independently analyze the first
> from subsequent cycles.
>
> DR. GIUDICE: Dr. Keefe.
>
> DR. KEEFE: It seems like a condition where there is only a few
> thousand people worldwide that are affected by it, and it has taken 10
> years to recruit, should try to get any cycles they can.
>
> Maybe Dr. Emerson could discuss how one evaluates cycles when there
> are two cycles from one person as opposed to two cycles from two
> people in terms of the data analysis.
>
> DR. EMERSON: Well, as I talked about yesterday, the way I would do it,
> by did they get pregnant or not, or did they have whatever endpoint
> they were having. Again, the pregnancy would be my top choice, and
> it\'s a question of treating them on those cycles post-randomization,
> and whatever happens happens, particularly in a blinded study, there
> should be no problem.
>
> DR. EMMI: I guess my question is to Dr. Liu. Does a washout period
> between cycles make a difference in these cases?
>
> DR. LIU: Biologically, if you were to suggest that there was some
> priming effect, it may affect the response in a subsequent cycle
> depending on the washout period, but no one has any data to suggest
> how much priming would occur or the length of the washout.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: In addition to the problems with the washout, and having
> to figure that out, which would prolong the study in terms of doing
> that, there is also issues related to the evidence that we heard
> suggesting that there should be some ability to titrate doses, and so
> on, so again, it\'s randomizing them to a strategy and allowing the
> clinicians to go forward in the most natural clinical manner would
> provide the greatest ability to discriminate between ineffective and
> effective treatments.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: I would say that if the question really is do you have to
> look at multiple cycles to answer the question, I would say no, I
> think a single cycle, as a strategy for experimental design, ought to
> be sufficient in this situation. In fact, the later cycles may,
> because of priming and what you learn the first time, be even more
> successful, it amplified the difference, but a single cycle ought to
> be good enough.
>
> DR. GIUDICE: Dr. Lewis, you had a comment?
>
> DR. LEWIS: I was going to make the same point.
>
> DR. GIUDICE: Okay. So, let me repeat the question. Should multiple
> cycles be considered for evaluation? It\'s a little vague, I think
> still, this question. Perhaps Dr. Slaughter or Dr. Shames could
> clarify this. Is this for study design?
>
> DR. SLAUGHTER: I am sorry.
>
> DR. GIUDICE: We are still a little confused about No. 3. Should
> multiple cycles be considered for evaluation? Is this for conducting a
> study for approval?
>
> DR. SLAUGHTER: Yes, should we look at more than one cycle.
>
> DR. GIUDICE: So, should the sponsor have built into the trial design
> more than one cycle?
>
> DR. SLAUGHTER: Right.
>
> DR. GIUDICE: As a requirement.
>
> DR. SLAUGHTER: Yes.
>
> DR. GIUDICE: Dr. Brzyski.
>
> DR. BRZYSKI: I guess I am still trying to clarify the question. Are
> the options either FDA will never look at more than one cycle, or you
> always must have more than one cycle? Are those the two options?
>
> DR. SLAUGHTER: This addresses just this trial or just should we have
> looked at more than one cycle for this trial for this indication.
>
> DR. GIUDICE: This is specific to this?
>
> DR. SLAUGHTER: Yes, today, it\'s specific Luveris.
>
> DR. EMERSON: A question. But by that, do you mean that as this data is
> submitted now, that that would be the best analysis, or should the
> trial have originally been designed and with that specified as an
> endpoint?
>
> Can I suggest that in the interest of expediency, so that you can use
> it, that we divide this into two questions? One is, is it permissible,
> and the second is, is it preferable?
>
> DR. SLAUGHTER: That\'s fine.
>
> DR. GIUDICE: Perhaps someone can restate the question.
>
> DR. DICKEY: Let me ask a question first and see if that helps.
>
> DR. GIUDICE: Yes.
>
> DR. DICKEY: If I recall the data, the only multiple cycles we looked
> at here were where patients were folded into the ongoing study.
>
> Is your question here whether the data from those people who had been
> folded into a non-randomized study should be considered or not?
>
> DR. SLAUGHTER: No, the question is really whether or not we should
> have looked at multiple cycles for trials for this indication. It\'s a
> design.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: I think the first question is should multiple cycles have
> been required, so we can go around and answer that.
>
> DR. GIUDICE: Dr. Rice and then we will go around.
>
> DR. RICE: If I understand it. Should multiple cycles have been
> required for this study?
>
> DR. GIUDICE: Correct.
>
> DR. RICE: No.
>
> DR. TONER: No.
>
> DR. GIUDICE: Dr. Brzyski.
>
> DR. BRZYSKI: No.
>
> DR. STANFORD: I am going to say yes because I think that it would be
> better to have a pregnancy outcome, and then in that case, you would
> have to have multiple cycles to make it meaningful, but it would
> depend on your outcome that you choose.
>
> DR. EMMI: No.
>
> DR. EMERSON: I will put in a different disclaimer, but it is the idea
> of you would have to have a much larger sample size to please me, but,
> no, it doesn\'t have to be required.
>
> DR. LIU: No.
>
> DR. KEEFE: No.
>
> DR. GIUDICE: No.
>
> DR. DICKEY: No.
>
> DR. TULMAN: No.
>
> DR. LEWIS: No.
>
> DR. MACONES: No.
>
> DR. CROCKETT: No.
>
> DR. HAGER: No.
>
> DR. GIUDICE: Okay. Now, 3(b).
>
> DR. EMERSON: Can we answer the question of whether we think it would
> be preferable, because the requirement is a very different issue to
> me.
>
> DR. GIUDICE: It\'s Dr. Slaughter\'s question.
>
> DR. SLAUGHTER: In looking forward to future designs, yes.
>
> DR. GIUDICE: As preferable or required?
>
> DR. SLAUGHTER: Required. No, we have already answered required, I
> think, and his question is can we get a vote on preferable. I think we
> can discuss that.
>
> DR. GIUDICE: There is a comment here.
>
> MS. JAIN: I just want to make it clear as to what we are voting on
> because there have been several reiterations of this question. I think
> what the committee voted on, unless I am confused, is whether there
> should have been multiple cycles required for this particular study,
> for this NDA. It did not address whether multiple cycles should have
> been required for a general study design.
>
> If you want to have an answer to that question, then, we need to have
> a separate vote.
>
> DR. SLAUGHTER: That\'s what they voted on, I believe.
>
> DR. GIUDICE: So, the next question is whether it is preferable in
> subsequent application.
>
> DR. SLAUGHTER: I am not asking for a vote on that. I mean I think that
> you wanted to have a discussion on that.
>
> DR. EMERSON: My point is, is I think it is preferable to use the
> multiple cycles, but again I agree that this question could be
> answered with a single cycle, it would just take a larger sample size
> to use a good endpoint, whereas, if you use multiple cycles, it
> doesn\'t take as large a sample size.
>
> DR. GIUDICE: So, for the record, I guess the comment has been made
> that it would be preferable.
>
> Shall we go on? Okay.
>
> No. 4. Was it appropriate to use a surrogate endpoint for pregnancy,
> for example, follicular development in this study of hypogonadotropic
> hypogonadal women seeking pregnancy? We have already begun this
> discussion.
>
> DR. HAGER: I would have a comment.
>
> DR. GIUDICE: Yes, Dr. Hager.
>
> DR. HAGER: It seems to me that it was fairly clear to the sponsor from
> the FDA that ovulation was going to be the endpoint, and the sponsor
> chose to use follicular development, and I realize they have every
> right to do that, but it just seems to me that they would have taken
> that advice and for all the reasons that we have talked about pro and
> con.
>
> We have talked about this over and over. I think that the endpoint,
> contrary to what was said just a moment ago, is clinical pregnancy. If
> I was going to drop back to another surrogate endpoint, I would at
> least desire ovulation rather than just follicular development.
>
> DR. GIUDICE: I think it\'s important to remember that in looking at
> the pharmacologic action of the drug, that the endpoint obviously is
> going to be steroidogenesis and estradiol synthesis.
>
> Many women in ovulation induction cycles, whether it is for a
> hypothalamic amenorrhea or other conditions, who have ovulation
> induction, there is not 100 percent correlation between follicle
> development, ovulation, and pregnancy.
>
> So, in looking at the endpoint, when I read the data, and again I
> realize we all may have different perspectives on this, but I want to
> know also, as a clinician, whether or not there is follicle
> development. My patient may not get pregnant, but she at least will
> have had follicle development.
>
> Along with that follicle development is the issue of her estradiol
> level. So, when I look at the composite endpoint of the follicle size,
> which is primarily an FSH action, the circulating estradiol level,
> which is primarily an LH on the precursor synthesis, and a mid-luteal
> progesterone, to me, those are very powerful signs of a medication
> working or not working.
>
> So, the question here\--and I realize we are probably going to go
> round and round and round, and we could do this all night, but the
> question at hand is whether pregnancy\--was it appropriate to use a
> surrogate endpoint for pregnancy, and the example given here is
> follicular development. It could have been ovulation induction in the
> study of hypo/hypo patients.
>
> Dr. Rice.
>
> DR. RICE: Where did we come up with this phrase \"surrogate endpoint
> for pregnancy?\" Was that in the NDA and I missed it or something?
> Okay. So, why are even using surrogate endpoint for pregnancy, why
> aren\'t we just saying either follicular development or ovulation
> induction, because I think you sort of started to confuse things when
> you say surrogate endpoint for pregnancy.
>
> Really, we are talking about follicular development and/or\--it
> depends on whose version you want\--ovulation induction. And I agree
> with you, in this population of patients, I am comfortable for many
> reasons that I think some of the people in the open forum really
> shared with us, that for many of these patients, to get to the point
> where they have follicular development, have a menses, is a success
> for them, and that to use pregnancy as an endpoint does not I think
> encompass the essence of what is happening to that patient.
>
> So, I kind of view this patient as that very severe patient who is
> anovulatory, and if I get that patient to ovulate, which is expressed
> by follicular development and estradiol secretion, an increase in
> estradiol, then, I would feel like I have jumped a large hurdle in
> increasing her chances of getting pregnant or given her the
> opportunity to get pregnant.
>
> When we talked about the group of patients who may not need pregnancy
> as that endpoint, it may be something earlier that we should have used
> as an endpoint, like follicular development, ovulation induction. I
> think this patient population fits that.
>
> DR. GIUDICE: Dr. Lipshultz.
>
> DR. LIPSHULTZ: Didn\'t we already decide on this yesterday?
>
> DR. GIUDICE: Yes, we did.
>
> DR. LIPSHULTZ: This was WHO-I that we said we would accept follicular
> development.
>
> DR. GIUDICE: Correct.
>
> Dr. Crockett.
>
> DR. CROCKETT: I want to discuss a little bit more about what the
> criteria were used to determine follicular development. When we look
> at the recommendations from the FDA, going back to the Phase III
> trial, they recommended a much higher estradiol level, in fact, a
> cutoff of 200 pg/ml rather than the 109 pg/ml.
>
> That is significant, and that makes that borderline 106 picogram
> patient much less on the borderline, so I would like some comment from
> the reproductive specialists on the board about which would have been
> an appropriate measure of follicular success as far as an estradiol
> level.
>
> DR. GIUDICE: Dr. Lewis.
>
> DR. LEWIS: I wonder where 200 came from. That sounds high to me for
> this population of patients if they don\'t have a lot of follicles and
> they don\'t have much LH action.
>
> DR. GIUDICE: Dr. Keefe.
>
> DR. KEEFE: If a woman starts with a peak estradiol or a baseline
> estradiol of 40, and then goes up to 100-plus, they are going to
> ovulate. You are doing something significant.
>
> I don\'t think we are ever going to see ovulation per se. That\'s a
> microscopic event, we are never going to see. We are always going to
> use a marker for that, and that is what we are discussing. I would say
> a rise from 40 to 100, 106, that\'s ovulation about to happen. It\'s
> as close as we can get to it.
>
> DR. GIUDICE: Thank you.
>
> DR. LIU: I would disagree that 100 is an appropriate marker. I think
> you are going to find the majority, in the normal menstrual cycle,
> it\'s about 300 to 350 picograms at the time of the LH surge, and that
> has been well established by very sensitive RIAs, and it is
> repeatable.
>
> With gonadotropins, you have an artificial environment and generally
> the estradiol production per follicle with gonadotropins are going to
> be lower, but 100 is still on the very low side, I think, and if you
> look at the endometrial development, that is inadequate for
> endometrial development unless you have an integrated maintenance of
> that 100 picograms for a long enough period of time.
>
> So, in that particular patient that miscarried, I don\'t remember the
> endometrial thickness, but it certainly, probably was borderline.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: I have heard a lot of contradictions here today from the
> sponsor and from the various experts that simultaneously say this is a
> group that is just not going to get pregnant by themselves, where they
> need to have this luteinizing hormone therapy, and then the statement
> that was made by the sponsor was people are so happy when I tell them
> that they will have normal fertility.
>
> If that is true, then, there is no problem in using a good clinical
> endpoint in this trial, either that LH therapy will return them to
> normal fertility in which case it can be managed, or there is some
> question that it really works. So, in that case, we ought to see
> whether it works.
>
> I would argue that a properly designed trial with this sample size or
> slightly larger would have stood a good chance based on anecdotal data
> that we have here, that I think we can only treat as observational
> data at this point, but it is suggestive that the effect might be in
> the range that another trial of approximately this size would work,
> and then why go to the surrogate endpoint.
>
> DR. GIUDICE: Well, there are things in biology that we still don\'t
> understand in terms of implantation especially in women during the
> process of an ovulation induction cycle.
>
> DR. EMERSON: I agree absolutely, so if we don\'t understand that
> biology, there is just the possibility that this therapy might
> actually be making it worse. So, again, if we don\'t know, then, we
> should answer it, given unlimited resources and unlimited numbers of
> patients, I would say answer those questions separately.
>
> Let\'s answer the question at every single stage, what can we do to
> increase follicle generation, what can we do to then have ovulation,
> what can we then do to have fertilization, what can we then do to have
> implantation, and go on to a live birth, that has no birth defects.
>
> If you have unlimited resources, answer each one of those questions
> separately, but we don\'t have unlimited resources, it is attainable
> within this population to answer the bottom line question, which is
> the one that I think is ethical to answer both from the standpoint of
> the patients who suffer from infertility, I think that they would be
> very, very irritated if they found out 20 years from now that they had
> been spending an extra \$10,000 for something that did not help them
> at all, or possibly was even harmful.
>
> So, when we can answer the bottom line question, and we can never
> answer the mechanistic question in terms of ethics and efficiency,
> then, go ahead and make certain that we at least answer the bottom
> line question.
>
> DR. GIUDICE: Well, we have heard the entire gamut from follicle
> development all the way through pregnancy. Yesterday, as a committee,
> we gave you our advice for this class of patients, WHO-I, that we
> would recommend follicle development as the endpoint.
>
> DR. EMERSON: I will just note there was not a vote on that, there was
> a consensus, but you can tell which way I would have voted.
>
> DR. EMMI: I thought that what we decided was that pregnancy wasn\'t an
> appropriate clinical endpoint and that some other endpoint would be
> established, but I don\'t remember that we actually ever said whether
> it would be follicle development or ovulation.
>
> DR. GIUDICE: Well, this is very germane to the question that is being
> asked because we, as a committee, need to make a decision (a) whether
> we think pregnancy should be an endpoint for now WHO-I patients, and,
> if not, then what the endpoint should be.
>
> I mean do you want that information from us?
>
> DR. SLAUGHTER: Pregnancy or live birth, and if you agree that a
> surrogate endpoint\--I am sorry for using surrogate, but to me,
> surrogate is the endpoint you use when you can\'t measure the direct
> effect, so I am calling it surrogate\--if you agree that a surrogate
> should have been used, what surrogate should we have used.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: Two quick comments. My understanding of yesterday\'s
> discussion was we said that live pregnancy was the best, clinical
> pregnancy would be acceptable. In the case of WHO-I, if we could not
> attain that because of power, if we could not attain it for power,
> then, we would accept follicular development or I actually don\'t
> remember exactly what surrogate we said we would accept.
>
> The question here seems to be a little bit one of fairness, because
> the FDA did tell the sponsor it would accept a surrogate, only the
> sponsor chose a different surrogate than what the FDA recommended.
>
> So, we have a subquestion. But to me there is a fairness issue and
> that the FDA did indicate a willingness to accept a surrogate, and
> that is a little bit of an issue there.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: I note that, of course, everyone on the committee can
> vote their conscience, I vote my opinion, and the question, you know,
> the FDA is possible of doing things that I don\'t think is
> appropriate, and I still give that opinion, so that is the question
> that I would answer is how should this trial be done that is credible
> evidence, not did they agree with the FDA.
>
> Am I correct that this question is not did the sponsor agree with what
> you said?
>
> DR. SLAUGHTER: Yes. It is simply your advice on which surrogate
> endpoint we should use, keeping in mind if there were to be future
> studies.
>
> DR. GIUDICE: Then, do you want us to vote on the various endpoints?
>
> DR. SLAUGHTER: No, this could be a discussion.
>
> DR. GIUDICE: Dr. Hager.
>
> DR. HAGER: May I read what we said yesterday? Drug manufacturers
> conducting studies for female infertility currently obtain the
> following indications: (a) induction of ovulation and pregnancy; (b)
> multiple follicular development and ART. These indications should be
> induction of ovulation and pregnancy, and multiple follicular
> development and ART and pregnancy.
>
> So, we added \"and pregnancy\" to those yesterday.
>
> DR. SLAUGHTER: Let me clarify how I understand this. Yesterday, you
> said that you thought, in general, clinical pregnancy defined by
> presence of a fetal heartbeat to be used, in general, for ovulation
> induction, and ART to be exclusive of patients with WHO Type I.
>
> Today, you said you thought that a surrogate would be possible, and
> you have now confirmed that we shouldn\'t look at pregnancy, we
> shouldn\'t be trying to establish a difference in pregnancy.
>
> If we don\'t do that, what should we look at?
>
> DR. GIUDICE: And the options that we have discussed so far are
> follicle development or ovulation induction.
>
> DR. SLAUGHTER: Follicle development defined on ultrasound, ultrasound
> plus hormone levels, how?
>
> DR. GIUDICE: We can discuss that.
>
> Dr. Stanford.
>
> DR. STANFORD: I think follicular development, if it\'s accepted as an
> endpoint. I think ovulation is probably better, but if follicular
> development is accepted as an endpoint, I don\'t think cancellation of
> cycles due to risk of OHSS should be included as follicular
> development.
>
> DR. RICE: Are we having a general discussion or are we discussing this
> product and this study? I think we are getting off track here. We have
> to give a decision on this product today, so we need to\--I mean it is
> already defined. They defined follicular development, you gave some
> criteria, you had some definitions for ovulation induction.
>
> So, we have to decide on whether or not the sponsor met the criteria
> that was laid out to them, whether follicular development or ovulation
> induction. I mean there may be subsequent some additional time when we
> can beat this idea again in the ground, but I think we need to decide
> on this product, and we are getting away from that.
>
> DR. GIUDICE: Is our charge to decide whether or not the sponsor
> complied with the recommendations of the FDA, or whether the endpoints
> that were used were appropriate for the study?
>
> DR. SLAUGHTER: The latter.
>
> DR. GIUDICE: Thank you.
>
> Dr. Brzyski and then Dr. Emerson.
>
> DR. BRZYSKI: Let me go back to that comment that you made specifically
> looking at this product and the pharmacologic effect. Somehow a
> consideration of estradiol production, I think needs to be considered
> or thought about because even in the sponsor\'s presentation,
> referring back to Dr. Shoham\'s experience, there are patients that
> will develop follicles measurable on ultrasound in the absence of
> estradiol production on pure FSH.
>
> So, to show efficacy of the LH, which we have a pretty good idea how
> it works and what it does, somehow I think you need to get the
> estradiol into that calculation as a surrogate.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: I was just going to suggest three yes or no votes to try
> to address those three major points. Ask one question of whether the
> study should have evaluated clinical pregnancy. That seems to be sort
> of a dividing point. The next one would be ovulation defined by a
> mid-luteal progesterone level, and not counting a risk of OHSS as an
> endpoint. The third level is a yes or no question on follicular
> development.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: That first question is not, in my opinion, appropriate for
> us to answer. The FDA and the sponsor, the only thing they are
> disagreeing on is whether or not they should have taken out ovulation
> induction. They never had an endpoint of clinical pregnancy on the
> table.
>
> Now, we can answer your question when we get down to 6. If we get down
> to 6 and you said there are additional studies that need to be done
> that address clinical pregnancy, we can have that discussion, but we
> shouldn\'t be voting today, in my opinion, to say whether or not they
> should have added clinical pregnancy to that, because that is not the
> question before us.
>
> DR. EMERSON: We are a scientific advisory board that is not subject to
> the FDA, nor subject to the sponsor. They want our opinions. So, if we
> can just as easily say that we think the FDA messed up, or we think
> the sponsor messed up, and that is our role. Our role is to give our
> opinions.
>
> DR. GIUDICE: I think this is not a boxing match, so I think we really
> need to hone in and focus in on the issues at hand.
>
> What I have heard the FDA say is that you want our opinion about an
> appropriate surrogate or an appropriate endpoint, and the options are
> either follicle development defined by\--and this is this particular
> NDA that we are addressing\--defined by follicle size, an estradiol
> level of greater than 109 or 106\--109, and a progesterone level
> greater than 7.9 pg/ml.
>
> That\'s not what your question says, but what we are addressing, as I
> understand it, is the appropriateness of the endpoints put forward by
> the sponsor.
>
> DR. SLAUGHTER: Yes.
>
> DR. GIUDICE: It is very difficult for us to come up with our
> questions.
>
> DR. SLAUGHTER: Let me try this one more time. If you don\'t
> agree\--and we have gotten past the clinical pregnancy thing\--if you
> are saying in WHO Type I, you should look at something short of
> pregnancy, what is it?
>
> DR. GIUDICE: Is this for general studies or for this particular study?
>
> DR. SLAUGHTER: This is for general studies. I am not going to ask you
> to comment on the appropriateness of it for this study, because that
> is what was done.
>
> DR. GIUDICE: So, then, we did that yesterday and we don\'t need to
> vote on that, do we, because it not specifically address\--
>
> DR. SLAUGHTER: Not for Group 1, I didn\'t understand you to have done
> that for Group 1.
>
> DR. GIUDICE: Perhaps we can repeat this then. Would someone like to
> summarize what we decided yesterday? Dr. Hager read it. I think what
> Dr. Slaughter is asking for is the follicle size, am I right or not?
>
> DR. SLAUGHTER: How would you define follicular development, should it
> be defined for all three of the criterion as the sponsor did here? If
> you are saying you should look at follicular development, should it be
> based on follicle size, estrogen, and progestin, or are you talking
> about just an appearance on ultrasound, follicles?
>
> And one other thing. Is estradiol and progesterone sufficient, should
> we also be looking at other factors that might come in for follicular
> development? This is for future considerations.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: I would say that in the context of this study, for this
> drug, it is not inappropriate at all to look for the follicles to
> grow, estrogen to be produced, and then progesterone to be above a
> certain level, but those criteria that here define follicle
> development might not be the pertinent ones if another drug that also
> has a role in follicle growth was being considered.
>
> So, again, for this particular product, I think these are satisfactory
> criteria to judge efficacy.
>
> DR. GIUDICE: Dr. Crockett.
>
> DR. CROCKETT: I was just going to make a suggestion that we kind of
> make a list of most preferable to least preferable evidence to
> consider for future drugs, and I would put forth that a pregnancy of
> any kind would be definite evidence of ovulation, that the
> progesterone levels and the estrogen and FSH and LH levels that we
> have discussed may be considered in some cases as acceptable evidence
> or probable ovulation, but I would want to use Dr. Liu\'s numbers
> rather than the lower numbers that were suggested in this study.
>
> I would suggest that folliculogenesis or growth by ultrasound or other
> means, by itself, should not be considered evidence of ovulation
> because so much of the background information that we heard, that
> other things, you know, the LH and the quality of the egg are
> important in determining whether ovulation occurs or not.
>
> For that reason, I would also not include the OHSS patients as proof
> of ovulation.
>
> DR. GIUDICE: Okay. I would like to address the OHSS patients because
> that does get to the last bullet on that question. To have an outcome
> or to look at that, of OHSS as an endpoint, is a bit peculiar, and I
> think when we all have read these data, I don\'t quite think that
> that\'s going to be one of the issues in terms of showing efficacy of
> drug.
>
> However, you are never going to get OHSS unless you have follicle
> development, so I would still argue that for this particular NDA, that
> it was an appropriate choice. In general, however, and this is where I
> think the FDA perhaps can use our help, and that is, whether this
> should be considered as an endpoint of the proof of either follicle
> development or ovulation in the future.
>
> Dr. Keefe and then Dr. Lewis.
>
> DR. KEEFE: I agree. Imagine if were to go back 80 years and we are
> looking at a new drug called insulin, and somebody gets hypoglycemia,
> and we say oh, it doesn\'t count. You know, we are just looking to try
> to control hypoglycemia, but we are not going to count that because it
> is not officially optimal control.
>
> I mean you have got to start somewhere. We probably spent one year of
> somebody\'s time for each patient, each cycle that somebody is going
> to be taking this, and I think we are missing the point. We are
> restoring physiological function for a group of patients that have
> very few alternatives. We should keep that in the context.
>
> DR. GIUDICE: Dr. Lewis.
>
> DR. LEWIS: Well, I think it depends very largely on how you define
> OHSS and for what study. If you say that it was defined as patients
> who had a certain number of 15-millimeter follicles, which is a large
> follicle, plus a high estradiol, then, I agree that that indicates the
> drug worked, but we just heard that FSH action alone is sufficient to
> get a large number of follicles, and if you had a little bit of
> estrogen from a large number of small follicles, guess what. Your
> estrogen would go up.
>
> So, I think you have to be very careful how you define OHSS, and as a
> general rule, it\'s not\--you just have to be careful if you are going
> to use that as a means of saying that that is drug efficacy.
>
> MS. WILLIAMSON JOYCE: Pardon me. I just want to remind that we are not
> talking about OHSS, we are talking risk, and again, the very low, low
> cutoff that we put, which is not necessarily the criteria that you
> would necessarily use to cancel a cycle.
>
> DR. LEWIS: Right. I am not arguing that that was appropriate, and I do
> think it did show that the drug had some effect.
>
> DR. GIUDICE: Dr. Crockett.
>
> DR. CROCKETT: I am not sure that it does show that the drug had some
> effect. We have seen and heard testimony that you can blast somebody
> with FSH and get follicular growth all by itself. In fact, we saw that
> in some of our placebo patients. There was one placebo that was
> removed from their study that had OHSS and didn\'t even have the LH
> challenge.
>
> So, my point being again you can have follicular growth without LH,
> and if you are looking at a recombinant LH product, that in and of
> itself does not indicate that it worked.
>
> DR. GIUDICE: Dr. Macones.
>
> DR. MACONES: I would just add that as we think about this, we are not
> just thinking about approving a drug, we are thinking about approving
> a drug at a dose, so the question of safety, I think is very relevant,
> whether the 75 units of recombinant LH is both effective and safe.
>
> To me, that is where the OHSS question or the risk of OHSS comes in is
> whether or not this is the right dose for this drug.
>
> DR. SLAUGHTER: Actually, a consideration for the patients who were
> taken out of the study and the cycles canceled, whether you really
> considered that as evidence that the drug is working, and in the end,
> that we should approve or we should consider that that drug showed
> efficacy for the endpoint.
>
> MS. WILLIAMSON JOYCE: Again, just for the sake of accuracy, the
> patients were not removed from the study. There were no patients
> whose\--the cycle cancellations did not remove the patients from the
> study.
>
> DR. SLAUGHTER: All right. Let me rephrase that. Patients whose cycles
> were canceled for risk of OHSS, does that show efficacy?
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: It does for me. Under the condition that apart from
> follicle growth, which probably didn\'t have anything to do with the
> LH, they went on to have estrogen production and progesterone
> production, which we have been assured has happened in those who were
> dropped from the study at that point. So, I would take that as
> efficacy of the drug doing what we hope the drug will do.
>
> DR. GIUDICE: Dr. Emerson.
>
> DR. EMERSON: To introduce a slightly different analogy than the
> diabetes, in hepatorenal syndrome, people did try dialysis to see if
> that would not cure it, because the people apparently had kidney
> failure after severe liver failure. They did try it. If they had used
> your criterion that, oh, well, we modified the BUN, dialysis does
> modify the BUN, it does not change survival one iota, and we would be
> dialyzing an awful lot of moribund patients today.
>
> The criterion is not just in a surrogate marker that is perfectly
> predictive in a natural state, once you intervene on that population,
> you cannot count on that same covariance, the same correlations which
> are your final endpoint, and there is a level of scientific
> credibility we need to say that that still obtains.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: I have a note written down here, and I just want to clarify
> this. The question was asked earlier, in those patients at risk for
> OHSS, that those patients were canceled because of follicular
> development, and five of those patients had no appropriate increase in
> estradiol production. Is that incorrect? So, what is the correct
> answer?
>
> MS. WILLIAMSON JOYCE: Yes, it is incorrect.
>
> DR. RICE: So, what is the correct answer?
>
> DR. KENLEY: Three were canceled because of large follicles. That is
> three follicles greater than 15 mm. One was on placebo and two were
> 75.
>
> DR. RICE: Before you go to the next part, what were those patients\'
> estradiol, was it appropriate, was it increased? Did they have
> concomitant\--I know you have the results.
>
> DR. KENLEY: They were greater than 109, and\--
>
> DR. RICE: No, no, go on. I want you to tell me about the rest of them.
>
> DR. KENLEY: And four patients were canceled because they had large
> estradiol. Two of those patients also had follicles.
>
> DR. RICE: So, essentially, four of those patients out of seven\--
>
> MS. WILLIAMSON JOYCE: Out of six.
>
> DR. RICE: Okay. Four out of six of them had appropriate increases in
> estradiol with follicular development.
>
> DR. KENLEY: Yes.
>
> DR. RICE: And estradiol, you are saying is appropriate, is greater
> than 109.
>
> DR. KENLEY: Well, no, they were greater than 1,100, because they were
> canceled.
>
> DR. RICE: But only four of those, but two of them, you haven\'t told
> me what the estradiol was. You just told me it was greater than 109.
>
> DR. KENLEY: Do you want to know what the estradiols are?
>
> DR. RICE: Yes.
>
> DR. KENLEY: One was 423 and the other one was 556.
>
> DR. RICE: So, they had increases in their estradiol.
>
> DR. KENLEY: Yes.
>
> DR. RICE: Now, let me ask this question. If you add those people into
> the analysis, in your calculation, is your data statistically
> significant, is it significantly different?
>
> DR. GIUDICE: Dr. Rice, what is your question?
>
> DR. RICE: My question is, if you add those patients back in as
> successes, do we have statistical significance, or do we have a
> difference?
>
> DR. GIUDICE: By the FDA analysis?
>
> DR. RICE: By the FDA analysis. I am asking FDA, if they take those six
> patients\--
>
> DR. SLAUGHTER: Can you address that? If you add the four patients back
> who had\--
>
> DR. RICE: Six.
>
> DR. SLAUGHTER: Is it six?
>
> DR. RICE: It would have to be six because she said two of them had
> estradiol levels, one was 400 and something, one was 500 and
> something. Those two and then the other four had estradiols over
> 1,000.
>
> DR. SLAUGHTER: If you don\'t count the ones who were canceled for OHSS
> as failures, then, yes, it would have been significant.
>
> DR. RICE: Okay. So, adding those six back makes it significant.
>
> DR. GIUDICE: Dr. Emmi.
>
> DR. EMMI: I am a little confused. I agree that we could look at the
> data for the OHSS patients. What I am confused about is did they
> actually meet their criteria that was set forth. I understand we are
> not getting progesterones probably because they weren\'t drawn, but
> did they have the size of development that the study had said was
> necessary, and did they have the amount of estradiol per follicle that
> was necessary, and I am not clear on this.
>
> DR. RICE: From my understanding, they had the size because of all of
> them had large size follicles.
>
> DR. EMMI: Fifteen.
>
> DR. RICE: Fifteen millimeters.
>
> DR. EMMI: Fifteen, not 17, which I thought was the criteria.
>
> DR. RICE: But 15 mm was the criteria for canceling for risk.
>
> DR. EMMI: Right, and what I am asking is if you are going to say that
> they met criteria for including them in the folliculogenesis phase,
> then, I think they needed to meet the criteria that were laid out by
> the study, which is 17 mm, and if they continued in the study, then,
> do they have that data? Do you understand what I am saying?
>
> It\'s 15 versus 17, and if they had 20 follicles with the estradiol
> 500, or if they had 6 follicles with the estradiol 500, it makes a
> difference in the quality of folliculogenesis to me, and I don\'t have
> that data available is what I am saying.
>
> DR. GIUDICE: Let me just try to bring us together here. I am not sure
> we have that information, but from what I have heard, it sounds like
> the estradiol levels were 4- and 500, and you don\'t usually get that
> from even 107-mm follicles. You need some kind of LH action.
>
> We are supposed to adjourn at 5 o\'clock, however, many of the flights
> to the West Coast actually stop leaving Washington at around 6:30, so
> we are going to lose some of our committee members in about half an
> hour.
>
> Because the FDA wants us to\--No. 4 has been converted to a
> discussion, and I hope that we have given you enough information
> regarding parameters.
>
> The other number that we have been asked to vote on is No. 5, and that
> is: Are the data sufficient to establish efficacy for ovulation
> induction? Then, we will get to No. 6. That will be in a discussion
> format.
>
> Dr. Shames.
>
> DR. SHAMES: I want to make things very clear when it comes to No. 5.
> Five is really the essential question. There is no doubt we have got
> to answer the question is the data sufficient to establish efficacy
> for ovulation induction.
>
> The reason for that is because that is the indication that is in the
> NDA, which we did not approve.
>
> Now, several weeks ago the sponsor did ask or request a re-analysis or
> discussion regarding follicular development. If the sponsor wants to
> do that, then, they need to resubmit data to us, and we can consider
> that as something called a complete response. That is another issue.
>
> The issue is, though, we need to know the answer to No. 5 as it
> pertains to ovulation induction. If we discuss follicular development,
> I am not going to know what to do about that, because that is not the
> indication that was in the NDA.
>
> So, we can have discussion about follicular development, but we need
> to know the answer to Question 5 as it pertains to ovulation
> induction.
>
> MS. WILLIAMSON JOYCE: I am sorry. Then, I would suggest that perhaps
> the question should include the\--I mean we did include follicular
> development in the NDA indication.
>
> DR. GIUDICE: Can the FDA give us some guidance here? The sponsor is
> stating that what they had was follicle development and ovulation
> induction, and then they dropped the ovulation induction for other
> reasons.
>
> DR. RICE: Why can\'t we vote on them separately? Why can\'t we vote on
> them as follicular development, and then we can vote on ovulation
> induction, and then you all can decide if you have the right
> information.
>
> DR. SLAUGHTER: Ovulation induction first, please.
>
> DR. GIUDICE: Okay. Would you define that for us, please?
>
> DR. SLAUGHTER: We base ovulation induction on the progesterone level
> alone.
>
> DR. GIUDICE: Okay. Is there any discussion about this before we vote?
> Yes, Dr. Emerson.
>
> DR. EMERSON: Also, it generally takes more than one study to really
> establish these things. It is not the idea that do they have one
> result, and what the FDA claimed, and which I personally concur with,
> is that the 6905 study, well, actually, we all concurred with that
> unanimously, that that was not too germane to this point, and that
> neither of these studies stand on their own when you do not count the
> OHSS as an endpoint, that neither of them achieve any level of
> statistical significance.
>
> The Phase II study was an unblinded study, as well, so it is really
> there is this real paucity of scientific evidence and credibility that
> is lacking on this submission.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: Is that data that we have for ovulation induction, as you
> define it, as progesterone, greater than 7.9? Is the correct data that
> we have from Slide 46 of your presentation? Because as I can recall,
> Serono, did you present any data to us on progesterone levels? If you
> did, maybe you want to put it up.
>
> MS. WILLIAMSON JOYCE: Yes.
>
> DR. RICE: Which slide is it?
>
> MS. WILLIAMSON JOYCE: First of all, the p4 was one of the three
> elements of the composite endpoint. So, we have the composite endpoint
> plus any indication of pregnancy as being a success.
>
> The study, however, was not prospectively defined using ovulation
> rates as the endpoint. So, we have data on p4, but any statistical
> analyses done post-hoc on a single element of that composite endpoint
> need to be considered for what they are.
>
> DR. RICE: When you all agree, the pre-meeting that you had when you
> had the discussion, I mean what you were defining ovulation induction
> as? You didn\'t agree what you were going to define ovulation
> induction as?
>
> MS. WILLIAMSON JOYCE: We have always defined the endpoint as the
> composite endpoint of follicular development with those three elements
> plus any sign of pregnancy, whether it be a positive beta hCG or
> confirmed by ultrasound.
>
> Again, we agreed in the meeting of May of 1999 that the FDA
> recommended that we use ovulation rates as the endpoint measured by
> p4, and that recommendation was considered carefully along with all of
> the other recommendations including the blinding of the study, but we
> continued to maintain that the composite endpoint of follicular
> development as defined prospectively in the protocol, and as also
> defined in 6253, was the correct endpoint.
>
> DR. GIUDICE: Just before getting to Dr. Crockett, the composite
> endpoint, it is not one or two or three, it\'s all three of them, so
> it\'s the follicle size, the estradiol, and the progesterone, it\'s
> not just a single progesterone level. I just wanted to make that
> clear.
>
> DR. SLAUGHTER: Along with the escape, the cycles are canceled.
>
> DR. GIUDICE: Yes, and along with any pregnancy.
>
> Dr. Crockett.
>
> DR. CROCKETT: Just a point of clarification. In the large green folder
> that we were supplied with, there is a copy of amended NDA from 2001,
> Section 2.3 in our folder, and it clearly says that the indication at
> that time was stimulation of follicular development and ovulation in
> infertile women with LH and FSH deficiencies.
>
> Am I mistaken?
>
> DR. GIUDICE: Yes, I don\'t think that is the NDA. I think that was the
> penultimate one.
>
> MS. JAIN: What the sponsor is referring to is an additional amendment
> that they sent in August of this year.
>
> DR. CROCKETT: In August of 2003?
>
> MS. JAIN: Yes.
>
> DR. CROCKETT: This is the NDA from 2001.
>
> MS. WILLIAMSON JOYCE: No, these are the medical reviewers and the
> statistical reviewers\' reviews of the original NDA.
>
> DR. CROCKETT: So, we don\'t have a copy of what the original NDA said
> or what the NDA from 2001 said as the indication?
>
> DR. SLAUGHTER: No, I don\'t have that label with me.
>
> DR. GIUDICE: Can we get back on track here.
>
> Dr. Keefe.
>
> DR. KEEFE: It seems to me most of the crux of the argument rests in
> Serono\'s or the sponsor\'s table at the bottom of page 29 of their
> presentation, and the FDA\'s at the bottom of page 14, and just lining
> up those two tables, there is one cell that differs, and that\'s in
> Luveris treatment, you know, the FDA claims there is 16 out of 26, and
> Serono claims it\'s 17 out of 26, so if we could just find out about
> why those numbers differ. I mean that is the crux of it, right,
> that\'s where they really differ. That is where the rubber meets the
> road.
>
> DR. GIUDICE: That was that one patient.
>
> DR. KEEFE: That\'s the one patient. So, that is what we should be
> discussing, right? The pregnant patient.
>
> DR. SLAUGHTER: I just wanted to get back. I don\'t have the label, but
> when I put up the screen, I copied that directly from the label.
>
> I also have the medical officer\'s review that put the labels,
> applicant\'s proposed indication for concomitant administration with
> recombinant human follicle stimulation hormone for the induction of
> ovulation in infertile women with severe LH and FSH deficiency.
>
> DR. GIUDICE: Thank you.
>
> We are now trying to address the issue of whether or not the data are
> sufficient to establish efficacy for ovulation induction where
> ovulation induction has been defined by the FDA apparently as a p4,
> and by the sponsor as a composite endpoint including OHSS patients and
> also pregnancy defined from chemical through clinical.
>
> Dr. Stanford.
>
> DR. STANFORD: Again, can we vote on those separately? Let\'s vote
> first on the p4 definition and then, second, on the sponsor
> definition.
>
> DR. GIUDICE: If the FDA wants us to do that. Do you want us to do
> that, or how do you want us to define ovulation induction? Then, we
> will go to follicular development.
>
> DR. STANFORD: And if I am understanding what the sponsor is saying in
> making their revision of their indication, is they are actually not
> defining ovulation induction, they are actually defining follicular
> development, because they submitted a modification to their NDA to say
> what we want to approve is for follicular development, and that is
> their definition of follicular development.
>
> DR. GIUDICE: Dr. Slaughter.
>
> DR. SLAUGHTER: Yes. We would like you to take a vote on both. Take it
> on ovulation induction as defined by the sponsor\'s follicular
> development, looking at the data as proposed by the sponsor and the
> FDA, and ovulation induction as defined by progesterone level, looking
> at the data as put up by the FDA.
>
> I don\'t think the sponsor gave you progesterone-only data.
>
> DR. GIUDICE: I don\'t think we have that information.
>
> MS. WILLIAMSON JOYCE: No, we wouldn\'t have done that. That was post
> hoc on an endpoint that wasn\'t\--
>
> DR. GIUDICE: Other discussion about this? Dr. Keefe.
>
> DR. KEEFE: Just a question. The patient, the pivotal patient who got
> pregnant, did she have a progesterone level drawn?
>
> DR. SLAUGHTER: Yes, she did, and she would have been counted as a
> positive in the progesterone analysis.
>
> Kate, can you put up your progesterone analysis again.
>
> DR. GIUDICE: Dr. Emerson and then Dr. Lammers.
>
> DR. EMERSON: Just as a parting shot because I have to go, but I think
> if you listen to us very, very closely, as we are sitting and
> discussing one patient and saying how this one patient would sway us
> one way or the other, I don\'t think it takes being a statistician to
> say that that is not exactly credible evidence.
>
> I would hope that we would operate where one patient didn\'t make a
> difference.
>
> DR. GIUDICE: Dr. Lammers.
>
> DR. LAMMERS: Can I have the slide on, please.
>
> DR. SLAUGHTER: Excuse me. Can we go ahead and proceed to the vote?
> People are leaving, and we would like to take the full benefit of
> people being here, so can we please vote?
>
> DR. LAMMERS: Can I reply to Dr. Keefe\'s question briefly? She had a
> p4 value of 13.2 nanograms per ml.
>
> DR. GIUDICE: So, you want us to vote. Let\'s first vote on whether or
> not the data are sufficient to establish efficacy for ovulation
> induction (a) as defined by the sponsor.
>
> So, that includes the three parameters that are and, not or, follicle
> development, estradiol, and progesterone, and also including the
> patients who were canceled for risk of ovarian hyperstimulation
> syndrome, and also patients who had pregnancy of any type.
>
> So, we will start with Dr. Hager.
>
> \[Vote taken.\]
>
> DR. GIUDICE: Now, the second is to answer the question, the same
> question, but with the FDA definition of ovulation by a progesterone
> level. Understand that on both sides, there are issues, the whole
> issue of doing that analysis without having it prospectively put into
> the protocol.
>
> \[All voted no.\]
>
> DR. GIUDICE: The follicle development piece. Now, we are going to take
> a vote unless\--no, there is no further discussion\--on whether or not
> the\--let\'s give it the same level of rigor\--are the data sufficient
> to establish efficacy for follicle development, and the only
> definition of follicle development that we have is the sponsor\'s.
>
> We will start on this side of the table.
>
> \[Vote taken.\]
>
> DR. GIUDICE: Any other subpieces of No. 5 that you want votes on?
> Okay.
>
> We are just doing the tallies here. We have no hanging chads, so we
> have to be sure we have everybody.
>
> Drs. Brzyski, Stanford, and Emmi, there was a lapse here of receiving
> your information, so could you please restate your vote for the last
> one.
>
> Brzyski said yes, Stanford no, Emmi yes.
>
> We are now down to No. 6, and that is: If additional clinical studies
> are recommended, what type of study or studies should the Division
> request in order to provide sufficient evidence of efficacy? Should
> additional studies evaluate lower doses for efficacy?
>
> This is now open for discussion, and we are not voting on this.
> Correct?
>
> DR. SLAUGHTER: Correct.
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: My vote would be not to bother about lower doses. We use
> doses higher than this all the time clinically without any evidence of
> harm. I would rather invest the time and money in trying to free up
> the investigator for varying the FSH dose as they go to avoid the
> problem of OHSS cancellation risk.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: I agree with that. I fully agree with that, that if a
> future study is done, the ideal design would be double-blind with the
> 75 IU, with yes or no with the double-blind, and then the investigator
> is left free to vary the FSH dose, and I would argue for an outcome of
> clinical pregnancy with multiple cycles.
>
> DR. GIUDICE: I think it is going to be quite a challenge to find that
> many hypothalamic hypo/hypo patients, but it\'s the study design that
> we are after.
>
> DR. STANFORD: I am just making my opinion, and I would refer again to
> what Dr. Emerson said, and again I would defer to him for power
> calculations, but he is of the opinion it wouldn\'t take that many
> more than what we have got.
>
> DR. GIUDICE: Thank you.
>
> Any other discussion? Additional studies to be proposed? Yes, Dr.
> Tulman.
>
> DR. TULMAN: I would just like to propose that since we voted to
> approve this drug for a very limited population, although not to
> disparage this population in any way, but the evidence for the drug
> and our approval for it is based on a very limited population, and if
> this drug were to be approved and used, it would probably wind up
> being used in a larger population, and I don\'t think that we really
> have the evidence to say what would happen in that larger population.
> I think we need that research both for safety, as well as efficacy.
>
> DR. GIUDICE: I just want to clarify that this committee has not done
> any approval of any drug.
>
> DR. TULMAN: I believe I said were to be.
>
> DR. GIUDICE: Were to be.
>
> DR. TULMAN: Were to be.
>
> DR. GIUDICE: Thank you.
>
> Dr. Hager.
>
> DR. HAGER: I would just echo that again. I think that our
> recommendations heard today are for a very narrow, specific
> population, and even a subpopulation of that group with very low LH
> levels, and to discourage the use in a general population.
>
> You can just see where this could go with off-label use. I think that
> what you have heard today is that we don\'t see the evidence, barely
> evidence of effectiveness, and a sincere concern about extending this
> use to patients off label.
>
> DR. GIUDICE: Dr. Rice.
>
> DR. RICE: I think it has also been evident from our discussions that
> the communication between the FDA and the sponsors needs to become
> more transparent and clear, and that a lot of this confusion probably
> could have been avoided if there was some better documentation.
>
> I think it puts the committee in a difficult situation when we are not
> clear about what we are to provide advice on. So, I would hope that in
> the future, that there is some improved communication such that we can
> make sure that we can fulfill our duty, and that is to make our
> recommendations that is based on very good, sound evidence and a clear
> understanding of what the expectations were that the sponsor were to
> meet from the FDA.
>
> DR. GIUDICE: I just want to clarify something that Dr. Hager said. I
> am not sure I heard this correctly or maybe I did, but I am not sure I
> agree with it, and that is that the FDA has heard from us a committee
> that there is not much information about efficacy.
>
> Is that what you said? If you could clarify that, please.
>
> DR. HAGER: What I was saying was that the FDA has heard our
> deliberations regarding the efficacy of this drug. I didn\'t say that
> it wasn\'t effective. I said they have heard our deliberations about
> the efficacy, but I have a concern also about off label.
>
> DR. GIUDICE: Thank you.
>
> I am wondering if the FDA could let us know, now that you have some
> information from us in an advisory capacity, what you will do with
> that and what the next step will be.
>
> DR. SHAMES: Well, I will give you a bureaucratic answer. I guess the
> answer is that we will evaluate these various votes and evaluate the
> comments, and meet internally to see how we will move forward. I
> didn\'t even count up the votes, but you did.
>
> I thought I heard that from the p4 definition, the data was not
> sufficient. Is that the vote?
>
> DR. GIUDICE: The p4 was uniformly no.
>
> DR. SHAMES: Right.
>
> DR. GIUDICE: And the ovulation induction by the sponsor\'s definition,
> we have to determine what that is for the final tally. Apparently,
> that is going to come out in the minutes that Shalini will pass out
> just to the committee participants.
>
> DR. SHAMES: We will go back and have our own internal discussions and
> come to some conclusion. As you know, we weigh heavily your opinion,
> and we have to exactly extract what that was. Then, it is ultimately
> up to us to come to the decision.
>
> Of course, we interact now with the sponsor to see what will come with
> this, ultimately, how we will go.
>
> DR. GIUDICE: Thank you.
>
> Is there anyone who wants to make any additional comments before we
> conclude?
>
> MS. WILLIAMSON JOYCE: I would. First of all, I would like to thank the
> Division for bringing this NDA before an advisory committee. This is
> an important part of the process. I would like to thank all of you for
> having spent the two days here and stayed long enough to go through
> the entire process, and just to say on behalf of Serono we do look
> forward to continued discussions with the agency, so that we can bring
> this application to approval.
>
> Thank you.
>
> DR. GIUDICE: Shalini has a comment to make.
>
> MS. JAIN: I just wanted to say thanks also to all the committee
> participants today, both our SG consultants and the committee members,
> as well as the division representatives, and wanted to let people know
> that if they would like to leave their briefing documents, they can do
> so, and I will mail them back to your home or work if you would just
> specify what you would prefer.
>
> Also, for those of you that need to catch your flights immediately,
> there are shuttle drivers outside the store that can take you to
> whichever airport you had designated to me previous to today.
>
> Thanks.
>
> DR. GIUDICE: I also would like to convey my thanks to the committee
> members and to all participants and to the sponsor for their
> contributions today.
>
> Our meeting is now officially adjourned.
>
> Thank you.
>
> \[Whereupon, at 4:00 p.m., the meeting was concluded.\]
>
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