ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> UNITED STATES FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH DRUGS**
>
> Monday, September 29, 2003
>
> 8:35 a.m.
>
> Hilton Hotel
>
> The Ballrooms
>
> 620 Perry Parkway
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Linda C, Giudice, M.D., Ph.D., Chairman
>
> Shalini Jain, PA-C, M.B.A., Executive Secretary
>
> MEMBERS
>
> Susan 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 VOTING CONSULTANTS
>
> 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, 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.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Opening Remarks:
>
> Linda Giudice, M.D., Ph.D. 4
>
> Conflict of Interest Statement:
>
> Shalini Jain, PA-C, M.B.A. 6
>
> Opening Remarks:
>
> Daniel Shames, M.D. 9
>
> Ovulation Induction and Assisted Reproductive
>
> Technology\--Background and Practice:
>
> David L. Keefe, M.D. 11
>
> Questions from the Committee 34
>
> Gonadotropins in ART:
>
> James P. Toner, M.D., Ph.D. 73
>
> Questions from the Committee 116
>
> Human Gonadotropins\--Regulatory History:
>
> Shelley R. Slaughter, M.D., Ph.D. 147
>
> Questions from the Committee 158
>
> Open Public Hearing
>
> Dr. Robert Kirsch 173
>
> Dr. Kurt Barnhardt 179
>
> Mr. Sean Tipton 185
>
> Presentation of Questions and Committee
>
> Discussion 190
>
> [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 and Opening Remarks**
>
> DR. GIUDICE: Good morning. I would like to begin our meeting this
> morning. This is the FDA Advisory Committee for Reproductive Health
> Drugs. I am Linda Giudice from Stanford University and I am the Chair
> of the Committee. Today, we will have a general discussion and
> tomorrow we will have a product-specific discussion with Sorono.
>
> Some housekeeping issues before we have introductions of the committee
> members. Please, if you would turn your cell phones and beepers off or
> at least put them on \"Silent\" so that the proceedings are not
> disturbed. Rest rooms are down towards the main desk.
>
> So I would like to begin with introduction of the committee members
> and perhaps we can start on this side with Dr. Hager.
>
> DR. HAGER: David Hager, University of Kentucky.
>
> DR. CROCKETT: I am Susan Crockett and I am from Christus Santa Rosa in
> San Antonio, Texas.
>
> DR. MACONES: George Macones from the University of Pennsylvania in
> Philadelphia.
>
> DR. LEWIS: Vivian Lewis from the University of Rochester.
>
> DR. TULMAN: Lorraine Tulman, University of Pennsylvania, Consumer
> Representative.
>
> DR. LIPSHULTZ: I am Larry Lipshultz from Baylor College of Medicine in
> Houston.
>
> DR. KEEFE: David Keefe from Women and Infants Hospital and Brown in
> Providence, Rhode Island.
>
> DR. DICKEY: Nancy Dickey from Texas A&M Health Science Center in
> College Station.
>
> MS. JAIN: Shalini Jain, Executive Secretary to the Advisory Committee
> for Reproductive Health Drugs.
>
> DR. EMERSON: Scott Emerson from the University of Washington in
> Seattle.
>
> DR. EMMI: Adelina Emmi from Medical College of Georgia.
>
> DR. STANFORD: Joseph Stanford from the University of Utah, Salt Lake
> City.
>
> DR. BRZYSKI: Robert Brzyski from U.T. Health Science Center, San
> Antonio.
>
> DR. TONER: Jim Toner, Atlanta Center For Reproductive Medicine.
>
> DR. RICE: Valerie Montgomery Rice, Meharry Medical College.
>
> DR. GASSMAN: Audrey Gassman from the FDA.
>
> DR. SLAUGHTER: Shelley Slaughter from the FDA.
>
> DR. SHAMES: Dan Shames, FDA.
>
> DR. GIUDICE: Thank you very much. Dr. Layman just walked in.
>
> DR. LAYMAN: Hi. Larry Layman, Medical College of Georgia.
>
> DR. GIUDICE: Thank you.
>
> I would like to introduce now Shalini Jain who will talk about the
> conflict-of-interest statement.
>
> **Conflict of Interest Statement**
>
> MS. JAIN: Thank you, everyone, for participating today. I would like
> to read the conflict-of-interest statement for the Advisory Committee
> for Reproductive Health Drugs for September 29, 2003.
>
> \"The following announcement addresses the issue of conflict of
> interest with respect to this meeting and is made a part of the record
> to preclude even the appearance of such at this meeting. The committee
> will discuss issues relevant to the conduct of clinical trials and
> outcome measures for consideration of approval of drug products for
> the indications of induction of ovulation and pregnancy in anovulatory
> infertile women and development of multiple follicles, and pregnancy
> and ovulation women participating in assisted reproductive technology,
> or ART, programs.
>
> The topic of today\'s meeting is an issue of broad applicability.
> Unlike issues before a committee in which a particular product is
> discussed, issues of broader applicability involve many industry
> sponsors and academic institutions.
>
> All special government employees have been screened for their
> financial interests as they may apply to the general topics at hand.
> Because they have reported interests in pharmaceutical companies, the
> Food and Drug Administration has granted general-matters waivers to
> the following SGEs which permits them to participate in today\'s
> discussions; Dr. Scott Emerson, Dr. W. David Hager, Dr. Larry
> Lipshultz, Dr. Valerie Montgomery Rice, Dr. Susan Crockett, Dr.
> Adelina Marie Emmi and Dr. James Liu.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building. Because general topics impact so many
> institutions, it is not prudent to recite all potential conflicts of
> interest as they apply to each member and consultant.
>
> FDA acknowledges that there may be potential conflicts of interest
> but, because of the general nature of the discussion before the
> committee, these potential conflicts are mitigated. 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.
>
> I would now like to introduce our first speaker, Dr. Daniel Shames,
> who is the Director of the Division of Reproductive and Urologic Drug
> Products at the FDA.
>
> **Opening Remarks**
>
> DR. SHAMES: Thank you. I would first like to welcome everybody this
> morning and I would like thank Dr. Giudice and all our advisors and
> consultants and speakers for taking time out of their busy schedules
> to educate us about the issues surrounding the use of drugs for the
> treatment of female infertility.
>
> I would also like to take this opportunity to thank the two members of
> our division that were most responsible for assembling and producing
> the elements of what I believe will be a very exciting forum. Both are
> fully trained and certified reproductive endocrinologists and the
> division is fortunate to have them. Thank you to Dr. Shelly Slaughter
> and Audrey Gassman.
>
> In our division, we regulate a diverse group of drug products for such
> indications as advanced prostate cancer, sexual dysfunction,
> post-menopausal therapy, incontinence, BPH, among others. I must say
> that, among all the indications that we deal with, I find female
> infertility the most challenging from a clinical-trial-design,
> scientific and regulatory perspective.
>
> As you know, FDA approves for marketing safe and effective drugs.
> Safety and effectiveness are demonstrated by adequate and
> well-controlled clinical investigations. Science and drug development
> have considerably advanced using randomized, blinded, controlled-trial
> design. The randomized clinical trial has revolutionized our view of
> what are effective treatments for many diseases such as cancer therapy
> and heart disease.
>
> For female infertility, we want to make sure we provide the public
> with drugs that are safe and effective. This is accomplished by the
> provision of evidence from properly designed and conducted trials. The
> complex nature of clinical treatment protocols and the rapidly
> changing technologies and pharmacotherapy makes it a challenge to
> establish standards for insuring that clinical trials of drugs for
> female infertility are appropriate.
>
> There is an overriding charge for the assembled experts attending
> today and tomorrow. This charge is to inform the division regarding
> elements that must be incorporated into clinical trials for
> pharmacologic therapy of infertile women so that these trials will
> provide the level of evidence needed to conclude that these therapies
> are, indeed, safe and effective.
>
> With this information and input from all appropriate sources including
> the pharmaceutical industry, the division will write a guidance for
> the clinical evaluation of drugs in this area resulting in more rapid
> and efficient development of pharmacologic therapy for female
> infertility.
>
> Thank you.
>
> DR. GIUDICE: Thank you very much.
>
> We now have a guest speaker, Dr. David Keefe, who will talk to
> us\--who is the Director of the Reproductive Medicine and Infertility
> Unit at Women\'s and Infant\'s Hospital in Rhode Island. He will talk
> to us on Ovulation Induction and Assisted Reproductive Technology,
> Background and State of the Art.
>
> Dr. Keefe.
>
> **Ovulation and Assisted Reproductive Technology**
>
> **Background and State of Practice**
>
> DR. KEEFE: Great.
>
> \[Slide.\]
>
> Thank you, Dr. Giudice and thank you for the opportunity to come here
> today and share in this very important forum.
>
> \[Slide.\]
>
> There are a number of aspects to my presentation. I am going to give
> an overall introduction to the ART procedures and, in particular, in
> vitro fertilization and comment in particular how they relate to the
> issues of study design, particularly the study population, study
> design and then, hopefully, give you a sense of what I think is the
> future of ART, particularly the issue of ART outcomes.
>
> \[Slide.\]
>
> Assisted Reproductive Technologies actually encompass a variety of
> different techniques. The one most commonly practiced in the United
> States is in vitro fertilization with embryo transfer. It is a little
> bit of a misnomer to call it in vitro fertilization because probably
> the most crucial part is the actual implantation which follows. But
> convention calls it in vitro fertilization.
>
> In addition, gamete intrafallopian transfer is a variation on this
> theme in which the gametes are placed in the fallopian tubes or placed
> after the fertilization has actually occurred, zygote intrafallopian
> transfer or tubal-embryo transfer.
>
> These three are almost of historic interest because they are not
> widely practiced. There are rare indications and I am not going to
> discuss controlled ovarian hyperstimulation with intrauterine
> inseminations which some would put under the rubric of assisted
> reproductive technologies. Rather I am going to focus most of the
> discussion this morning on in vitro fertilization, the most widely
> practiced of the assisted reproductive technologies in the United
> States.
>
> \[Slide.\]
>
> The first step is to downregulate the ovaries, typically done with
> oral contraceptive pills or progesterone with gonadotropin-releasing
> hormone agonists or antagonists, to first try to synchronize the
> follicular cohort since the idea is to superovulate the woman. The
> controlled ovarian hyperstimulation step is typically done with
> gonadotropins and monitored with a number of ultrasound and estradiol
> levels.
>
> Next, after the ultrasounds and estradiols have identified a size of
> follicle and an estradiol level consistent with oocyte maturation
> within the follicle, then hCG human chorionic gonadotropin is used to
> trigger maturation largely because hCG serves as a kind of a surrogate
> for luteinizing hormone, the physiologic trigger of oocyte maturation.
> Just practically hCG has a much longer half-life and is more
> practical, at least under current technologies.
>
> Retrieval is done under general sedation and then fertilization is
> typically performed transvaginally. Fertilization is effected either
> with an incubation with the gametes in the test tube or through direct
> injection of the sperm through intracytoplasmic sperm injection.
>
> Next, the embryos are cultured for a number of days, between two and
> six days, depending on protocols, particularly under the indications
> of the patient. The embryos, then, are transferred through a very
> non-invasive procedure in which a very small flexible catheter is used
> to place the embryos up into the uterus, typically without but
> occasionally with a hatching procedure in which the shell, the zona
> pellucida, around the embryos is first thinned or breached.
>
> Next, and finally, the luteal phase, that second half of the menstrual
> cycle, is supplemented since the retrieval had aspirated a number of
> the follicular cells and the gonadotropin-releasing-hormone agonists
> or antagonists may have shut down their ability to produce
> progesterone adequately initially. So progesterone is administered
> either vaginally or intramuscularly for a number of days.
>
> \[Slide.\]
>
> So just an overview here. You have the follicle stimulation. I think
> this gives you a sense of the time frame. This is a very drawn-out
> procedure which may go up to six weeks for an individual single cycle
> in which these follicles are stimulated with gonadotropins after
> downregulation and then the mature eggs are removed with a 15 or
> 20-minute aspiration under general sedation.
>
> Then the eggs and sperm are joined together in the fertilization step
> and the embryo is cultured. So it gives you a sense of the drawn-out
> nature of this procedure which is, I think, particularly challenging
> for the couples going through\--when the woman often is working or has
> a life outside the IVF cycle.
>
> \[Slide.\]
>
> The in vitro fertilization step also involves a number of laboratory
> procedures, and each of them provides a potential for an outcome; the
> number of eggs retrieved. The next step is that the eggs are stripped
> and they have to be equilibrated in the culture media. And then
> fertilization, how effectively was that performed?
>
> Then the incubation provides at least up to six days when each of the
> steps of embryo development can be monitored in vitro. So these
> processes can be broken down and a number of metrics can be applied to
> each, useful for outcome studies if one is evaluating the efficacy of
> the various medications that are used.
>
> \[Slide.\]
>
> Controlled ovarian hyperstimulation is going to be dealt with by the
> next speaker in much more detail, but you can see at least these two
> commonly used protocols, the GnRH agonists protocol, first.
>
> This is the one down below, the lower in the panel here, in which this
> agonist is administered in the luteal phase of the preceding cycle
> that we are actually going to move forward on the aspiration. Because
> there is an initial stimulatory effect, the luteal phase is the most
> refractory phase of the menstrual cycle to gonadotropins. This flare
> effect is masked by the high levels of progesterone in the luteal
> phase of the antecedent cycle and then allowed to move, five to seven
> days later, into the suppressive phase when, then, the stimulation can
> begin and then, finally, the hCG trigger.
>
> The antagonists are direct inhibitors of the GnRH receptor and,
> therefore, do not need to be preceded by\--or administered in the
> preceding luteal phase. Instead, the gonadotropins are initiated at
> the beginning of the cycle directly and then the antagonist is added
> later towards the mid-portion to later portion of the sort of mock
> follicular phase finally hCG is triggering. So you can see at each
> point along the way, a number of potential markers.
>
> \[Slide.\]
>
> With regard to how we evaluate studies now, the study populations that
> are used, it is really important to note that there are\--each of
> these procedures done, in vitro fertilization, intracytoplasmic sperm
> injury in donor egg, are very, very different. These are different
> procedures but they are administered in very different patients. So it
> is very problematic to group data from each of these.
>
> \[Slide.\]
>
> They really reflect quite different pathology. The diseases that are
> being treated with these oftentimes are not even reflected in the
> diagnosis that may appear in the chart. Intracytoplasmic sperm
> injection implies, therefore\--you know, it is a very significant
> sperm problem and assumes, oftentimes, that there is a normal egg
> complement although that also may be a concomitant problem.
>
> Donor egg, at least when it is administered on the recipient side,
> means presumably the eggs are actually quite healthy. So there is a
> major difference in egg dysfunction with in vitro fertilization having
> a higher likelihood of poor egg reserve and function, more than
> intracytoplasmic sperm injection, and egg donation, of course, would
> have the least likelihood of having dysfunctional eggs.
>
> Indeed, egg dysfunction, also known as ovarian reserve and very
> crudely estimated by the chronological age of the woman, is the best
> predictor in virtually every study that has ever been published on the
> outcome of in vitro fertilization, more important than the diagnosis,
> more important, oftentimes, than the chronologic age, itself.
>
> Indeed, there are log-order differences in pregnancy rates among
> groups of patients from a woman who is in her mid-40s with a
> diagnosis, say, of tubal disease as opposed to a woman in 20s. And
> there may be women who are matched by age but exhibit markedly
> different reproductive-aging markers.
>
> So egg dysfunction underlies much of the outcome and has to be very
> carefully controlled in any studies, either through
> inclusion-exclusion criteria, case control or stratification.
>
> \[Slide.\]
>
> There are a number of issues regarding study design, particularly
> efficacy measures and the question of how we should define success and
> what are safety endpoints are also quite important in evaluating in
> vitro fertilization and the status of IVF today.
>
> \[Slide.\]
>
> Of course, deliveries, the number of babies that actually come out of
> a study, the cycles that were initiated, is the gold standard in any
> study. But this is, as you can imagine, costly and the power needed to
> show differences when you have something that is happening 20percent
> to 50 percent of the time is quite large.
>
> So a number of surrogate clinical outcomes, as well as surrogate
> biological outcomes, are frequently employed in studies. Ongoing
> viable pregnancies and clinical pregnancy rates, which is essentially
> a sac with a fetal heart detectable, are widely used as is biochemical
> pregnancy rate which is the very earliest marker of a pregnancy even
> before the sac or the fetal heart is detectable, typically with just
> the beta hCG rising appropriately, are widely used.
>
> The surrogate biological outcomes that have been employed in studies
> include the number of follicles, the peak estradiol, the number of
> eggs that are aspirated and the fertilization rate as well as the
> embryo cleavage and morphology rates.
>
> \[Slide.\]
>
> The deliveries per initiated cycle, of course, is the gold standard
> but you need huge power to show differences between a study that\--in
> a study where the expected outcome is 30 percent. This makes is very
> expensive. It is also difficult to measure, at times, but it is
> important because there may be huge patient-specific differences in
> groups that are oftentimes subtle and not obviously reflected in
> simple things like the FSH or the age.
>
> \[Slide.\]
>
> The surrogate clinical outcomes are closer to the gold standard than
> the purely biological ones. You need much less power because of this,
> but they are clinically important outcomes as well. There are
> differences, though, in miscarriage rates according to protocols as
> well as with patients that may make it less than desirable, less than
> the optimal.
>
> They also may be contaminated heavily by clinical practices. For
> example, clinics vary significantly in their level of cancellation,
> the criteria they will use to not allow a patient to go to transfer or
> not even to start a patient or, once they are started, to cancel them.
> So there can be a lot of confounders in any studies and these are ones
> that clinicians have been very careful to evaluate themselves when
> they look at the study.
>
> \[Slide.\]
>
> Looking at biological outcomes, they are quite distant from the gold
> standard of the pregnancies per cycle started but much more sensitive.
> They may not reflect really clinically important outcomes. For
> example, there are many women that have a low response to controlled
> ovarian hyperstimulation but they still have excellent outcomes.
>
> So if you were using just peak estradiol or the number of eggs in a
> 25-year-old, that is something very, very different than if she is a
> 45-year-old. There are subtle differences, as well, in drug potencies
> on egg yield in estradiol that may be interesting and significant
> statistically but not so important clinically because you just manage
> that by changing the dosing.
>
> \[Slide.\]
>
> So how should success be defined with assisted-reproductive-technology
> studies? It has been proposed that there should be placebo controls.
> It is a little hard to do that in a situation in which, say, somebody
> is going through in vitro fertilization because they have blocked
> tubes.
>
> \[Slide.\]
>
> Rather, I think success should be defined according to the pregnancy
> rate but also according to a number of other issues which include
> things like convenience and discomfort level. The pregnancy rate is
> important but there are a number of other factors.
>
> You saw, at the beginning, when I discussed the IVF proposals, how
> complex and time consuming they are. So a study which showed
> equivalence but convenience, as one of the outcomes, was superior in
> one of the arms could actually be a superior product. So convenience
> and discomfort are very important.
>
> \[Slide.\]
>
> The other issue is that, with regard to the importance of accepting
> sort of noninferior or equivalent drugs, is that we really need
> competition in this area. There are also a number of patient-specific
> preferences. Options in allowing patients to choose would be enhanced.
> There would be an enhanced sort of customer satisfaction.
>
> For example, some patients prefer vaginal-route progesterone over
> intramuscular administration of progesterone, or vice-versa. So it is
> important to have variation and different options available for
> administration routes and other factors.
>
> An example of this would be, as I mentioned, the vaginal progesterone
> versus intramuscular and, of course, the differences in the number of
> days that the agonist is administered versus the antagonist. I showed
> you at the beginning the very long cycle that the agonist requires and
> the antagonist shortens that.
>
> So, just look at pregnancy as the only outcome would really miss
> important factors because of the time cost and the convenience cost
> and the comfort cost that couples accrue, particularly the woman, as
> they proceed through IVF.
>
> \[Slide.\]
>
> Safety endpoints conventionally include the ovarian hyperstimulation
> syndrome, miscarriage, multiple pregnancy rate and ectopic pregnancy
> rate. Because ectopic are so rare with IVF, I won\'t even discuss
> them.
>
> \[Slide.\]
>
> But, obviously, ovarian hyperstimulation\--this is a life-threatening
> condition, potentially life-threatening condition, in which some
> factor emitted from the ovaries, secreted from the ovaries, confers a
> vascular permeability throughout the body of the woman and can lead to
> ascites, large accumulation of fluid in the abdominal cavity, pleural
> effusions, instabilities in the hemodynamic system as well as
> increased coagulation. There have actually have been a number of
> deaths, strokes, loss of limbs from clotting and vessels.
>
> So this really sets the upper limit on the controlled ovarian
> hyperstimulation that the woman is going through for in vitro
> fertilization. There is a pretty good correlation between the amount
> of stimulation, the number of eggs, the peak estradiol, sort of the
> number of lottery tickets we buy each time we put the woman through
> IVF and this sets the upper limit.
>
> It constrains how high you can go. The risk may be modified by
> lowering those peak estradiols. A number of examples include recent
> introduction of aromatase inhibitors and luteinizing hormone which may
> alter the peak estradiol and alter some of the estradiol-related
> molecules, vascular endothelial growth factor, and so on, that may be
> mediating the risk for control of ovarian hyperstimulation.
>
> So it may alter those, but not alter the success rate. And that would
> be a big win.
>
> \[Slide.\]
>
> Miscarriage is a very common occurrence following assisted
> reproduction as well as following any pregnancy. It is quite common,
> even in young women going through IVF. Up to 15 percent of them
> undergo a miscarriage after conception. In older women, women who are
> in their early 40s, up to 70 percent of their pregnancies will end as
> a miscarriage.
>
> These rates are highly affected by patient-specific factors\--for
> example, the age of the woman, her ovarian reserve\--but also could be
> influenced by a number of stages of the assisted reproductive
> technology that she is undergoing. The stimulation regimens
> theoretically could influence the risk of miscarriage. Particularly
> overstimulation with luteinizing hormone has been shown to disrupt
> developmental potential of the embryos, disruption of the normal
> luteal-phase support as well as a number of laboratory-related
> processes that we are not discussing this morning, the culture media.
>
> So this is a very important endpoint.
>
> \[Slide.\]
>
> Multiple gestations are major risks for IVF. It is very common,
> between 15 and 50 percent, depending on the aggressiveness of the
> center. There are, of course, major obstetric pediatric and
> public-health concerns from multiple gestations including prematurity.
> Cerebral palsy risk is increased threefold with twins and twelvefold
> with triplets, Caesarian section rate from almost 100 percent with
> triplets to 40 to 50 percent with twins, preeclampsia, gestational
> diabetes. The list goes on. This is a major risk which has actually
> reached public-health proportions.
>
> It is affected by patient-specific factors; for example, her age and
> her ovarian reserve. It is affected by rather illusive clinician
> practices, the number of viable embryos transferred. It is obvious
> that the doctor is very committed to optimizing the success rate, not
> only for the patient but for his or her own center, and it is a very
> tricky thing to figure out exactly how many embryos to balance the
> needs of the couple going through the procedure versus the bigger
> concern about preventing multiple gestations.
>
> Of note, monozygotic twinning is also increased significantly after
> all forms of assisted reproductive technology, not just after IVF, not
> just after blastocyst transfer, but even after clomiphene citrate
> ovulation and gonadotropin ovulation and induction. This is a real
> significant problem as well. While it is not anywhere near as common,
> it approaches 3 to 4 percent in some IVF practices including
> blastocyst transfer as opposed to the 1 in 800 baseline.
>
> It is a significant cause of morbidity because of the twin-twin
> transfusion syndrome that can result from a monozygotic twin; that is,
> where a single zygote or embryo later has split. It is, by the way,
> more difficult to control through modifying the number of embryos
> transferred because you could put in one embryo and still end up with
> monozygotic twins.
>
> A number of other developmental anomalies are just sort of appearing
> on the horizon. It is more of a question of whether some of these
> should be included as potential risk factors or safety concerns with
> assisted reproductive technology. I think it really just requires more
> studies before we conclude about their importance.
>
> But imprinting abnormalities, and particularly the Beckwith-Wiedemann
> syndrome and Angelmann syndromes have been implicated in complications
> of IVF. Pregnancy-induced hypertension is increased even when you
> control for multiparity following in vitro fertilization and Baha
> Subai and others have argued that one of the etiologies of
> pregnancy-induced hypertension is an imprinting abnormality.
>
> So I think we just need more data before we know. They tend to be
> quite rare to begin with so it is a little hard to know to what extent
> what we are seeing is a detection bias.
>
> \[Slide.\]
>
> Finally, just to look into the future of where IVF is going and,
> particularly, assessment of IVF, we really do need more randomized
> clinical trials.
>
> \[Slide.\]
>
> We need multicenter networks doing these randomized clinical trials. I
> think those of us who deal with menopause patients are just
> overwhelmed by the impact of the Women\'s Health Initiative on our
> clinical practice and why can\'t we get this far in fertile patients.
> They deserve it. There should be more randomized clinical trials to
> answer these questions.
>
> In addition, we need more racial and ethnic diversity in our clinical
> studies to ensure generalizability, particularly as mandates for in
> vitro fertilization coverage spread across the country. I work in two
> states, Massachusetts and Rhode Island, where we have a mandate and it
> is really gratifying to see couples from all walks of life coming
> through our practice, not just very wealthy investment bankers,
> doctors and lawyers.
>
> \[Slide.\]
>
> In addition, we need to improve biological surrogate markers. I think
> is going to come before the other two. In particular, aneuploidy is
> ubiquitous and it is related to assisted reproductive failure. There
> is increased embryo apoptosis or cell death. There is implantation
> failure and miscarriage from aneuploidy that is abnormal chromosome
> number.
>
> This could, then, provide a meaningful biological surrogate for
> outcomes. In addition, a number of safety problems in in vitro
> fertilization stem from attempts to overcome egg dysfunction and its
> core aneuploidy through controlled ovarian hyperstimulation.
> Essentially, what we are doing is we are pushing harder and harder to
> get more and more eggs in the hopes that we will find one or two, and
> then we will put more and more in until we finally find the right one.
>
> But if we could figure out which of those embryos are the
> developmentally competent ones up front, we would avoid much of that.
> There is some evidence that controlled ovarian hyperstimulation,
> itself, may predispose to aneuploidy by shortcutting sort of the
> normal selection process of follicles and by altering the follicular
> environment.
>
> There are a number of new technologies on the horizon to diagnose
> aneuploidy which will make it practical. Just to give you an example,
> many of the studies we read in the literature will use high-quality
> embryos, or healthy-appearing embryos or viable embryos as a marker,
> an outcome measure.
>
> \[Slide.\]
>
> This just shows you a number of photomicrographs of a
> healthy-appearing embryo that, on Day 3, was diagnosed with trisomy 21
> by preimplantation genetic diagnosis with normal development of
> blastocyst. Indeed, there is some evidence that certain trisomies are
> more likely to reach blastocyst than others suggesting that blastocyst
> development culture in vitro to this later stage of Day 5 or 6 is not
> the answer and, as we know, it also may introduce other complications
> through enhanced stress on the embryo.
>
> \[Slide.\]
>
> Preimplantation genetic diagnosis is probably going to improve the
> implantation rate. This is a study from Gianaroli showing a doubling
> of the implantation rate when he prescreened them with a set of nine
> probes. It seemed to predict the outcome.
>
> \[Slide.\]
>
> Here patients had failed IVF three times and were, then, submitted to
> preimplantation genetic diagnosis and were either found to have no one
> or a greater than one normal embryo with these limited number of
> probes.
>
> \[Slide.\]
>
> You can see, at each point, an increase, a significant increase, in
> the birth per patient suggesting, again, that this is going to be key.
> Tony Pellicer in Valencia showed that you could also reduce the
> pregnancy loss in IVF patients that he had gone through.
>
> \[Slide.\]
>
> Gonadotropins are key to this. This is where evaluating gonadotropins
> and how well they do, we know that it is the gonadotropins that, of
> course, when we stimulate the immature follicles, develop and it is
> these spindles within the eggs that are teasing apart the chromosomes
> here at metaphase 1 lined on the metaphase plate. This is when the
> aneuploidy first appears.
>
> \[Slide.\]
>
> You can see that there are abnormal spindles. This is a shameless
> self-promotion of my own research here for a moment, if you will\--you
> can see abnormal spindles by Battaglia in these eggs from abnormal
> spindles.
>
> \[Slide.\]
>
> This just shows that we can actually image this noninvasively using
> some pole technology that we were involved with and, by doing this,
> demonstrate improved development and improved pregnancy rate when we
> do this noninvasive investigation of the egg quality.
>
> \[Slide.\]
>
> In addition, there is a new area that we are working on in which we
> look at some of the chromosome structure and its propensity to
> aneuploidy and we have shown a number of factors that predispose to
> chromosome abnormalities in embryos that can be predicted by this
> biological marker.
>
> So, in summary, then, in vitro fertilization is improving. We have got
> still a very complex proposal. We need it to be simplified. We need
> studies that show which of the better drugs\--that use randomized
> clinical trials. In the meantime, we need to continue to improve these
> shorter-term biological markers as surrogates.
>
> Thank you.
>
> DR. GIUDICE: Thank you, Dr. Keefe.
>
> **Questions from the Committee**
>
> The committee now has several minutes to ask questions of Dr. Keefe,
> if there are any. While people are gathering their thoughts, David, I
> would like to ask you if you could please comment upon the issues and
> challenges of placebo control in ART treatment and also the issue of
> blinding.
>
> DR. KEEFE: Okay. The issue of placebo control is problematic in ART
> for a number of reasons. In particular, a number of the treatments
> that we now use in in vitro fertilization have already been
> demonstrated to be better than nothing. For example, the Canadian
> study has shown that untreated infertility, unexplained infertility,
> over the course of five years while Canadians were waiting to get into
> the Canadian health system had an expected fecundity of around 2
> percent per month, which is significantly less than what we experience
> through most of these treatments.
>
> In addition, a number of diagnoses for which we now use in vitro
> fertilization would be expected to have a zero percent pregnancy rate,
> especially completely blocked, occluded fallopian tubes. Finally,
> those with severe male-factor infertility in which there is no sperm,
> azoospermia, in which the sperm has to be extracted from the testicle
> and has essentially zero motility, or very low motility, and is only
> going to get into the egg through a direct injection route, I think it
> would be unethical to use a placebo.
>
> I think in other areas, where there is questionable value, you can
> imagine the utility of a placebo. Unexplained infertility when
> everything else seems to be working but there is no pregnancy is one
> example, a 2.5 percent pregnancy rate per month. I think that is one
> area where there might be some use of it, but, for the most part,
> especially for in vitro fertilization, I think it would be better to
> use existing technology as the control and then add in the additional.
>
> And then the second was a placebo and then blinding? Blinding is
> difficult for in vitro fertilization compared to placebo, obviously,
> but, for in vitro fertilization with Treatment A as opposed to
> Treatment B, it is very reasonable. Blinding, of course, is a
> fundamental study design and is always desirable.
>
> I don\'t think that there is much impact of blinding on the patient
> side. I don\'t think there is much of a placebo effect here but,
> certainly, on the clinician side where you can see the complexity of
> the treatment regimens, where there is a great potential for
> confounders to be introduced in terms of the way the cycle is handled,
> it is a very valuable strategy to be able to control for those
> potential confounders in which the doctors may be treating differently
> the treatment versus the control group. So I think blinding would be
> very valuable, particularly with medications in which there is a
> potential to treat according to what you think might be the best or
> the more desirable way.
>
> So I think both blinding on the patient and the doctor side was
> desirable although, obviously, on the doctor side of it is more
> important.
>
> DR. GIUDICE: I think we all realize\--
>
> DR. KEEFE: There is a question. Do you have a question?
>
> DR. GIUDICE: I think we also all realize, though, that in doing an
> ovulation induction cycle or ovulation enhancement for ART, if there
> is a placebo involved, that blinding is nearly impossible because of
> the follicular response. In monitoring a cycle with the placebo, if
> there is no follicle response, it is very clear on ultrasound and so
> that is an issue that I think is important as we look forward to the
> subsequent discussions that we will be having.
>
> There are other questions. Yes?
>
> DR. EMERSON: On one of your slides, you remarked about the superiority
> of being\--whether it was necessary or not and you included in there
> superiority against a placebo would potentially have\--would not be a
> necessity and due to convenience of what? I guess I am not
> understanding where you would not require superiority against a
> placebo.
>
> DR. KEEFE: The emphasis in that slide was that superiority does not
> need to be demonstrated to show superiority\--if the outcome is
> pregnancy, it is not necessary because there may be superiority in
> other outcome variables such as convenience, pain, and so on. So the
> emphasis there was on the importance of taking a broad view of the
> outcomes, not just pregnancy rate, or not just ovulation, but also
> user-friendliness, the intrusion on the person\'s life.
>
> So the placebo issue, as I mentioned, I think there is a limited role
> for placebo treatment in most IVF studies at this point, although I
> could imagine for ovulation induction, certain treatments are
> unexplained in fertility, there could be a limited role. So there, the
> importance of that slide, or the point was that it isn\'t just
> pregnancy outcome but also convenience and pain would also be
> important outcomes.
>
> DR. EMERSON: Another question. When you were listing your potential
> for improved biological surrogate markers, it wasn\'t immediately
> clear to me whether this aneuploidy, as a predictive value, could just
> be used to improve the efficiency of the whole procedure rather than
> be a surrogate endpoint, as itself. I mean, is there enough evidence,
> really, to suggest that it, as a surrogate, would be indicating
> whether the treatments were successful or is that just a means whereby
> we can improve the whole IVF process and it is not really indicating
> the drug response.
>
> DR. KEEFE: Those are good questions. We don\'t have enough evidence at
> all. I mean, there are only limited studies from Gianaroli\'s group,
> from Santimine\'s group, that are suggesting its potential value. I
> mean, we really need to do more studies, larger studies.
>
> But that really was looking to the future. As we look forward, I think
> we will see new technologies that allow us to look at all of the
> chromosomes. Once you have a helpful predictor of outcome, that, I
> believe, will become the most useful marker of the outcome.
>
> So, if you have something that is predicting with high fidelity the
> implantation rate of a given embryo, then that will become a useful
> marker of how you are doing with that, and one of those factors will
> be the treatment. It is true, though, that, as even with IVF, itself,
> probably the most important thing is not the drugs that are used or
> the way they are used. It is the patient. There is a huge
> patient-specific or patient-dependent parameter that is difficult to
> get our minds around and to measure.
>
> I suspect that a lot of that will be aneuploidy. Then, once you have
> that nailed down, then you will be able to look at the potential
> effects of drugs or stimulation regimens on that. Until we do that,
> you know, we use things like age or FSH. These are explaining about 10
> percent of the outcome in logistic regression equations. They are
> almost noise.
>
> They are the best we have but we don\'t have a good understanding of
> the factors that drive the outcome. My bet, and, again, this is pure
> speculation at this point, that a lot of this will be aneuploidy. It
> will be the propensity towards aneuploidy. PDG is just the tip of the
> iceberg. I suspect that SKY or comparative hybridization will allow us
> to really get the handle on that and then, once you have that level of
> determinism, then you can look realistically at potential impacts of
> drug-stimulation regimens on the outcome meaningfully.
>
> Of course, as it is now, you can just randomize everything and it will
> all fall out. But you have a lot of noise in the system and it makes
> it very hard to do studies in a practical way that shows anything.
>
> DR. GIUDICE: Dr. Macones, Dr. Rice and then Dr. Stanford.
>
> DR. MACONES: Dr. Keefe, you had a couple of slides about ovarian
> hyperstimulation. I was wondering if you could give me some
> information about how predictable it is based on estradiol levels and,
> I believe, either follicle size or number.
>
> DR. KEEFE: So ovarian hyperstimulation syndrome is a really, really
> adverse outcome that is very hard to predict. So, for example, there
> is a review by Mary Lau for Infertility and Sterility about six or
> seven years ago in which he sort of put it all together. Most of us
> use the cutoff that he used which is 3500 picograms per ml of
> estradiol at the peak to block the trigger, to stop us from
> triggering. But that gives a predicted risk of hyperstimulation of
> about 5 percent.
>
> So we are acting very conservatively because of the risk, the low
> risk, of a severe outcome. Just as PGD, preimplantation genetic
> diagnosis, should enable us to better understand the things that are
> driving outcome, the increased understanding of the pathophysiology of
> ovarian hyperstimulation, I suspect, also, will allow us to get around
> that outcome, adverse outcome\--growing evidence that
> vasculoendothelial growth factor is one of the drivers of this
> vascular permeability may allow us to use that as a maker.
>
> But, in the meantime, most of us use a very conservative cutoff to
> avoid the risk of the severe sequelae of hyperstimulation even though
> it is a quite rare outcome.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: Dr. Keefe, you briefly mentioned the SART database which I
> guess now is sort of the SART-CDC database. I am wondering, your
> comments on that database and how we can effectively use it as to help
> us address some of the outcomes or address any differences in product.
>
> I was struck by the fact that I sat on a thesis committee for one of
> our colleagues who was getting his Masters about 1998, 1999 and he
> used that database as the basis for his thesis and really did show
> that African-American women who participate in ART procedures, even
> when you control for Day 3 FSH or age, had lower pregnancy rates and
> this was never really brought out in a real public manner.
>
> So I am just wondering if we could better utilize that database to
> help us address some of these questions.
>
> DR. KEEFE: That is a really good question. I think the SART database
> is a beginning. We have begun to answer some interesting questions.
> There is a tension within the community about the SART database. On
> the one hand, some view it as sort of a threat, that they are being
> exposed, the real size of their pregnancy rates is being revealed
> before everyone else.
>
> They will often argue that, gee, the patients don\'t really want to
> see all these numbers. It is very complex. On the other hand, there is
> a huge potential. I think what we should use\--get a lot more
> information from that on the patient side. There has been an argument
> that there is too much on there already. Patients go to it and they
> get just overwhelmed by so much information in front of them.
>
> I think that what we could do is we could use, like, hyperlinks. If
> you want to know more about the inclusion and exclusion criteria about
> a specific clinic, that should be put in there. One of the problems is
> there is a lot of variability among clinics and who actually is going
> through. That should be posted. It should be \"buyer beware.\" In
> other words, all information available for those who want it and then
> you could have hyperlinks which you click and that brings you into
> inclusion and exclusion criteria for a given clinic.
>
> If the inclusion and exclusion criteria are not published there, the
> patient should have full rights to go through it, whatever particular
> situation they have.
>
> On the research side, I agree with you. There are a lot of interesting
> questions that could be asked. One of the concerns that I have had is
> I am not sure how available that database is to those who have
> questions. I have talked to a couple of colleagues who have approached
> them and discussed projects, and they kind of go into a queue.
>
> I am actually just newly elected to the Registry Committee for SART so
> that will be one of the issues I will be bringing up is accessibility.
> I think that the data should be transparent. It should be accessible.
> It should be available. People that have interesting questions like
> the one you are raising should have a shot at it. Only then, you know,
> we will be able to really take advantage of it.
>
> As we used to say, they have all the answers but we have all the
> questions.
>
> DR. GIUDICE: Dr. Stanford?
>
> DR. STANFORD: Dr. Keefe, I wonder if you could comment generally on
> the issue that these ART protocols involve multiple complex regimens,
> as you mentioned, multiple drugs with multiple different scheduling of
> them. When it comes to investigating and trying to establish the
> efficacy of a new drug, you have all these other variables, all these
> other drugs, drugs that you are using with it that may or may not have
> been approved for that protocol or that indication as well as the
> patient factors.
>
> This may be something that we discuss later as well and I would be
> interested in FDA staff input, but I am just interested in your\--what
> perspective you would have on that if you are trying to nail down, is
> this drug effective, when you have all these other variables.
>
> DR. KEEFE: That is a great point. I think it was Alfred North
> Whitehead that said that science is the art of the answerable. This is
> a lot of art and not too much answerable. I agree with you. It is such
> a complex moving target. But that is why, in a blinding, at least with
> regard to drugs, it would be very helpful because if all that goes out
> in the wash, then it is less important. But if those other things are
> being tweaked in response to the biases on the part of the
> investigators about the control versus the new drug, you can imagine a
> lot of mess that would create.
>
> But I think if you can let it all fall out in the wash, you could
> still find useful information out of it. It is just the numbers are
> just enormous when you have so much noise, so much error, in the
> equation.
>
> You are right. It is a very complex experiment we are doing.
>
> DR. GIUDICE: Dr. Toner?
>
> DR. TONER: Just a point of information regarding the question of the
> SART database. It is, at this point, a joint effort with the CDC and,
> to use those data, you need permission from the CDC. That is doable. I
> have done it on a couple of occasions.
>
> But probably more pertinent to the gonadotropin question is the fact
> that, at this time, the database simply collects how many units of FSH
> were used in that cycle. So you have nothing about the brand, nothing
> about how much LH was or wasn\'t part of it, or any concomitant
> medications that certainly would influence outcome.
>
> So I doubt that that database, in its current form, will be of much
> use for this topic.
>
> DR. GIUDICE: Dr. Crockett?
>
> DR. CROCKETT: Yes. I am particularly interested in the research that
> you presented about the abnormal spindle formation and the aneuploidy
> rates. It struck me, as I was listening to your talk, when we talk
> about using control groups and placebos and double-blinded studies,
> there is very little discussion about comparing these outcomes to what
> are normal, healthy, fertile, maximum fecundability is as humans.
>
> Particularly regarding the aneuploidy and the miscarriage rate, could
> you just discuss the ramifications of using our healthy human
> population as a comparison?
>
> DR. KEEFE: That is a good question. Battaglia\'s research on spindles
> actually used normal volunteers. He had an NIH grant and normal
> volunteers were monitored and then their eggs were retrieved under the
> spontaneous surge, hence the low numbers in the study It is hard to
> get a single egg.
>
> That is one of the few studies. Others have used natural populations,
> natural cycling populations, to look at aneuploidy rates. Placheau has
> found 25 percent of eggs are aneuploid in normal situations when they
> are aspirated. Also, Pat Hunt has found similar rates with using
> karyotypes.
>
> There are no head-to-head comparisons, but if you look at assisted
> reproductive technology cycles, the rates go much higher, particularly
> as you get into women who are in their late 30s and early 40s. Using
> comparative genomic hybridization, and SKY, the group in St. Barnabas
> is finding the majority of eggs in women with infertility have
> aneuploidy, so more than 50 percent, one study up to 70 percent, of
> the eggs could be identified.
>
> There is also a false-positive rate with that. Hypoploidy is actually
> a missing chromosome that washed off the slide. But, still, there is a
> very, very high rate of aneuploidy in humans. One wonders why any of
> us are walking around talking like this because we are all survivors
> of this massive struggle for existence.
>
> Some have argued that, in fact, the human has evolved as a
> mono-ovulator with subfecundity because it is such as social species
> and there is such an important role for socialization. You can see the
> same pattern of reproduction in other long-lived social species like
> whales and elephants and primates.
>
> So there are two parts to it. One is that we are mono-ovulators and we
> sort of get programmed in a very limited fecundability and, on top of
> that, we live long. So you have sort of two hits. You have a defective
> egg, or a low number of eggs that are likely to be defective at any
> given time plus a long period of time where wear and tear sort of
> damages what minimal reserve we started with.
>
> DR. CROCKETT: I guess what I am asking is when we look at these
> reproductive technologies, is our goal to overcome that or to match
> it.
>
> DR. KEEFE: That is a good question. A lot of people argue, well, gee,
> disease\--aging is not a disease. Aging is a natural process. But I
> think that draws a distinction that doesn\'t exist in the rest of
> medicine. For example, I have a bad hip. No one has ever questioned
> that, as a 49-year-old walking into an orthopedic surgeon, that I
> shouldn\'t expect to have a bad hip when I work out every day and so
> on. Yet, no one questions whether that should be covered by insurance.
>
> I work in a state where there is an IVF mandate but almost every day I
> have to battle with the insurers that a 38-year-old, 39-year-old,
> 40-year-old going through infertility with a high FSH is going through
> a natural process.
>
> Nature has never been thought to be benign. I mean, nature causes
> diseases. This is sort of the equivalent of a balanced polymorphism.
> It is like sickle cell in certain populations that lived in
> environments where that was advantageous. I think reproductive failure
> in women was advantageous at a certain time in history. Currently, it
> is a disease. It gets in the way of women who make great sacrifices in
> their lives to do things for other people and then, at their stage of
> life, are now prepared to complete a family and nobody told them that,
> by the way, this is a natural process, you should have done this
> instead of go to law school or med school.
>
> So this is a disease like any other disease. You know, sure; it is a
> natural process but it is a natural process which wreaks havoc. It is
> a misadventure for our current society. It is the other side of the
> contraceptive evolution and one that we should, I think, attack with
> equal vigor.
>
> DR. GIUDICE: Dr. Brzyski?
>
> DR. BRZYSKI: I would like to ask, thinking about the different types
> of patients, you mentioned a little bit about the different types of
> patients that are treated with fertility medications. Do you think
> that that should be taken into account in terms of the safety and
> efficacy outcome variables that we look at?
>
> For instance, a specific example I was thinking about is women with
> polycystic ovaries have a high miscarriage rate. So you could envision
> an intervention that might not be very efficacious in terms of
> ovulation rate but may significantly reduce miscarriage rate whereas
> that might not be an outcome that might be of relevance to someone,
> say, with hypogonadotropic hypogonadism.
>
> So I just wanted your opinion about whether the outcomes that you look
> at should vary from patient population to patient population or should
> it be standardized across the whole drug group?
>
> DR. KEEFE: I agree with you there. There are important diagnostic
> distinctions to be made. The one you described is probably one of the
> most important as well as the male-factor patients that\--there is a
> big difference between hyper-responders, particularly those with a
> polycystic-ovary-type dynamic in unexplained infertility patients or
> patients with tubal disease and what is going on inside their ovaries.
> So that is a useful distinction.
>
> I think less useful distinctions are minimal endometriosis, mild male
> factor, unexplained infertility. Those diagnostic categories are much
> less meaningful. So it might be useful to set up a series\--sort of
> revise our diagnostic categories as a field. We have been very hazy in
> our thinking.
>
> You wouldn\'t see this with cancer or heart disease. You have
> different stages. You have very clear-cut diagnostic categories. We
> tend to use these textbooks that we all read back in, you know, the
> first year of medical school about the causes of infertility. Most of
> them are not really that useful.
>
> I think the one you mentioned is, polycystic ovary syndrome, severe
> male factor. Those really mean something. Complete tubal disease,
> tubal obstruction, those are meaningful. And then the rest, sort of
> the rest, of the diagnoses have much less meaning in terms of outcome.
> They are not anchored as much in\--they are not as valid.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I think Dr. Toner made a good point when he captured really
> the essence of what I was getting to that we probably don\'t ask all
> the right questions of the SART database in order to do the right
> research.
>
> I want to ask you your opinion on this. You are in a mandated state
> and I know the insurance carrier there requires that you get a certain
> amount of information on a patient before starting her on an IVF
> cycle. Are you finding a level of consistency by these insurance
> carriers requesting similar types of information when you are in
> mandated state versus when we are in a non-mandated state where people
> don\'t have maybe the same criteria for starting a patient on IVF? Are
> you seeing any inconsistency?
>
> DR. KEEFE: There is a lot of inconsistency. It is a huge problem. We
> spend a lot of time haggling over whether somebody, indeed, merits IVF
> treatment or not. We have convened a group, sort of working group, of
> the different IVF programs to come up with a consistent series of
> inclusion and exclusion criteria that we can all agree on.
>
> The problem there is that, even within our group, there is a
> disagreement, particularly as you get into the low-prognosis patients.
> Are those the ones that should first be treated because they have the
> least probability of conception on their own? Or should they be the
> last that are treated? So there is a lot of inconsistency.
>
> DR. GIUDICE: Are there any other questions from the committee? Yes;
> Dr. Shames?
>
> DR. SHAMES: I just wanted to make a comment sort of to prod the
> committee, and this is early in the process, to start thinking a
> little about the problems that we have as regulators. Dr. Keefe
> brought up one point which makes me want to use as an example. Is the
> point of doing a noninferiority trial, say, for a drug in a situation
> where the procedure or drug would have an advantage of convenience or
> discomfort, et cetera, et cetera, which we all certainly understand.
>
> The problem for us, of course, is how to measure the convenience and
> discomfort, how to incorporate it actually into a statistical analysis
> plan, et cetera, et cetera, on top of a noninferiority trial. I am not
> asking for details. I am just saying ultimately we want to sort of
> standardize things which we will believe will help move this process
> faster.
>
> We need to standardize to be sort of fair so when we discuss things
> like this, any of these issues, we should have in our minds how we
> actually are going to translate this into real trial designs and
> analysis plans, things like that. That is my comment.
>
> DR. GIUDICE: That is an important comment. We will get to Dr. Lewis in
> just one moment. Along the same lines, in addition to outcomes, there
> is also the issue of time for getting to a particular outcome which,
> in infertility therapy, some women respond very quickly to
> gonadotropin stimulation. Others take a very long time. Those are
> measurable outcomes.
>
> On the patient side, there is also the issue of getting to the clinic
> or getting to the office, time away from work. So, somehow, I think we
> also probably should keep that in mind.
>
> Dr. Lewis?
>
> DR. LEWIS: I agree with the points you just made. the other thing I
> wanted to just mention briefly about the SART database, while it is
> useful to look at, it is all retrospective data and it is not
> controlled. It is particularly biased by the specific clinic and what
> their criteria or prescribing habits might be as well as their
> selection criteria which vary hugely.
>
> So I don\'t think that it can substitute for a well-designed,
> prospective trial.
>
> DR. GIUDICE: Thank you for your comments. Are there any additional
> questions from the committee? Yes?
>
> DR. EMERSON: I would just like to visit the question of the gold
> standard that you listed which was the number of live births per cycle
> of therapy. I guess, you know, there are some worse in terms of
> needing larger sample sizes and you could be looking at the time until
> you had successful live birth, so measuring the number of cycles
> needed until someone got that. These have some problems as well.
>
> I guess what I am worried about most in all of these is the ability of
> bias to creep in for one treatment versus the other in terms of the
> clinicians response to cancelled cycles or to not trying further
> cycles with a patient. Could you comment on that?
>
> DR. KEEFE: That is a huge factor. In clinical practice, it is an
> enormous factor, enormous, because now, all of a sudden, any patient
> can go to the web and pull down the statistics which are a reflection,
> largely, I think, today, with standardized media, with standardized
> training for most of the embryologists, with standardized protocols
> for clinical, a lot of the variability is arising from the patient
> mix.
>
> There is a growing practice of explicit or implicit exclusion of the
> sickest patients which I think is immoral. On the other hand, some
> would argue that physicians are increasingly charged with allocating
> scarce resources. But those are tricky and difficult to balance. I
> don\'t think, from the standpoint of the traditional mission of the
> physician, it was our major commitment.
>
> There is a growing practice of what I call the Lake Wobegon effect
> where everybody is above average in my practice so we are above
> average. That is a problem.
>
> There was an article in The New York Times Magazine about healthcare
> about two or three months ago. The only other area of medicine that
> has a registry that is so visible as that for in vitro fertilization
> is cardiovascular surgery. That is exactly what is going on with
> cardiovascular surgery.
>
> There was an article by a cardiologist in New York City about how
> difficult it is to get a bypass on a patient who really needs it in
> New York City today because the \"best\" surgeons don\'t want to touch
> the poor guy. So that is a problem for all of us in medicine.
>
> I am the first one to believe in consumerism. There is sort of an
> avalanche of consumerism. That is great. But my response to that
> wouldn\'t be to stop the data from coming but to increase the flow.
> So, for the registry, I think we would mandate inclusion and exclusion
> criteria be attached through a hyperlink to those clinic-specific SART
> rates so that, if a patient goes there and they get cancelled, and
> they go on the web and say, whoa; wait a minute. This isn\'t on your
> exclusion criteria for who can to through the next cycle, then they
> have a right to go through again.
>
> I think the AMA and ACOG, ASRM, all have, in our ethical sort of
> statements, the right of every physician to not treat a given patient
> as long as it is standardized and mutually agreed upon and it is
> explicit.
>
> So I think the data should be there so that couples can decide, up
> front, or women can decide up front, whether they want to go to this
> center that is extremely exclusionary versus another which isn\'t and
> so they can go the whole ride if they need with a given center. That
> is the only way I think we can deal with it.
>
> We can\'t have less data, less information. We need more information.
> The argument that patients don\'t want to see all this. They don\'t
> have to. They can have a hyperlink.
>
> DR. EMERSON: I guess one of the points I was at was a more technical
> one. It is the concept that, for instance, there can be differential
> actions by treatment arm according to deciding to cancel a particular
> cycle and not go forward with the stimulation or whatever.
>
> DR. KEEFE: That is a good point. In terms of the outcome, if you were
> randomized, again, that should fall out in the wash. You might want to
> balance both arms of the treatment within a given center because they
> tend to be center-specific criteria. You also might want to make
> explicit up-front the clinic\'s criteria before they start to enroll
> patients.
>
> DR. EMERSON: Although, it won\'t pick that up if you are using as your
> denominator the number of cycles. There is a lot of room to play with
> number of cycles that you go through, both in terms of sort of the\--I
> always look at things from the \"intent-to-cheat\" perspective and
> say, how can people cheat on a particular thing to make something look
> good.
>
> If you set out to do it, what would you do? And I say, well, gee, if I
> want my treatment to look good, what I will do is, as soon as I hit a
> patient that looks pretty hopeless from, for instance, aneuploidy or
> whatever, that they do that, if they are on the arm that I don\'t
> like, I will just keep on sending them through cycles and, if they are
> on the arm that I like, they won\'t.
>
> Similarly\--
>
> DR. KEEFE: Can\'t you just deal with that by, once they get included
> in the study, then they get randomized after inclusion?
>
> DR. EMERSON: The idea is\--the problem is using the number of cycles
> as a denominator whereas, if you just used time, and said, we are
> going to measure everyone as the time until you achieved a live birth,
> and people who you cancelled permanently after that, and you just
> refused to do more cycles on them, well that is at infinity.
>
> DR. KEEFE: The other way to do that is just to include first cycles in
> the study which I think, in terms of the way IVF works, is probably
> not a bad idea because there is that huge source of confounder which
> is whether they get to go through it again, according to the policies.
>
> But there is also a difference, not so much first and second, but
> first and third, first and fourth, in terms of the mix of the
> patients. They are different people.
>
> DR. GIUDICE: Yes; Dr. Stanford?
>
> DR. STANFORD: I think there is another potential concern. You talk
> about a gold standard being live births per cycle initiated. But then
> there may be\--ART, obviously, there are certain categories that you
> mentioned where it may be the only way for a pregnancy, azoospermia,
> et cetera. But there are other categories where it is becoming more
> broadly used and there is debate about should you go with controlled
> ovarian hyperstimulation versus ART or metformin for certain
> categories of PCO and all that kind of stuff.
>
> I don\'t think you can make a fair comparison on the per-cycle
> pregnancy basis. I think, in those cases, you have to come up with
> some kind of measure that is an overall\--given a course of treatment,
> whatever that is, which may take longer on a non-ART side or a
> non\--whether or not you call controlled ovarian hyperstimulation part
> of ART, but on a non-IVF side, you have account for another course of
> treatment that may be cheaper, may have less risk in some ways but may
> take longer.
>
> Could you comment on how you could compare those in a randomized way?
>
> DR. KEEFE: One study design that I think has been underutilized is a
> crossover study. Because the majority of our patients are not going to
> get pregnant in the first cycle, and the first and second cycles are
> not that different in terms of the patient mix, one way to do it is to
> do a crossover where each patient is their own control.
>
> Of course, there are problems with that, obviously, but one of the
> huge advantages is that, as I mentioned, and I think everybody would
> agree in this room who takes care of these patients, that the biggest
> confounder is the patient, herself, her eggs, her aneuploidy, whatever
> is going on inside there.
>
> There are fertile people and there are infertile people. So if you
> randomize the patient up front to Treatment A in the first cycle, or
> B, and then flip it around on the other side, then I think that is a
> very sensitive way to tease apart some of these.
>
> Of course, it gets around the issue of not allowing them to go through
> because they are stuck. I mean, they have got to do at least two
> cycles if they don\'t get pregnant the first. If you get pregnant with
> the first, obviously that creates a problem; they don\'t get to the
> second, and how you treat those.
>
> But, given the problems with the other study methods, you can imagine
> a way that that could be a very powerful way to be able to put
> together all these very complex factors that are influencing the
> outcome.
>
> DR. GIUDICE: Yes?
>
> DR. TULMAN: I have a question about the gold standard as well. You
> mentioned the gold standard being a live birth. Could you comment on
> adding the adjective of \"healthy\" live birth to that?
>
> DR. KEEFE: Okay. The issue of anomalies with assisted reproduction is
> really important. I put them in safety concerns. I think I would still
> leave them as a distinction. I have, in my practice, my office, last
> week a woman who came\--she is a physician, actually, an OB-GYN, who
> brought her twins from IVF. Both have cerebral palsy and she was
> coming back for some more.
>
> I said, \"How can you do this? You must have a lot of stuff on your
> plate.\" She said, \"They are my babies. They are my kids. People say
> they are abnormal. I love them. They are beautiful.\" And she wants
> more.
>
> Now, that is not everybody. I think there is enormous value for
> somebody who has never had children to have a baby. Not everybody
> receives their cerebral palsy the way she did, but I would still put
> down the birth of a child as a benefit. I would put down the others as
> side effects, as potential complications, and try to eliminate them or
> reduce them.
>
> We don\'t know all the mechanisms. We know that the biggest component
> is the multiple gestation. That is the biggest driver. But there may
> be other abnormalities as well that arise from imprinting
> abnormalities, problems with polarity. This monozygotic twin thing is
> huge. It is not just the zona hardening. There is a lot going on
> there. They tend, overall, to be so rare that you have to use a study
> like the Australian with 10,000 patients following in a registry over
> huge periods of time before you find them.
>
> So I would hold fast that we still are looking at babies. I think the
> definition of a healthy baby\--it is important to put that in as a
> complication, but, for the vast majority of patients, and I think a
> number of studies have looked at that, they are very happy with that.
>
> DR. TULMAN: Just a follow up, if I may. Is there any move within the
> FDA or CDC to establish some sort of registry within the United States
> of the children who were born as a result of the reproductive
> technologies to follow them for not only the problems that may be
> apparent at birth or soon thereafter but in terms of a longer range,
> in terms of other health problems?
>
> DR. GIUDICE: Dr. Brzyski?
>
> DR. BRZYSKI: I will comment on that. I am the President of the Society
> for ART and so work very closely with the CDC on the registry. That
> discussion has been, at several levels. CDC has certainly recognized
> in their publications the issues of, say, adverse outcomes and the
> problems that are associated with trying to identify adverse outcomes
> such as birth defects, congenital anomalies. That has been discussed
> in some of their publications.
>
> From the CDC\'s standpoint, well, let me just say that from the
> consumer standpoint, that is certainly an issue that I have discussed
> with patient advocacy groups. There are sort of two opinions about
> that. There is a group that believes it is extremely important to
> collect this information and another cohort that is concerned about
> privacy issues and stigmatizing the children born from ART
> technologies by sort of identifying them or categorizing them in that
> way.
>
> So it is definitely an issue that needs to be discussed more, both
> from sort of a philosophical standpoint and from a practical
> standpoint in terms of the cost of generating such an effort.
>
> DR. GIUDICE: I am wondering, Bob, if you could comment on the European
> experience of keeping long-term outcomes compared to in the United
> States because that may address some of the question.
>
> DR. BRZYSKI: I don\'t have direct experience with this, but there have
> been discussions at the SART Executive Council level of the experience
> in Belgium with ICSI outcomes. My understanding is that it has been an
> extremely expensive and time-consuming effort to collect those data on
> ICSI cycles, even in a relatively homogenous environment of a small
> country like Belgium. Well, I guess it is not really that small
> because there has been some\--those patients have probably traveled
> from various places.
>
> But it has been a noteworthy effort to collect those data but at a
> significant price.
>
> DR. KEEFE: I think the European experience has been an excellent one
> in terms of generating very useful data for the rest of us to use. We
> started on a small project that was funded by the Rhode Island
> Foundation to look at outcomes of IVF babies born in Rhode Island
> because we are sort of a Mayo Clinic, the only IVF program for this
> million-and-a-half people.
>
> So we had a lot of potential there. About three months into the study,
> we got a letter from a very irate former patient who had a beautiful
> baby from IVF but was, herself, a lawyer for the American Civil
> Liberties Union. She was absolutely livid that this letter arrived at
> her house, which had been approved by our IRB, that her mother-in-law
> had inadvertently spotted and mistakenly opened because they have
> similar names, threatening to sue us for revealing\--the problem is we
> are in the frontier here and we still have a lot of sort of notions of
> individuality and freedom and so on that it makes it a little harder.
>
> They shut down our study. That one example was enough to scare the IRB
> and the hospital to shut it down and say, \"No more.\" So it is
> tricky, in America, where there is so much concern of privacy and
> individuals\' rights. I think it is valuable information, though.
>
> DR. GIUDICE: I think it is also important to point out that there is
> no organized effort for keeping track of babies born from gonadotropin
> stimulation cycles as opposed to ART.
>
> Dr. Layman, did you have a comment?
>
> DR. LAYMAN: Yes; I had a comment. I think it is important to try to
> collect the data. I know it is difficult, especially with HIPAA. We
> know that, in general, congenital anomalies are in 2 to 4 percent of
> all couples and that IVF increases slightly sex-chromosome
> abnormalities and some other aneuploidies, but I think, as far as the
> issue of the imprinting disorders, if we don\'t start getting a
> database, we will never know for sure whether this is a real issue and
> whether it is due to IVF or ICSI or both, or whatever.
>
> So I think it is important to address this, at least future SART
> collection data.
>
> DR. GIUDICE: Thank you. Are there any further questions? Yes; Dr.
> Emmi?
>
> DR. EMMI: I just wanted to ask a question, or if you would just
> comment. You had said that different infertility diagnoses are not
> quite so important. Would you just comment about different
> institutions using different policies for diagnosing conditions in in
> vitro, even, as far as unexplained or male factor and how that might
> affect the studies.
>
> DR. KEEFE: The rigor of the diagnostic categories used for IVF is very
> low. So you will see frequently minimal endometriosis scattered
> throughout. That is probably a much better marker of whether the
> patient had a laparoscopy as part of her workup than it is about her
> disease or her prognosis.
>
> Similarly, with unexplained, it depends on how extensively you look
> for other factors. So, as I mentioned, I think the most important
> diagnoses are severe male factor, complete tubal occlusion and
> polycystic ovary syndrome with insulin resistance. These are the sort
> of diagnostic categories which I believe, in the end, will hold their
> own, at the end of the day, will still be standing after critical
> review.
>
> We, as a field, I think, should revamp our diagnostic categories. I
> think we should also have a dual classification for infertility,
> differing staging for the level of infertility rather than\--age is a
> very, very poor predictor of anything. Chronologic age is not a good
> predictor of biological age.
>
> Just look at anybody\'s clinic when you look at patients who had an
> anastomosis failed or who had a tubal ligation and they go through
> IVF. They have a very good prognosis independent of age. If you look
> at the registry, these studies that use sperm donation clinics to look
> at the effects of age on fertility, 45-year-old women still have sort
> of a 30 percent pregnancy rate, 25 percent pregnancy rate.
>
> The fertility rate doesn\'t drop that precipitously in the general
> population as it does in the IVF placebo because the IVF population is
> that subset of the general population that really has it bad. I mean,
> clearly, age affects fertility but the relative impact of age on a
> given\--or senescence, I should say, or aging rather than chronologic
> age, is highly variable. That is the key factor.
>
> We should develop way more rigorous work. I know Jim Toner\'s very
> important work on FSH is a beginning, but there is a need for
> increasingly precise measures of a specific patient\'s individual
> senescence level or aging factor.
>
> DR. GIUDICE: Dr. Shames?
>
> DR. SHAMES: I just want to make a comment that the FDA can and does
> ask sponsors, as part of the approval process, to do some pregnancy
> registries. However, this is voluntary and we cannot compel them to do
> it.
>
> The other problem, of course, is, in this area, we are dealing with
> multiple drugs and procedures, for that matter, so it is difficult, of
> course, to tease out the cause of some particular abnormality. But we
> can, in the process, ask sponsors to do that.
>
> DR. GIUDICE: Thank you. Dr. Rice?
>
> DR. RICE: Why does the FDA have limited authority in requiring that
> part of the registration of a drug, approval of a drug, not lead to a
> pregnancy registry?
>
> DR. SHAMES: That is sort of a legal question. There are certain things
> that we can and cannot do by regulation. I mean, I would have to go
> back and ask that, why we do not have regulatory authority. It would
> have to be created as a regulation or a rule which has not yet been
> done. Whether we would even have the right to do that, is a whole
> legal issue which I cannot speak to. But we can certainly investigate
> that situation.
>
> DR. GIUDICE: Thank you. Any further questions? If not, I would like to
> thank Dr. Keefe again and the committee members. Let\'s take a break
> and return at 10:15. Thank you.
>
> \[Break.\]
>
> DR. GIUDICE: For the second half of this morning\'s session, I would
> like to introduce Dr. James Toner who is Director of the Atlanta
> Center for Reproductive Medicine in Woodstock, Georgia. He will tell
> us about Gonadotropins in ART.
>
> **Gonadotropins in ART**
>
> DR. TONER: Thank you, Dr. Giudice and thanks for the invitation to
> attend this panel.
>
> \[Slide.\]
>
> I hope it leads to more streamlined ways for us to understand what
> kind of efficacy endpoints are expected of us in evaluating new drugs.
> I was asked to talk about a few different components of this and we
> will start, really, by talking about in vitro in this country, kind of
> how we have come in the first twenty years of use and then tie in the
> approach we have taken on the clinical basis to achieve these improved
> outcomes, especially as regards to gonadotropin usage patterns.
>
> \[Slide.\]
>
> As most of you in the room know, IVF has been successful for almost
> twenty-five years now, the first birth being in England and a birth
> shortly thereafter in the United States in 1981 in Norfolk, Virginia.
>
> \[Slide.\]
>
> The story within this country, ever since that beginning, has really
> been one of improving success rates, reduction of multiple pregnancy
> rates, introduction of new therapies. It also, I think, is a story of
> the advantage, in a way, of the American system, the flexibility we
> have had as clinicians in this country to incorporate new treatments.
> To adjust the number of embryos going back according to age and other
> things has led to higher success rates in this country than certainly
> in Europe.
>
> \[Slide.\]
>
> The simpler treatments include things such as the ability to remove
> eggs transvaginally. It used to always require a laparoscopy and a
> transvaginal approach under a light sedation is certainly an
> improvement and, also, the essential abandonment of replacement of
> embryos into the tubes, also through laparoscopy.
>
> In the early days, most of us also asked the women to come daily or
> nearly daily through the whole stimulation process to evaluate their
> response. That is not necessary anymore. Also, in the beginning,
> essentially all the medications that we needed to give were given by
> the intramuscular route. Now, with the possible exception of
> progesterone, almost none of them are.
>
> So those have all been improvements in the treatment simplicity.
>
> \[Slide.\]
>
> There has also been introduction of new therapies. Initially, it was
> designed as a process to deal with the problem of blocked tubes but it
> has since turned out to be quite effective when sperm numbers or
> quality are quite diminished, when eggs, themselves, are diminished by
> really substitution therapy, using donor eggs. When the uterus has an
> intractable problem, a carrier can be brought into the mix and that is
> a very successful strategy.
>
> Initially, surplus embryos were a problem but cryopreservation is now
> quite an effective use of those extra embryos. As Dr. Keefe alluded
> to, genetic problems, either that come with age or might have been
> there all along, in particular, couples can be screened for with
> preimplantation genetic diagnosis. None of these things were there at
> the start.
>
> \[Slide.\]
>
> Now, the innovations over time have really proved to be a fairly
> steady progression. Cryopreservation in the early 80s, donor egg in
> the mid-80s and then the attempts at putting the embryos or eggs back
> into the tube, themselves, where they normally would have been by GIFT
> and ZIFT were widely practiced for a time but, as you can see, are not
> common anymore. Co-culturing of embryos, dissecting away the zona to
> some extent in hopes of permitting sperm easier entry or simply
> putting the sperm under the zona were early efforts to achieve
> fertilization when sperm were a problem, again, approaches that have
> since vanished for all intents and purposes.
>
> Those have been replaced by ICSI, the direct injection of sperm into
> eggs. Hatching was introduced in the mid 1990s, preimplantation
> genetic diagnosis, again in the mid-90s. In efforts to get around
> problems of diminished egg quality, attempts have been made to either
> transfer cytoplasm from healthy eggs into aging eggs or to move the
> nucleus across to a healthy egg.
>
> So, in the field, there really have been steady innovations. The three
> that I have put Xs next to are no longer permitted to be done in this
> country until appropriate, I guess, safety studies have been
> performed.
>
> \[Slide.\]
>
> Now, the focus of this meeting really is gonadotropins. I wanted to
> illustrate, first, a time line that illustrates when these
> gonadotropins and the things that affect gonadotropins have been
> introduced.
>
> As many of you know, the urinary products came first. hMG was
> available even years before in vitro came into existence and was
> really the only gonadotropin available for use in the earliest years
> of IVF. In the mid-80s, a more purified version, still urinary but
> with a dominance of FSH, was released.
>
> In the late 80s, Lupron, which is a GnRH agonist was released and
> widely incorporated into practice shortly thereafter. More and more
> purified forms of FSH were also developed in the mid-90s, again
> urinary at first and then recombinant shortly thereafter.
>
> The most recent development has been the development of GnRH
> antagonists. It took us actually years, on a clinical level, to figure
> out how best to use the GnRH agonist and we are still, I think, on a
> learning curve of the same sort when it comes to understanding how
> best to use the antagonists. But they have become adopted into
> practice pretty widely.
>
> \[Slide.\]
>
> Now, kind of with that as a background, let me describe to you what I
> think has been the general trend of use of these medications over time
> for the purposes of in vitro. The very earliest success with in vitro
> was, in fact, in natural cycles. That is how the cycles went in
> England, initially. But the Jones, who tried to get it going in the
> States, had a very poor experience with that and, instead, moved
> quickly to Pergonal, an hMG product and used, as you can see, at very
> low dosages, 2 amps a day, typically.
>
> It wasn\'t long thereafter that the advantage of even stronger
> stimulation was recognized because, other things being equal, within a
> certain range of hMG use, the more you give, the more eggs you can
> allow to grow or cause to grow. So 2-amp-a-day protocols became very
> uncommon and more typical dosages were 4 or even 6 amps of medication
> per day.
>
> They were often blended with FSH in those years although, in the early
> years, there was typically always some use of hMG which contains not
> only the FSH but the LH product, the LH hormone, I should say.
>
> When Lupron became available, it was first employed as a suppressive
> drug starting in the preceding luteal phase and seemed to very clearly
> allow more eggs to grow, at least more synchronous growth of eggs, so
> that, in most patients, simply by adding this sort of a pre-treatment,
> you were apt to get more high-quality eggs than if you went without
> such a product, even with the same dose of stimulation.
>
> A few years later, it was discovered that you could take advantage of
> the fact that the agonists first cause a flare of gonadotropins and
> that flare was then used to augment the stimulation and was begun
> typically at the early part of a menstrual cycle along with the other
> stimulatory drugs to cause an even stronger response.
>
> For a time, there was a lot of advocacy of the use of pure FSH rather
> than the hMG-style product through the mid-1990s but many clinicians
> have since gone back to a blended protocol where you are taking at
> least some LH in many cycles.
>
> Birth-control pills were introduced in the mid- to late 90s as a way
> to control the cycle start time, especially in a case where you are
> not going to use a suppression protocol of this sort. Without PCO
> pretreatment, you really had very little control of when the cycle
> would actually start and the pills have been useful in that arena.
>
> Then the most recent change has been the introduction of the
> antagonists into clinical practice which have largely been used simply
> late in the stimulation to prevent the premature LH surge.
>
> \[Slide.\]
>
> Now, with those medications being used in the way that they have been
> used, there have been certain trends over time. Clinics; we have,
> obviously, many more treatment clinics in the country now than we did
> in the early years which, in turn, has led to many more cycles of
> treatment, now over 100,000 such on an annual basis and many more
> deliveries.
>
> \[Slide.\]
>
> But really, more importantly, is the fact that the success rate per
> treatment cycle has steadily climbed no matter which major kind of
> treatment you want to consider. In vitro is here in the middle, in
> green. In the early days, 15 percent of cycles produced pregnancy per
> transfer. Now, 40 percent of them do.
>
> The orange at the time is donor-egg success rates which have doubled
> from 25 to 50 percent per try. And freezing, which didn\'t work well
> at the beginning, in yellow here, now adds about 20 percent or 25
> percent advantage to the cycle if you have had extras and can freeze
> them.
>
> The other two little things in here are the ZIFT and GIFT which were,
> at first, more successful than standard IVF, at least on a national
> basis, but, as the IVF success rate rose, that advantage has
> disappeared and, in a sense, killed off that therapy altogether. This
> shows the proportion of cycles over time that were GIFT and were ZIFT.
> You can see these things peaked in the late 80s but, as the success
> rate between them and standard IVF has increased, their usefulness has
> gone down to the point where only 2 or 3 percent of cycles are done by
> that method.
>
> \[Slide.\]
>
> One real success story has been\--my computer has frozen. I will tell
> you what that slide said. I don\'t know why it wasn\'t working. In the
> early days of in vitro, when sperm were not normal, simply putting
> sperm in the eggs, sperm in the same dish as the eggs, produced some
> pregnancies but nowhere near the normal rate.
>
> The short story is that this direct injection of individual sperm into
> eggs, ICSI, has taken a very low poor outcome that was happening
> before the technique was introduced and erased that problem altogether
> to the point where now, as long as there is sort of one living sperm
> for every living egg, it is as if there is no male-factor problem at
> all in terms of pregnancy rates.
>
> \[Slide.\]
>
> This shows the incidence of multiple pregnancies over the years as
> well which have been highest in donor egg and lowest in frozen embryos
> and mid-range, about 35 percent, in standard IVF which is higher than
> we would like but I did want to emphasize the problem of triplets and
> quadruplets, at a minimum, has certainly been decreasing. The last
> year for which we have data is already four years ago but, even then,
> you could see that the triplet rate was declining and, also, and
> dramatically so, the quadruplet or worse rate.
>
> \[Slide.\]
>
> One factor in IVF success that continues to be a thorn in all of our
> sides is this very strong effect of a woman\'s age. Apart from
> substitution therapy with donor eggs, we have not really been able to
> lick this one with in vitro fertilization. These are the published
> results on the CDC\'s website from 2000, the top line being pregnancy
> rate and the bottom line being delivery rate.
>
> You can see that, by and large, the pregnancy rate holds together
> pretty well until the mid-30s and then declines with each year, almost
> being a zero percent pregnancy rate at 45.
>
> \[Slide.\]
>
> The flip side of that is miscarriage which increases with those same
> years. Again, this is not something that we have been able to work
> around using in vitro fertilization.
>
> \[Slide.\]
>
> In those women with older age, the only solution that has proved
> rather effective is to become a recipient of donor eggs. This is an
> example of a study actually done with this SART CDC dataset over a
> three-year swath in which you can see that the clinical and ongoing or
> delivered rate among women using donor eggs stays good and high until
> the late 40s. So this is a solution for women who are running into
> difficulties with their own eggs, not necessarily one that appeals to
> everyone but it does work and it does tell us that the problem of
> being 45 or 46 is not the uterus or the body, in general. It is the
> eggs, themselves, because, with substitution therapy, that probably
> disappears.
>
> \[Slide.\]
>
> I also mention that in the United States, we have had better success
> than in Europe with our therapies. Again, the last year for which we
> have got comparable data is \'98. In that year, IVF worked 10 percent
> better here than in Europe, donor egg, 9 percent better and frozen
> cycles, 10 percent better.
>
> There is a cost to that, in part because we, in the States, are
> typically putting back an extra embryo or so and the cost is reflected
> here in the multiple-pregnancy rates. In the U.S., as in Europe, most
> pregnancies are still singletons and most of the rest are certainly
> just twins. But, in that year, we had a 6 percent triplet rate and a
> 0.2 percent quadruplet rate.
>
> \[Slide.\]
>
> So that is kind of where we have come in the States with success
> improving, getting a handle on the problem of multiples, newer
> therapies and simpler therapies. Now, I wanted to kind of move our
> focus to considering the ovarian stimulation component.
>
> Obviously, IVF is a treatment process for which there are many, many
> influences in terms of ultimate success rate. Ovarian stimulation is
> one of the things we have to do to make in vitro work but it isn\'t
> the only thing that influences whether or not in vitro works.
>
> For the purposes of this meeting, I think we want to focus on the
> ovarian response, the thing that the gonadotropins can influence. For
> the next several slides, that is what I am going to talk about.
>
> We need to understand, really, before going any further, that most
> women, given the right gonadotropin stimulus, can be made to produce
> multiple eggs in a cycle. But there is quite a bit of individual
> variation here. Some women can make a lot of eggs. Some women can make
> very, very few eggs. Those differences we consider to be differences
> in ovarian reserve.
>
> Since there is a wide range here, we have to adjust to that range in
> terms of how we would manage the stimulation, and you will see that as
> the slides play out. All of this has implications for how one might
> assess the efficacy of gonadotropins which, again, is the point of
> this.
>
> Let me use this as sort of an orienting slide. I think we all know
> that women are born with all the eggs they will ever have in their
> life. Over their life span, those eggs are doled out. Now, most of
> them are never ovulated. Most of them never grow much at all. But,
> nonetheless, they are lost. The rate of loss over time is fairly
> constant but it is logarithmic so that things go down by an order of
> magnitude at each even interval.
>
> Within all of the eggs that are available, a very small proportion of
> those eggs are available for recruitment at any one point in time. But
> that percentage that is available is pretty much fixed at all points
> in one\'s life and seems to be, as I said, a very, very small number,
> a thousandth of the percent, perhaps.
>
> What that means is that, since a woman at 25 is apt to have still a
> very large number of eggs, let\'s say, 100,000 altogether, whereas a
> woman ten years later will have a tenth of that number and a woman ten
> years beyond that, a tenth of that number.
>
> If you apply the expectation that a fixed proportion are recruitable,
> what you see is that a woman at 25, given a full stimulus to egg
> growth, could make 100 eggs whereas you can give a woman at 35 the
> very same stimulus and get a tenth as many eggs and, ten years later,
> the very same stimulus, and get one egg.
>
> So we need to understand that. I think that is a very important thing
> before we decide how studies would be done here to understand that
> there really is a ceiling within a particular cycle of ovarian
> reserve. There is a potential number of eggs but, no matter how much
> drug you give, you can\'t ever get past that number. You can\'t make a
> 45-year-old make 100 eggs. There is no way to do it, given, at least,
> current technology.
>
> \[Slide.\]
>
> Now, with that in mind, clinicians try to estimate what kind of an
> individual is this. Is this an individual who has 100 eggs,
> potentially, or an individual that just has ten or five or one because
> then we are going to adjust the stimulation strength to that
> expectation.
>
> So, if a woman, in fact, could be arrayed along this dimension of how
> many eggs are potentially available, we are going to take a different
> approach depending on where she happens to lie along this dimension.
> For the purposes of IVF, we generally would say that our goal would be
> to get 10 to 20 eggs. We don\'t want 30 or 40 because of the risk of
> hyperstimulation and because it seems that the eggs, then, aren\'t
> even as good as they could be if you had fewer.
>
> So we have a target for the number of eggs that we bring into
> development, 10 to 20 for IVF, maybe three to six for ovulation
> induction. To reach these targets, we are going to do things
> differently according to where we think the individual woman is.
>
> Perhaps the easiest case to understand is this one. If we have a woman
> who could make 100 eggs, we want to be very, very careful and not
> overdo it because, to get 100 eggs, will not only make her sick but we
> won\'t be able to do a fresh transfer. So, in women with a high
> ovarian reserve, we are going to use very low dosages of drug.
>
> On the other hand, if we think we have got a woman who has just two or
> three eggs, max, per cycle, we are going to throw all the drug at her
> we can because we really believe there is no danger in overdoing it.
> We might as well get every blasted egg that there is to get.
>
> There are those in the middle where we take kind of a middle course.
> Women in the middle can surprise you. They can underdo it and they can
> overdo it. So, sometimes, we guess wrong about what is going to
> actually work out. But these predictions of response do certainly
> influence our choice of therapy.
>
> One of the things that you have to notice here is that there turns out
> to be an inverse correlation between the dose employed and the
> response observed. So it is kind of counterintuitive. You are giving
> hardly any drug here and you are still probably going to get 20 eggs
> or 30 eggs. You give four times as much medicine over here and you are
> excited if you get three, again, because of the underlying physiology,
> that there is a limit in the terms of the number of eggs that a cycle
> can produce.
>
> Sometimes that limit is so low, we are concerned that we may have to
> cancel. Sometimes it is so high that we have to be very, very careful
> not to overdo it.
>
> \[Slide.\]
>
> Again, clinically, how do we try to get a handle on that? It tends to
> be two things that we use clinically to assess what category of
> reserve do we think this particular woman is. In those with what we
> think is going to be low reserve, we typically see very, very few
> follicles if we do an ultrasound. We can hardly see any of these small
> antral follicles.
>
> When we look at the ratio between FSH and LH in these women, it will
> typically be high. And when we see this pattern, we think this is
> probably the actual operating range of number of eggs that we might
> get and, for that reason, use a very strong stimulation protocol
> understanding that, even if it works, we are not going to get 20 eggs.
>
> At the other end of the extreme, if we think a woman is apt to be one
> with many, many eggs, 30 to 80, for instance, in a particular cycle,
> the ultrasound might show some of those, typically not all of them.
> But, on the ultrasound, we see a very different pattern of many, many
> little follicles. Here the LH tends to exceed the FSH and, with that
> pattern, we are going to be very gentle and hope that we don\'t overdo
> it.
>
> Again, our goal is 10 to 20 in this case but sometimes we shoot a
> little too high and find ourselves getting 30 or 40 and would, for
> instance, cancel if we have really guessed wrong and overdone it.
>
> Then the average patient, we see some follicles. We see more typical
> FSH being around the same level as LH and would use a middle-ground
> stimulation in hopes of getting that 10 to 20.
>
> \[Slide.\]
>
> A consequence of these sorts of principles is that, yes, dose does
> directly affect ovarian response. No matter what category of reserve
> you are talking about, if you go up in the dose within that reserve,
> yes, you will get more of a response. But the dose you typically would
> choose to use is inversely correlated to what you judge the reserve to
> be; namely, in the low responder, you are going to use a lot of drug.
> In the high responder, you are going to use hardly any.
>
> So, unless, in a study, we control for this, we are going to get it
> completely backwards.
>
> \[Slide.\]
>
> Now, the process of IVF is illustrated on this slide and it really
> revolves around this ovarian stimulation. That is the heart of all of
> these efforts to get eggs. It typically involves, for sure, some FSH
> and either LH as an injection or LH from endogenous contributions to
> allow us the appropriate level of steroidogenesis to go on.
>
> These other things that are typically done along with the heart of the
> stimulation are applied to certain kinds of patients in hopes of
> either better controlling the stimulation here or augmenting it, as
> you will see in the slides that follow.
>
> \[Slide.\]
>
> What I have just flashed up there in these little red lines are
> supposed to be illustrative of the change in the FSH levels that occur
> when you do these things. So, when you give FSH injections, for
> instance, the FSH level goes up. That is what the point of it is.
>
> \[Slide.\]
>
> If you give luteal Lupron, you get this initial little flare in
> endogenous FSH which lasts a few days but then turns into a
> suppression of LH below baseline and a suppression of FSH below
> baseline. That is used in one particular patient type I will discuss
> in a minute.
>
> If, instead, you use this so-called microdose flare, a very small dose
> of Lupron, you get this initial flare but it stays up forever. It
> really never turns into suppression and so can be used to augment the
> stimulation throughout.
>
> \[Slide.\]
>
> Then the antagonist of GnRH shuts off without any kind of a flare
> effect the FSH and the LH secretion instantly and is typically used
> simply to obliterate the potential for a premature LH surge.
>
> \[Slide.\]
>
> So I am going to give you kind of an example of how these are applied
> to patients of different response types as we would use them in our
> clinic and I think many clinics would do something like this, if not
> the same thing, but certainly for the same kinds of reasons.
>
> Among low responders, what we are trying to do is stimulate very hard,
> not only with the exogenous use of gonadotropins but by getting the
> body, itself, to contribute extra FSH by using this dilute Lupron or
> microdose flare approach because we can\'t really have too much FSH
> stimulation.
>
> In the average patient, we have now switched to antagonists because it
> minimizes shots. You often reduce three weeks worth of shots by making
> this shift. We still rely on the gonadotropins as the primary vehicle
> for inducing follicle growth and simply add the antagonist at the tale
> end once the risk of a surge starts entering into the picture.
>
> And then the high responders are ones that we really want to dampen
> down quite a bit and would typically put them on pills in the month
> before and also on Lupron which will downregulate their endogenous
> secretion so that the only stimulation they see, once they get
> underway, is that from the gonadotropins. The dose of that
> gonadotropin is apt to be a low dose as well.
>
> If all goes well, we hopefully will see, on ultrasound, a good number
> of follicles growing and, upon retrieval, get eggs from most and we
> would expect the majority, we hope, to be mature and with placement
> with sperm, or injecting sperm into those mature eggs, we would hope
> that most of them would fertilize normally.
>
> Among those that fertilize normally, some, but not all, we would
> expect to divide normally and, amongst those dividing normally, we are
> going to put back some at the point of transfer. Now, you can see
> there is a range here. The reason for the range is that an embryo from
> someone who is 30 is much more apt to implant than an embryo from
> someone who is 40 even when they look exactly the same.
>
> So there is a choice point here that hinges a lot on not egg
> production, per se, but rather on embryo quality which can have almost
> nothing to do with egg production. If there are extras, they can be
> frozen. Everyone with me on that point?
>
> \[Slide.\]
>
> But I alluded to the fact the while we use the gonadotropins to
> achieve a certain quantitative response, namely 10 to 20 eggs, if it
> works out well, there are other very important factors relating to
> quality that come into play typically past the point that we can
> readily observe.
>
> Let me tell you what I mean. Consider a 32-year-old going through IVF
> and a 42-year-old going through IVF. Unless this older woman is really
> in dire straights, we still might be able to get the same number of
> eggs from her as a 32-year-old if we get our stimulation approaches
> correct.
>
> So we get a certain number of eggs in both situations and about 85
> percent of them will typically be mature and 70 percent of them will
> fertilize and 60 percent of them will turn into pretty good embryos
> three days out, and half of those might go on to blastocysts. Those
> percentages are apt to be exactly the same whether or not we are
> talking about an egg that came from someone 32 or 42.
>
> But, beyond the point that we have got these blastocysts, the age
> matters a lot. In the 32-year-old, putting two blastocysts back will
> give a very high pregnancy rate and a relatively low miscarriage rate
> whereas, at 42, the story is very different, low pregnancy rate and
> high miscarriage rate. Even though we started with the same
> quantitative material, we ended up with a very different outcome, at
> least as judged at the point of pregnancy.
>
> \[Slide.\]
>
> Here is sort of a picture of the same thing. What this shows is
> potentially two different women. Let\'s say this is the 32-year-old on
> the top row and this is the 42-year-old on the bottom row.
>
> Again, odds are we can probably get the same number of eggs from both
> women. As the days go along, the behavior of those eggs in the lab may
> be indistinguishable. A good proportion of the eggs will fertilize. A
> good proportion of those that fertilize will divide and divide. So we
> may end up in the very same position come the morning of transfer.
> But, all along, there has been stuff that is important that we have
> never been able to observe; namely, which of these eggs are normal.
>
> The younger woman is, statistically speaking, much more likely to have
> a normal egg than an older woman. Those differences are invisible to
> us in the laboratory, by and large. But, again, let\'s, just for
> argument sake, say this 32-year-old who made these twelve eggs really
> had three good ones and nine klunkers. Of these three, two fertilized
> and carried on and turned into two blasts.
>
> If we put these back, she is apt to get pregnancy and she may even
> have twins. But the 42-year-old may only have had one good egg and it
> didn\'t fertilize. It didn\'t interact with the sperm appropriately
> and turn into a normal karyotype.
>
> So, even though we saw development, past that first day, we really had
> no chance for pregnancy left in that cohort of developing embryos. So,
> again, it is important to understand that there are really two
> categories of phenomena going on here. One is quantity and the other
> is quality.
>
> We can control quantity to some extent by our dosages but we can do
> nothing to the quality. It is just part of the process that is largely
> invisible to us at least clinically. Now, Dr. Keefe alluded to some
> technologies that may be brought to bear in upcoming years such as
> biopsying and embryo like this and testing its chromosomal
> constitution.
>
> If you could do such a thing reliably and relatively inexpensively,
> then you might know that there was really never any chance here and to
> dissuade a woman like this from trying again. But, at this point, it
> is not a widely practiced tool.
>
> \[Slide.\]
>
> The best predictor of the quality of an egg or an embryo seems to be
> the age of the woman. In in vitro, that quality decline is depicted
> here out of a study of a number of years ago. Again, it is important
> to understand that, and I may not have said it clearly before, that,
> within the laboratory evaluation process, a 42-year-old embryo
> typically looks no different than a 32-year-old embryo. So those age
> differences that are important in terms of pregnancy outcomes are
> largely invisible to us in the lab. The fertilization rate is the same
> in older eggs. The development rate is the same amongst older eggs.
>
> But we know that the probability of one of them taking is very, very
> different according to age.
>
> \[Slide.\]
>
> So we have got quantitative and qualitative effects that are strong
> influences on pregnancy rate. The best predictor of the quality seems
> to be the maternal age. The best predictor of the quantity seems to be
> the ovarian reserve and how you run your stimulation.
>
> \[Slide.\]
>
> In the end, you can see, in this slide, that both factors are very,
> very important. These are, again, some SART CDC data based on a study
> that has been submitted for publication looking at two-years worth of
> IVF data in this country broken out not only by age but by an estimate
> of ovarian reserve.
>
> \[Slide.\]
>
> We have already talked about ovarian reserve. It turns out that, for
> most clinics, the most convenient marker of ovarian reserve is FSH and
> the higher the FSH is, the worse the reserve is. FSH normally is under
> 10 always unless you get into some egg problems and, in menopause, it
> is going to be a 100 or more. So, in these normal women trying to get
> pregnant, you always hope to find the FSH to be low because then you
> hope that you are really in a situation with high ovarian reserve.
>
> But, as that FSH goes higher and higher and higher, the reserve goes
> lower and lower and lower. You can see how important this is. Not only
> within every level of FSH is age an issue, but within every age,
> reserve is an issue. Okay? These trends occur even though clinically
> we are trying our darndest to counteract them.
>
> The ones with high age or high FSH are the ones getting the high
> stimulations, the very, very strong dosages of gonadotropins and they
> are also the ones in whom we are putting back every embryo we can get
> our hands on. And yet, pregnancy rates, even so, decline.
>
> So these two factors of age and ovarian reserve are really fundamental
> influences on pregnancy.
>
> \[Slide.\]
>
> A general strategy clinically; we typically would adjust the
> stimulation strength to the predicted ovarian reserve in hopes of
> getting into that sweet spot of 10 to 20 eggs. That is what
> gonadotropins do for us.
>
> But we also, then, at a later step, a subsequent step, would adjust
> the number of embryos to be transferred according to our estimate of
> their quality. If they either are not good looking or are from a woman
> of advancing age, we are apt to put back more to try to compensate.
>
> But, in a way, these are different components of an overall treatment
> strategy. We deal with this thing first, how much drug to give in
> hopes of getting a certain number of eggs and then, subsequently, how
> many embryos to return.
>
> So I would argue that, in terms of assessing gonadotropin efficacy, we
> have to understand that both the FSH and the LH are playing critical
> and complementary roles. I will go into some of this in a minute. We
> certainly need FSH to get the follicles growing, the eggs to develop.
> This is the part that the clinicians are worried about when they pick
> a protocol and adjust the dose and strength of stimulation.
>
> But FSH doesn\'t have a whole lot to do with the production of the
> necessary hormones of estradiol and progesterone. It can only help
> once LH is in the mix. LH, on the other hand, is necessary for
> estrogen production. Without appropriate estrogen production and
> appropriate LH tone, even though you can get follicles to grow, you
> won\'t get pregnancies out of it.
>
> So both are needed. Maybe, since both do different things, we need
> different measures of efficacy for these different hormones.
>
> There has been an ever-increasing understanding, I believe, at least
> clinically, that LH does have a role to play and that there certainly
> can be such a thing as too little LH to foster appropriate follicle
> growth or healthy follicle growth and there may, in fact, be too much
> as well as is typical for very bad PCO patients.
>
> So, for LH, we are typically, in a clinical setting, trying to get
> kind of a permissive dose of LH to allow everything else to run the
> way it is supposed to and then titrate the FSH dose up and down to get
> the number of eggs that we would like.
>
> \[Slide.\]
>
> In considering this a little bit further, I wanted to highlight a few
> of the things that affect egg production. FSH, obviously, is sort of
> the driver. But, as I just alluded to, other things matter as well; LH
> tone during the stimulation. That means a few things. How much of the
> analogue are you using? Did you use birth-control pills in the prior
> cycle? Are you using hMG as your stimulating drug or pure FSH and are
> you using metformin.
>
> All of those clinical tools are affecting LH tone and LH tone, in
> turn, affects what good comes of the FSH you have been given. The use
> of hCG as a trigger is also important and all of us in clinical
> practice have probably had the unfortunate situation where a woman
> goes through all the trouble of taking stimulatory drugs for ten days
> but doesn\'t take her hCG and we get zero eggs.
>
> It also turns out that, at least within our practice, the doc doing
> the retrieval will affect how many eggs you get out of that ovary.
> That is another thing to keep in mind as studies are being designed.
>
> \[Slide.\]
>
> Let me talk for a moment about this LH phenomenon. I know this is a
> very busy slide but I think it helps us understand the ways in which
> both FSH and LH are important to successful treatment. This was a
> study in which the Ganirelix in a preclinical trial was given at
> varying doses to figure out how much of this GnRH antagonist was
> necessary or desirable to achieve orderly folliculogenesis.
>
> These were cycles in which the stimulus was pure FSH and there was no
> downregulation. So, endogenously, there was a little bit of LH in the
> mix. The Ganirelix was used to titrate that endogenous LH. With a very
> little dose of Ganirelix, your endogenous LH was still pretty high,
> 3.6. But, as your Ganirelix dose as increased ever higher, the effect
> on endogenous LH secretion was ever stronger to the point where he
> practically turned it entirely off. Okay?
>
> Again, a fixed dose of FSH in all these cases. Now, because you are no
> longer making LH at these high levels, and LH is critical to
> steroidogenesis, when you got deep into the stimulation, and normally
> would be making a good level of estradiol, instead, with high doses of
> Ganirelix, you were making very little estradiol because you had
> hobbled the system from being able to produce estradiol at high
> efficiency.
>
> Now, that influence had nothing to do with your ability to,
> nonetheless, grow eggs. At all of these doses of Ganirelix, the FSH
> still caused the same number of eggs to grow. And, in fact, the
> fertilization in the lab and the development of those embryos in the
> lab was also unaffected. So, for all you knew, it didn\'t matter that
> your estrogen was high or low, or your LH was high or how, because you
> ended up with the same number of eggs and embryos at all of these
> doses.
>
> But it did matter. It did matter, at least to pregnancy outcome, and
> that is shown in the graphing part here at the top. Let me first talk
> about the dark-blue bars, the pregnancy rates. You can see that they
> are pretty high up to the dose of 0.25 milligrams but low thereafter.
> You can also see, in the light-blue bars, that the implantation rate
> or probability of an individual embryo taking really paralleled the
> pregnancy rate and was highest with this 0.25 dose.
>
> Lastly, in the red, you can see that miscarriage was a very common
> event when these very high doses had been used. What does this tell
> us? I think it tells us a few things. One of them is, again, evidence
> that FSH is the driver for folliculogenesis. No matter what your LH
> tone is, you can probably still force egg growth with FSH alone. But,
> in terms of clinical success, LH has a huge role to play and there
> really may be a sweet spot where you can have too much but, certainly,
> too little LH to permit the eggs to be of any use.
>
> \[Slide.\]
>
> Another factor that can get in the way of seeing clearly an FSH effect
> is metformin. This is, perhaps, a good thing because we have known for
> years and years that PCO patients in IVF may make lots of eggs but
> still are less likely than many others to get pregnant.
>
> So Laurel Stadtmauer did this study a couple of years ago in which a
> group of PCO patients were randomized to go through standard IVF
> either without any metformin or with metformin. Metformin is an
> insulin-sensitizer that has now been commonly applied to PCO patients
> and, in many, will allow spontaneous ovulation.
>
> But it also had dramatic effects on what was seen in the IVF setting.
> First of all, those on metformin had a dampened response to follicle
> stimulation. Many fewer eggs were seen to be growing. But this
> reduction had mostly to do with the smallest of the eggs because, when
> you looked at how many big eggs, big follicles, there were, that
> difference was much smaller than the overall difference.
>
> At the point of egg retrieval, there was no difference and even more
> favorable with respect to metformin is the fact that, even though you
> typically got the same number of eggs with or without metformin, the
> number of mature eggs was a much higher proportion if metformin had
> been used and the fertilization rate was higher if metformin had been
> used and the pregnancy rate was more than twice as high if metformin
> had been used, again, with the same exact FSH stimulation. So this is
> a very significant modulator of response as well that we need to track
> if we are going to be doing a study asking about is this gonadotropin
> efficacious.
>
> \[Slide.\]
>
> The last example in this area that I would give is that, at least in
> our own practice, depending on who the doctor doing the egg retrieval
> is, you can end up with different egg counts.
>
> This is us over a couple of years. While the number of mature eggs in
> the end was hardly different and certainly isn\'t statistically
> different at all, this guy gets lots of immature eggs that the other
> doctors probably leave behind. So how would you control for this in a
> study? Perhaps by focusing on mature eggs rather than eggs altogether
> or hoping that the randomization will take care of it, that Dr. C
> won\'t happen to do a disproportionate amount of the retrievals on
> your old drug or something.
>
> But these are influences that kind of get in the way of understanding
> efficacy.
>
> \[Slide.\]
>
> A couple of other things and then I will be wrapping up. I think it is
> understandable to everybody in the room that many factors, in fact,
> affect outcomes here. We do things in terms of stimulation to get
> eggs. Eggs become embryos. We hope the embryos become pregnancy and
> pregnancy becomes a delivery.
>
> But the gonadotropins that are the topic of discussion today here
> really are tightly linked to eggs and less clearly linked to anything
> downstream of that event, I believe. Again, the gonadotropin response
> is affected by the LH tone as driven by metformin use and OC
> pretreatment and analogues and whether you gave the hCG. If you
> don\'t, you are not going to get any eggs. So there are a lot of
> simultaneous considerations here that have to be accounted for or
> controlled for, stratified for, whatever in terms of the quantitative
> character of eggs.
>
> But we also have to remember that there is this parallel quality
> factor going on, that not all eggs, even though they may look the
> same, are the same in terms of their potential. Consequently, age
> enters into the progression here at many points past the egg
> retrieval. A 42-year-old with the same number of embryos going back as
> a 32-year-old is not as likely to get pregnant and is substantially
> more likely to not deliver than that other gal who had the same number
> of eggs to start with.
>
> And then there are a bunch of doctor variables in here, too. Is it a
> good lab? Are the culture conditions up to date? What day did they do
> the transfer? Was it technically a good transfer? How many were put
> back? What kind of luteal support was given, et cetera, et cetera.
>
> So, because of all of these sort of downstream events, it can be very
> hard to clearly link a medication event to one that is very far
> downstream. And these are some of those other downstream influences
> that I just alluded to.
>
> Again, going back to this, one might have the same starting point in
> terms of quantity but a very different ending point in terms of
> quality. I am unaware, frankly, that gonadotropin use actually drives
> this difference which would be a pertinent question if it did. But I
> am unaware that, to get twelve eggs with a certain dose here and
> twelve eggs with a different dose here is the driver for what is
> normal and what is not.
>
> \[Slide.\]
>
> This is embryos that, in many clinics, are put back, eight cells,
> three days along. But if you wait a couple of more days, half of those
> that looked pretty good on Day 3 would have not progressed to Day 5
> and would, therefore, have been much more likely to implant and turn
> into a pregnancy. So, when you put them back matters.
>
> \[Slide.\]
>
> How normal the cavity is matters, what kind of an evaluation was done
> of the cavity. If it is just a plain old ultrasound, this big polyp in
> the cavity may have been overlooked. And, again, the fundamental ones
> that drive this more than anything else is our ability to estimate
> ovarian reserve and fertility. They, more than anything, can give you
> a heads-up about pregnancy events, downstream events, past the point
> of a certain number of eggs.
>
> \[Slide.\]
>
> As an example of how difficult these things are to predict, I put this
> slide up. This is old work but shows that\--and Dr. Keefe alluded to
> this\--that, as you go from proximal events in the process such as
> eggs to downstream events such as delivery, your ability to predict
> who it is that going to get enough eggs, embryos, pregnancies or be
> delivered goes down and down and down.
>
> \[Slide.\]
>
> There is very, very weak predictive ability of either, in a sense, age
> or FSH about who is going to be successful; much more predictive
> ability about eggs. In part, this is because of the difference in the
> nature of these datapoints. For instance, if you are able to pick an
> endpoint which can be characterized as means, such as how many eggs
> you got, as opposed to proportion such as who got pregnant, your
> sample size requirements are apt to be much, much lower when means are
> used, even with the same difference to be detected.
>
> \[Slide.\]
>
> You could take a 30 percent bump in the number of eggs that you were
> able to retrieve because of a new gonadotropin but if you were
> looking, instead, for that same 30 percent change in pregnancy rate,
> if it was even there, you would have to study almost three times as
> many patients to see it.
>
> \[Slide.\]
>
> Now, another very important consideration, though, is the fact that
> this benefit of high ovarian response is often not even something you
> can see in the fresh cycle. I don\'t know how to overemphasize this
> point and I will just describe the slide first and then try to say it
> a couple of different ways.
>
> In IVF, we typically try to get a lot of eggs. But we are not going to
> put a lot of embryos back. So we often are in a position where we, in
> fact, have a few extras that we opt not to transfer. Okay? Again, an
> old study, but really not different in any of the newer studies, in
> the old days of IVF, when the pregnancy rates generally were lower, it
> really didn\'t matter whether we had a few eggs or a lot of eggs to
> who got pregnant on that occasion because we were only going to put
> three of them back anyway, and we had three from here and three from
> here and three from here.
>
> So far as we could tell, everybody got equally pregnant. The advantage
> of those extra eggs really came, at least in this era, from the fact
> that they could be frozen and transferred back in later cycles. So it
> is clearly better to be in this greater-then-ten category. Clearly,
> many, many more people ultimately were pregnant.
>
> But, if you had picked as your primary endpoint fresh pregnancy rate,
> you would make a false conclusion which is that it didn\'t matter how
> many eggs you got when, in fact, it does. This phenomenon has really
> been seen in all of the comparative gonadotropin trials where you
> might get an extra egg or two here or one fewer egg here on
> antagonist.
>
> It makes no difference in the short run because you will always have
> enough embryos to go back in the short run but it may hold a benefit
> that appears a few months down the road. So this is another reason to
> be a little concerned that if the initial pregnancy rate becomes the
> primary endpoint that you will lose some of the effect that really may
> be going on with a new kind of a gonadotropin in producing extra eggs
> or extra eggs of good quality.
>
> So, I think that is all I want to say. Well, let me say this. I guess
> I would argue that, at least as one of the endpoints, therefore, one
> might want to look for endpoints that almost are observable before you
> even get to the retrieval. If the doctor can have an effect on how
> many eggs enter into the laboratory, that is a problem. Maybe you want
> to look for things that you can see on ultrasound or measure in the
> circulation that takes some of the operator dependence out of the
> picture.
>
> We can talk about what those might be over the next couple of days. I
> think that\'s it. So, again, my take is a little different, I think,
> than Dr. Keefe\'s. Certainly, the goal of the treatment called IVF is
> pregnancy. But the treatment, itself, is multifaceted. There are
> different components of that treatment.
>
> One of the components is ovulation induction. That component certainly
> does affect what happens downstream but it isn\'t the only important
> thing that affects who is going to get pregnant. There are many other
> equally important things.
>
> To the extent that gonadotropins, their efficacy is under
> consideration, it strikes me as most logical to try to link it to what
> is really happening with eggs being grown rather than those other more
> distal events which are subject to many other important influences.
>
> Thanks.
>
> **Questions from the Committee**
>
> DR. GIUDICE: I would like to open this up to the committee. Dr. Hager
> and then Dr. Crockett.
>
> DR. HAGER: Jim, that\'s an excellent presentation. Thank you. I have
> three questions and I will ask them individually and let you respond.
> You have indicated the benefit of cryopreservation and freezing
> embryos. With the current technology and work being done related to
> cryopreservation of oocytes, can you kind of update us on where that
> may take us also regarding ethical considerations and so forth?
>
> DR. TONER: Well, it would certainly be nice to be able to freeze eggs.
> For women who don\'t have a partner, for women undergoing cancer
> treatments that may erode their ovarian reserve, it would be a
> wonderful technology.
>
> It could also be used even among couples who are high-response type in
> which you may say, okay, well, I am only going to inseminate eight
> eggs and work with those for this transfer but then freeze everything
> else. If you don\'t get pregnant, we will thaw out a few, fertilize a
> few. But there are ethical things that come these days from the fact
> that we don\'t have an effective way of freezing eggs.
>
> You know, divorce happens. Embryos are then stuck between an
> impossible situation.
>
> DR. HAGER: Do you see a future for that technology?
>
> DR. TONER: Yes; uh-huh.
>
> DR. HAGER: Okay. Second, regarding age and retrievable eggs, if we
> could enhance the number of retrievable eggs in an older population of
> patients based on the information we have regarding aneuploidy, would
> that truly be a service and where do you see the future going
> regarding the ability to retrieve better quality eggs in the older
> patient?
>
> DR. TONER: We don\'t have an ability nowadays. Nowadays, all we can do
> is push with our drugs and accept what eggs are developed and hope
> they are not aneuploid. We could, as a first step, screen them for
> aneuploidy and transfer only the normal ones. That seems to be a
> short-term tool.
>
> But, in the long term, obviously, it won\'t be a good solution. We
> don\'t understand what it is that makes an egg recruitable. At this
> point, we just have to accept it for what it is. But there may be some
> cocktail of factors that could take the very limited supply of eggs
> from an older woman and make a higher proportion of them available for
> recruitment. But we don\'t know how that would work at this time.
>
> You know, take an ovarian biopsy and inducing these primordials to
> grow in the lab is something you can dream about but it isn\'t there
> now and it really wouldn\'t get around the aneuploidy problem. We
> think the aneuploidy problem is sort of preexisting, absent something
> like cytoplasmic transfer or nuclear transfer.
>
> There is some question that the aneuploidy may or may not be
> preexisting. Certainly, if it is already an aneuploid egg, you are
> probably not going to be able to do anything with it. But it is known
> that eggs from older women don\'t have near as many healthy
> mitochondria so they are kind of underpowered. And it may be that some
> of the aneuploidies developed in the growth process that weren\'t
> really there at the beginning. So if you could give them adequate
> energy, maybe it wouldn\'t have gone awry at near the same rate.
>
> That was the thought behind cytoplasmic transfer and nuclear transfer.
> But that is not permitted. We can\'t do that work at the current time.
>
> DR. HAGER: Finally, with the rate of multiples decreasing, probably
> because of limitations on transfer or self-imposed limitations, is
> that information transmitted to patients in a similar manner, do you
> think, by all centers. Do you understand what I am saying?
>
> DR. TONER: Is every center working to reduce the number transferred
> or\--
>
> DR. HAGER: No. Is that information being transmitted to the patients
> based on that risk? Do you think that everyone is making that
> information available, that risk?
>
> DR. TONER: The risk of multiples within that practice?
>
> DR. HAGER: Not only within that practice but based on the number
> transferred.
>
> DR. TONER: Yeah; I think so. I don\'t know that every center has a
> handout describing it, but most centers that I am aware of, if not a
> handout, have a discussion on the day of the intended transfer about
> what happens if we put back three, what happens if we put back two.
>
> DR. HAGER: Is SART monitoring that?
>
> DR. GIUDICE: Dr. Brzyski, do you want to respond?
>
> DR. BRZYSKI: No. Actually, I wanted to ask another question. But I
> would say that, you know, one of the\--speaking about monitoring.
> Everyone\'s program reports their multiple pregnancy rate to the
> national\--you know, that is published. Also SART members, when a
> center undergoes validation, which is a process whereby there is a
> random sampling where cycles are examined by the validation committee
> from SART. This is partly supported by CDC to get a handle on data
> quality so the records at the Center for that cycle are examined and
> compared to the data that are submitted to the CDC to test the
> accuracy.
>
> Part of that visit for SART members includes exploration of practice
> issues including, again, a random sampling of cycles, were the number
> of embryos transferred in that cycle consistent with the SART ASRM
> guidelines for transfer and, if not, was there some documentation of
> why there was a variation from that practice.
>
> That is one of the criteria that are used to determine ongoing
> membership in SART. So that is something that is done. Now, each year,
> about 10 percent of IVF programs are visited by validation committee
> members. So there is a random sampling of centers, also.
>
> Does that clarify? Now, can I ask my question? We talk about ovarian
> reserve clinically as something palpable. But I wanted to ask you your
> comments regarding the ability to determine ovarian reserve in terms
> of the way that we can determine\--if someone has blocked tubes or no
> sperm, it is a very black-and-white issue.
>
> But what do you think our positive predictive value or negative
> predictive value of identifying problems with ovarian reserve is with
> current technology? Is there a best test? Should we be critical of
> current technologies in determining that, what is in the future?
>
> DR. TONER: Well, the best test is not one that is used most times and
> really would be giving everybody a lot of drug and seeing how many
> eggs they do grow because that is what we are really trying to get a
> handle on. But it is impractical and expensive and it will make some
> women sick.
>
> So, instead, we use other things. The basal FSH level on Day 3 of the
> cycle is the most widely used. We actually have also looked at LH
> because the ratio, as I alluded to, seems to be very predictive of
> response. We have known for years that women with PCO have an LH, an
> exaggerated level of LH, with respect to their FSH. The people with
> low reserve are the opposite.
>
> Another convenient metric for most of us is simply the ultrasound. If
> we take a look at a gal early in a cycle, how many of those little
> follicles we see is also highly predictive of how many eggs she can be
> made to grow. So those are the primary clinical tools, I believe.
>
> DR. GIUDICE: Dr. Rice and then we will come to this side of the table.
>
> DR. RICE: I enjoyed your presentation but I do think there are some
> contradictory statements that I would kind of like for you to help my
> clarify. On one hand, you say that the number of oocytes retrieved is
> important because it will impact pregnancy rates, maybe not in that
> first cycle but in subsequent frozen cycles if there are enough
> embryos left over.
>
> But then, on the other hand, you recognize that regardless of the
> number of eggs retrieved for an individual woman based on age, ovarian
> reserve, et cetera, that there may be only one or two eggs in that
> cohort that are ever going to lead to a pregnancy.
>
> So, when we look at gonadotropins, do we only assess them for the
> number of oocytes they produce or should we really be looking
> downstream, looking at the fertilization rate of those oocytes that
> are produced by that specific gonadotropin and then, finally, looking
> at the pregnancy rate because I think that is the big question of how
> we should be judged, so when we set up these clinical trials, we are
> asking the right question of that gonadotropin.
>
> DR. TONER: Yeah; I think that is why we are all here. My own view is
> that the thing the gonadotropins do is induce follicles to grow. The
> potential follicle is kind of on the launching pad, will be permitted
> to grow if they see enough FSH. But the FSH that is used doesn\'t
> determine whether or not they are aneuploid. That is determined by
> other things, age being a convenient marker, typically.
>
> So, while obviously this is all being done for the purpose of
> pregnancy, my fear is that if you use pregnancy endpoints, then you
> would\--in terms of evaluating gonadotropin efficacy, you would
> probably have to restrict the range or at least stratify by those
> other dimensions such as age and reserve that we know also matter and
> might predict the aneuploidy piece.
>
> DR. GIUDICE: Going up here. Dr. Crockett, please?
>
> DR. CROCKETT: Thank you. I also enjoyed your presentation. I want to
> talk a little bit more about FSH as a determinant of ovarian reserve
> particularly from the standpoint of when you look at the graphs about
> FSH declining with women\'s age increasing, it looks like a nice
> linear graph. But we know that each woman within that graph is, in
> essence, an n within herself and that FSH and ovarian reserve can
> fluctuate within a woman. For instance, when a woman starts to go
> through menopause, ovaries don\'t just decline gradually. There are
> some cycles where they ovulate and some cycles when they don\'t.
>
> It is also my understanding that there can be sort of transient
> ovarian failure in even younger women where it appears like they are
> not ovulating or their FSH may be elevated for a period of time and
> then it goes back up to a normal level and they are able to conceive.
>
> Long way of asking a question, but my question to you is how do you
> take these into account in dosing the gonadotropins or should be we
> taking that into account when we look at the safety and efficacy of
> these medications?
>
> DR. TONER: I think most of the clinicians in the room would agree that
> there is some month-to-month difference in ovarian responsiveness and
> in measures of ovarian reserve. You might have a high FSH this month
> not followed by a high FSH next month. This cycle, with a certain dose
> of stimulation, you might get ten eggs. Next month, same stimulation,
> you might get 14 eggs. So there is a bit of difficulty in this sort of
> one-to-one mapping. Every cycle isn\'t the same.
>
> But, at the same time, I think you would get argument from a lot of
> the clinicians that people move wildly from one category to another. A
> woman who is given a strong stimulus one month and makes four eggs is
> never going to make 20 eggs, never, no matter what her FSH is next
> month or next year.
>
> At the same time, a woman who makes 40 eggs is never going to make two
> within that year unless you hardly give her any FSH. So, in terms of
> the full range of ovarian reserve, people tend to stay where they are.
> Over time, they tend to run down hill.
>
> The problem of fluctuating predictors\--FSH, for instance, can be high
> one month, low another\--has led, again, most clinicians to adopt the
> view that the highest one you ever had is the real one because that
> tends to be the best predictor or responsiveness. It has been done
> three or four times in different studies.
>
> If you have a high FSH of 14 this time, and you say, well, that is a
> bad cycle, obviously I will wait until it is low. And you wait until
> it is low and they still don\'t make a normal number of eggs. I am not
> sure that the ultrasound assessment is subject to that level of
> variance, though. I think the basal antral follicle count that a lot
> of programs would do would be subject to much less of this noisiness
> that FSH can have.
>
> DR. GIUDICE: Thank you. Dr. Macones?
>
> DR. MACONES: I think you just partially answered my question. You
> presented a great slide looking at retrieval rate by physicians
> suggesting that looking at retrieval rate probably isn\'t a great idea
> if we look at these gonadotropins.
>
> Again, you suggest using ultrasound as a primary measure, of course,
> assuming that ultrasound is reliable and has good intra- and
> inter-observer reliability. Is that the case? I assume it is, but\--
>
> DR. TONER: I think it is until you get to lots of follicles, lots and
> lots of follicles, because then you will find some clinicians say, I
> can\'t measure 45 follicles. I lost track of the last three anyway.
> But I think, within the normal operating range of zero to 20, if the
> question is how many follicles are there and are they bigger than 14,
> there would be a lot of reliability in that kind of an assessment.
>
> DR. GIUDICE: Dr. Lewis? Please go to the microphone.
>
> DR. LEWIS: Thank you. I enjoyed your presentation. I think you raised
> a lot of important issues one of which, of course, has to do with
> aneuploidy screening. Aneuploid eggs, I am sure, are very important
> but, at this point, we don\'t have any way of assessing what baseline
> aneuploidic rates are.
>
> We believe they would increase with age but we just don\'t know. So,
> to use that as a measure of how effective a gonadotropin is I don\'t
> think would be something we could practically do at this point in
> time.
>
> I do want to just comment on your slide showing that having some
> frozen embryos would give us another measure of efficacy of a drug,
> but I think that is subject to tremendous inter-laboratory variation.
> We did hear Dr. Keefe say that if you had healthy embryos, they would
> be frozen. That is something that is done in a lot of centers and that
> is going to vary according to what kind of quality to laboratory has,
> what kind of culture system they are using, whether they are freezing
> at the one-cell or blastocyst stage. So I don\'t think that that would
> be something that would be practically useful.
>
> I wonder if you and, perhaps, people from the FDA could comment on
> what kind of trial designs are used in European centers where many of
> these drugs are approved for use in ART cycles as they may not be in
> the United States. What endpoints do they use there?
>
> Then, finally, just two small comments. If you could also comment on
> assay variation, LH and FSH. A lot of centers are using different kits
> which may not give the same exact values. Lastly, co-culture, you
> commented on as not being done because it is not safe. It is really an
> aside, but I do think that there haven\'t been safety concerns raised
> about autologous co-culture of embryos and there are a few centers
> that are doing that.
>
> DR. TONER: I am not sure that there is any evidence that it is unsafe.
> I think the judgement was that it is not known and, until we know, we
> won\'t proceed with the nonautologous.
>
> The European trials; I have not been inside the regulatory systems
> there. Typically, what we see are the published studies which, as you
> can imagine, typically report all the endpoints. They are typically
> comparative trials with blinding and multicenter and that kind of
> deal. What you typically see in them is similar efficacy, again, at
> least with respect to fresh pregnancy rates because everyone is
> getting the same number of eggs back, embryos back, even if they got
> very different numbers of eggs initially and that you would see, for
> instance, that antagonist trials have typically shown two fewer eggs
> than in the other approach and one fewer embryo than the other
> approach. But it didn\'t matter to the pregnancy rate in the short
> run.
>
> The frozen rates, I wasn\'t arguing as something that you probably
> should include for the reasons you alluded to plus the reasons of
> years. I mean, when are they going to get around to getting them
> back\--you never get an answer\--but, rather to show that the
> differences that may, in the long run, be meaningful to the patient
> are inapparent in the short run, if you use pregnancy as your
> endpoint.
>
> DR. GIUDICE: Dr. Slaughter, will you be addressing any of the
> clinical-trial endpoints in your talk today?
>
> DR. SLAUGHTER: I will be addressing just some of the applications that
> have come through to the FDA and the actual endpoints that were used
> in that trial, in those trials.
>
> DR. GIUDICE: Okay. Thank you. Dr. Layman?
>
> DR. LAYMAN: I had a comment on the ovarian reserve. According to John
> Collins, at least, who has done a lot of the work on the positive
> predictive value, at least what I heard him say six months ago was
> that Cycle Day 2 or Day 3 FSH was the best predictor, the estradiol
> wasn\'t good and HIPN-B wasn\'t good and I can\'t remember if the
> clomiphene challenge was as good as FSH, but I kind of think it was
> either not quite as good or, because it is less involved, was
> preferred.
>
> But the other thing to remember, of course, that really the only part
> that is predictive is that, if the FSH is high, you predict a poor
> outcome. For some of the members of the audience, if the FSH is
> normal, that certainly doesn\'t guarantee a good stimulation. It is
> only that if the FSH is elevated, there is a high predictive value
> with a poor response.
>
> DR. GIUDICE: Thank you for your comments. Dr. Lipshultz?
>
> DR. LIPSHULTZ: As the only urologist here, I think I kind of keyed in
> on your statement that with ICSI, if there are ten sperm available,
> then, basically, there is no male factor. That, unfortunately, is a
> general consensus and, unfortunately, it is not true.
>
> A man who produces ten sperm, obviously, has a disease and deserves
> the same amount of evaluation as the female. The question becomes one
> of, given these patients who do have a disease process, we know now
> that these normal-looking sperm have a very high rate of aneuploidy
> and we are learning each year of the increased genetic problems that
> these men have that, in fact, probably are one of the reasons why they
> are not producing sperm.
>
> So, your end result, then, will be embryos with increased
> abnormalities and, perhaps, children with increased genetic problems
> which goes back to the question about how to look at this outcome in
> terms of ICSI and IVF.
>
> DR. TONER: Yeah; I grant you that I oversimplified the system. I was
> trying to make the point that, before IVF, before ICSI, was available,
> men with few sperm were not well helped by IVF at all but that ICSI
> has at least permitted fertilization and pregnancy to be established.
>
> While there are some concerns, admittedly, that there are higher sex
> aneuploidy rates and other things with the pregnancy outcomes,
> themselves, still the biggest study is Van Steerigum\'s and the rates
> of problems are not astronomical. They are higher than the background,
> higher than the reference population, but not \"no go\" kind of rates,
> in my opinion.
>
> DR. GIUDICE: First Dr. Emerson and then Dr. Keefe.
>
> DR. EMERSON: I guess my questions are, again, relating to this
> question of the egg production as being the endpoint. Do we actually
> have evidence that says that this FSH regimen can\'t affect the
> aneuploidy rates in these? Do we have any baseline rates of what that
> should be and how it has changed by the FSH regimen?
>
> DR. TONER: Not that I am aware of. But I would say that the rates that
> are observed line up fairly nicely with the incidence of no pregnancy
> or failed pregnancy in natural populations.
>
> DR. EMERSON: Yes. But we are also addressing the idea with new
> treatments. This is a problem with any surrogate endpoint is that the
> validity of the surrogate endpoint is an interaction between the
> treatment and the disease. So the idea is that, just because you have
> shown that something is a perfectly good surrogate in one treatment
> does not mean it would necessarily be in another treatment and that we
> may have one regime that doesn\'t cause aneuploidy and another one
> does and that would be the pregnancy rate.
>
> DR. TONER: Absolutely.
>
> DR. EMERSON: I will note that, of course, your evidence that you are
> saying that we need to consider the effects of cryopreservation is, in
> fact, based on the idea that it affects the pregnancy rate, not the
> number of eggs produced.
>
> But I guess my other concern, as we are trying to talk in generalities
> here, is where there are differences in the FSH-LH combination and
> that we are talking about that, and where you have suggested that the
> LH level has an impact, and I am presuming\--I am not too
> knowledgeable on the nonstatistical aspects here\--but the idea of the
> uterine environment, the uterine effects, ought to be able to be
> affected somewhat by the FSH and LH and do we have very much data on
> how the subsequent, the implantation of cryopreserved, might different
> from the fresh cycle and whether any element of differences there can
> be the regimen that goes in before the\--for the harvesting of the
> eggs relative to not having that cycle just before the implantation.
>
> DR. TONER: That model has not been very instructive because two things
> are changing. I mean, yes, you have a more natural endocrine
> environment in a frozen cycle but you have also got an embryo that was
> frozen. So the two things may cancel one another out.
>
> DR. EMERSON: A surrogacy.
>
> DR. TONER: Yeah. Another model that has been done to try to get the
> same answer involves, for instance, egg donors who might take a few
> embryos back, themselves, and give others, also fresh, to another
> woman whose uterus has been prepared in a more natural way.
>
> There, the evidence, in small studies, has been pretty contro\--not
> controversial but there is a group of three or four studies that I
> know of that showed no benefit of them going back into a more natural
> cycle and, two, showing a trend favoring the more natural cycle as the
> better environment.
>
> You can also look at those who happen to make a lot of estrogen and
> those who happen to make a little and that will modulate the uterine
> milieu. Again, that doesn\'t seem to be very instructive because, even
> though the high levels might, other things being equal, be averse,
> they typically come from the women who are younger, making more eggs,
> et cetera. So it is an important question but it has been a tough one
> to answer.
>
> DR. GIUDICE: Thank you. Dr. Keefe, you had a comment?
>
> DR. KEEFE: Sorry to ask this with my back turned to you but a comment
> and then a question. The comment is that you kind of circled around
> the issue of nuclear transfer and cytoplasmic transfer, especially in
> the context of your introduction where you emphasized the freedom that
> ART developed in the U.S. and the advantage of that.
>
> I think it is important to put it on the table. There is not a shred
> of evidence, not a shred of clinical evidence whatsoever, that either
> of those procedures ever made a single difference in anybody\'s life.
> They were totally uncontrolled studies. In the published study in
> Lancet there were 17 patients in their mid-30s who had an average of
> something like 18 embryos. These women did not have egg dysfunction
> the way we are talking about egg dysfunction.
>
> The whole story is completely based on a biologic rationale which is
> frail, very frail. I mean, the energy theory is completely lacking in
> evidence. Microtubules are stored with energy. They don\'t need ATP
> from the mitochondria. The mitochondria are quiescent. They have no
> cristae, just almost zero oxygen consumption in eggs at the time of
> fertilization in humans and mice.
>
> There is no evidence whatsoever that there is a positive ATP driving
> aneuploidy in any mammalian egg that has been credibly deduced.
>
> Conversely, you can imagine a number of biologic rationales that would
> make this a very dangerous procedure because it is very clear that
> mitochondria are involved in apoptosis and killing bad eggs that are
> predisposed towards aneuploidy. In recent published studies
> from\--like, Nature Genetics had a paper two months ago that
> polymorphisms in mitochondria determine intelligence in mice.
>
> I don\'t know exactly how they determine intelligence in mice. I guess
> Mickey Mouse would have starred in their intelligence testing, but it
> is very important in brain development. Most mitochondrial disorders,
> should they be passed forward through this process, we, and others,
> have shown small levels of mitochondrial DNA mutations in eggs from
> infertile women would only appear later.
>
> So there is no way that this could be considered safe. It is germ-line
> gene therapy. It is very clearly germ-line gene therapy and somebody
> should stop it, whether it is the federal government, whether it is
> ourselves as a profession. Since we didn\'t do it, I think it is very
> important that somebody did it. Anyway, that is an editorial comment.
>
> DR. TONER: And that may all be true. I agree that it is premature to
> be doing those things. What I was trying to highlight, though, really,
> is the fact that, for reasons that are still mysterious, a 42-year-old
> egg, although it looks like a 32-year-old doesn\'t behave like a
> 32-year-old egg. So all we have now for those women is substitution
> therapy.
>
> We don\'t have a way to remedy the egg and those procedures that you
> allude to were conceived in hopes that that would be a remedy. That\'s
> all.
>
> DR. KEEFE: Yeah. I think we agree. The question is should we consider
> frozen embryos a benefit exclusively or should there also be
> considered a side effect. Consider there are a quarter of a million
> embryos that are in freezers in the United States and I think up to 5
> to 10 percent of those are abandoned. There is a double-edged sword to
> the excess embryos.
>
> I agree with you that it is very valuable but, to sit down with a
> couple who has their twins and now are figuring out what to do with
> these embryos that are excess is kind of a double-edged\--how do you
> see that in terms of trials?
>
> DR. TONER: Kind of the same way but I think it may be a bridge
> technology. Again, if we could freeze the eggs, themselves, even among
> married couples, that would really be the preferred avenue so as to
> avoid these conundrums that we find ourselves in.
>
> But I think, again, my point was that if the primary effect of a
> gonadotropin FSH is egg production and one is stronger than another
> and produces more eggs but it gets buried in the fact that you are
> never going to put as many embryos back anyway as to show the benefit,
> then you wouldn\'t want to use the fresh pregnancy rate as your only
> endpoint, or you would miss the benefit.
>
> DR. GIUDICE: Dr. Emmi?
>
> DR. EMMI: I had a couple of questions. My first is you had spoken
> about ovarian reserve as being the best predictor or how people will
> respond. And then, later, you talked about PCO and the fact that
> metformin will actually change the response in a PCO patient and we
> all know that they tend to be super-responders.
>
> How would you factor that into a protocol since they do tend to
> respond differently. Most people treat them differently and start them
> on different levels of gonadotropins.
>
> DR. TONER: You might either require it being used in all people who
> meet the criteria for PCO or balance for it, you know, stratify by it,
> so that you don\'t end up with one treatment having an
> disproportionate number of people who happen to get that adjunctive
> treatment.
>
> DR. EMMI: You used as your main protocol called the antagonist, you
> said, for the average patient. How many programs in the country do you
> think are probably\--I mean, just average? Do you have any idea how
> many are using that now?
>
> DR. TONER: I would guess half or more are using it some way or other.
>
> DR. EMMI: But I mean in their average patient population, I guess, is
> my question.
>
> DR. TONER: Don\'t know.
>
> DR. EMMI: Okay. Thank you.
>
> DR. GIUDICE: Dr. Stanford and then Dr. Rice.
>
> DR. STANFORD: I guess I would just like to amplify again on the
> comments of Dr. Rice and Dr. Emerson in that I was a little bit
> confused by\--I thought I heard you say that we can\'t really affect
> the egg quality by the gonadotropin stimulus.
>
> But then you had a clear study where the amount of LH clearly did
> affect ovum quality, whether the LH was in the optimum range. So, to
> me, it seems that, at least in that way, gonadotropin stimulation
> protocol does affect egg quality. So, that raises, in my mind,
> questions for using just pure number of eggs as an outcome.
>
> DR. TONER: I don\'t think we know in that Ganirelix trial whether the
> lower pregnancy, higher miscarriage, was actually an egg effect or an
> endometrial effect. So it could be that it did nothing at all to the
> eggs that would have otherwise grown as evidenced by embryo
> development in the lab and had everything to do with the fact that the
> endometrial development was deranged.
>
> But I agree that, given the nature of the structure of the study,
> there is no way to know which it is because it could also be eggs that
> were adversely affected.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I guess this is more of a comment. I am sort of brought back
> to my early work when we used our mouse model and were looking at PMS
> and hCG and we were excited about the number of oocytes that we could
> get and then we got purified FSH and we were still excited about the
> number of oocytes we could get.
>
> Then we did a study where we looked at FSH and then we looked at FSH
> as the trigger for ovulation instead of HCGM. We were still excited
> about the number of oocytes we got but our fertilization rate dropped
> off significantly. So you can\'t just stop at the number of oocytes
> that you get. You have got to look downstream and then account for the
> other variables that affect the downstream outcome.
>
> But just looking at the number of oocytes is not enough when it looks
> at differences between gonadotropins. You have got to look at those
> other variables. Now, the question is how far downstream do we look
> and then how can we account for those or control for those
> confounders.
>
> DR. GIUDICE: Did you want to comment, Dr. Toner?
>
> DR. TONER: I am not sure, in my own mind, that it has to be downstream
> events. I think, if you have the appropriate LH tone and the
> appropriate embryology support, then you might see a very clear FSH
> effect holding all those other things constant that has nothing to do
> with anything but now many eggs you get.
>
> I think, in the studies where we have seen problems, we have monkeyed
> with a part of the system that didn\'t have anything to do with FSH,
> really, in the first place. If you take away all the LH and then have
> a bad outcome, it isn\'t because the FSH was a problem. It is because
> you mucked up with the LH side of the equation.
>
> So I think it depends what kind of a\--what gonadotropin you are
> trying to examine. If it is FSH, and you put parameters around what
> else needs to be there for me to ask the question fairly of FSH, that
> would include adequate LH. It would include metformin for PCO,
> perhaps. It would include adequate luteal support.
>
> But, with that frame, then I think you could potentially get a very
> clean answer about what FSH is doing or not doing with endpoints not
> past egg retrieval.
>
> DR. KEEFE: I have a question.
>
> DR. GIUDICE: Yes; one last question.
>
> DR. KEEFE: Just a comment. It is hard to do these studies looking at
> the effects of gonadotropins on egg quality in humans but there is a
> great study by Barry Bavister in the hamster which has kind of a
> subfertility that approaches that of the human. He took
> PMSG-stimulated hamster donors and then he took naturally cycling
> donors, and they were both fertilized in vivo. He then transferred the
> zygotes into the horns, the right and left horn, of the hamster and
> found that the development of the naturally ovulated embryos was
> severalfold that of\--the implantation rate was severalfold that of
> the PMSG-generated embryos suggesting that there could be some
> detrimental effects on development.
>
> It is just harder to do those studies in humans without the controls.
> But there is evidence that, in normal donors undergoing controlled
> ovarian hyperstimulation for egg donation who are not split-cycle
> donors, they don\'t have, themselves, infertility\--they are normal
> unselected donors\--that they have about 40 to 50 percent of their
> embryos that are aneuploid. This comes from Tony Pellicer in Valencia
> where they have done PGD in donors.
>
> Frank Barnes who goes around the country as the itinerant PGD
> biopsy\--this is a sort of business he has\--has found similar
> experience working with Santimine who has, again, it is a reference
> lab for PGD\--there is a growing evidence that normal donors,
> unselected, have high rates.
>
> What isn\'t known is if you just check their eggs on unstimulated
> cycles, would they approach that level, although Placheau had found
> about 25 percent of oocytes. So there may well be an effect. It is
> just hard to get that into a way we can study it carefully.
>
> DR. GIUDICE: Any further questions from the committee? Okay. I want to
> thank Dr. Toner. We will now adjourn. The committee will be having
> lunch at the hotel restaurant. For the others, you can also have lunch
> at the hotel restaurant and also there are restaurant names available
> from the front desk.
>
> We will reconvene at 1 o\'clock. For the committee members, we have
> just distributed questions from the FDA that we have been asked to
> review for the afternoon session. Thank you.
>
> \[Whereupon, at 11:55 a.m., the proceedings were recessed to be
> resumed at 1:00 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> \[1:00 p.m.\]
>
> DR. GIUDICE: We are now starting. I would like to introduce Dr.
> Shelley Slaughter who is the Medical Officer Team Leader at the
> Division of Reproductive and Urologic Drug Products. She will be
> talking on Human Gonadotropins and the Regulatory History.
>
> Dr. Slaughter. Where is Dr. Slaughter? She will talking about that
> very soon. While we are waiting for Dr. Slaughter to get to the
> podium, for the committee members, you have a list of questions. We
> have a session later this afternoon at 3 o\'clock, a presentation of
> questions and committee discussion. We will have 13 questions with
> various subparts and we have about an hour and a half to go through
> those.
>
> Some of them are\--well, actually, the division has asked that we come
> up with recommendations for each of these questions. So we have a task
> ahead.
>
> Dr. Slaughter, we have already introduced you in absentia so welcome
> to the podium.
>
> **Human Gonadotropins\--Regulatory History**
>
> DR. SLAUGHTER: Thank you.
>
> \[Slide.\]
>
> This afternoon, I am going to present the FDA\'s regulatory
> perspective on clinical trials of human gonadotropin drug products. As
> Dr. Shames said this morning, the purpose in convening this meeting is
> for us to get some information from you and some recommendations from
> you in order to craft a Guidance Document for Industry.
>
> \[Slide.\]
>
> The Guidance Document for Industry represents the agency\'s current
> thinking on a particular subject. It does not create or confer any
> rights for or on any person and does not operate to bind the FDA or
> the public. An alternative approach may be used if such approach
> satisfies the requirements of the applicable statutes, regulations or
> both.
>
> \[Slide.\]
>
> First up, I would like to thank Drs. Keefe and Toner for their
> excellent presentations this morning. I really could stand up here and
> just throw the questions out, but I will spend just a little bit more
> time. But thank you, Drs. Keefe and Toner.
>
> \[Slide.\]
>
> Briefly, I will review some gonadotropin drug products, give an
> overview of the clinical studies for selected approved gonadotropin
> drug products and, hopefully, all of the discussions that you have
> heard today will lead to a very productive discussion by the committee
> and we all take your suggestions into consideration, as I said, to
> craft our guidance document.
>
> \[Slide.\]
>
> There are two types of gonadotropin drug products that are marketed,
> urinary-derived gonadotropins and recombinant gonadotropins. This is a
> somewhat busy slide, just gives a picture of those approved products
> under both of those categories.
>
> \[Slide.\]
>
> The approved indications are ovulation induction in chronic
> anovulatory women and some of the labels will actually say ovulation
> induction and pregnancy in chronic anovulatory women and the second
> indication, multiple follicle development in ovulatory women for ART.
>
> \[Slide.\]
>
> The goal.
>
> \[Slide.\]
>
> In the 30 years since the FDA approved the drug Pergonal, the
> technology use in the treatment of infertility and the resulting
> clinical pregnancy rates have improved. I think Dr. Keefe brought this
> point out very well this morning. With that, it is time for the FDA to
> reexamine the clinical studies for gonadotropin drug products.
>
> \[Slide.\]
>
> The purpose of this overview that I will present will not be to
> reexamine the data for efficacy to make any reassessment of that data
> but rather to give an historical perspective on the study design, the
> efficacy surrogate endpoint and analysis, and safety endpoints.
>
> \[Slide.\]
>
> I probably don\'t have to have this slide, but I will just read it.
> \"A surrogate endpoint is the laboratory or physical sign that is used
> in therapeutic trials as a substitute for a clinically meaningful
> endpoint that is a direct measure of how a patient feels, functions or
> survives and that is expected to predict the effect of the therapy.\"
>
> \[Slide.\]
>
> The first of the gonadotropin drug products to be approved was
> Pergonal. It was approved on June 23, 1970 for induction of ovulation.
> The second indication was added on March 1, 1988 for development of
> multiple follicles in ovulatory patients participating in an IVF
> program.
>
> \[Slide.\]
>
> The data to support the efficacy and safety of Pergonal came from
> literature reports of IVF data representing the clinical experience
> with 192 patients at the Jones Institute over the period of 1981
> through 1984 and IVF data from Australia and New Zealand from 1979
> through 1984.
>
> \[Slide.\]
>
> The endpoint that was evaluated as this literature was assessed was
> the mean number of oocytes retrieved at time of laparoscopy.
>
> \[Slide.\]
>
> Metrodin, a FSH product, urinary FSH product, was approved on
> September 18, 1986.
>
> \[Slide.\]
>
> The data to support efficacy and safety for Metrodin was also a
> literature review of retrospective data from five open-label,
> noncomparative, clinical studies of ovulation induction in 80
> patients. There were observational reports of ovulation and pregnancy.
> The medical officer felt that Metrodin should not be approved.
> However, this issue was taken before an advisory committee in 1985 and
> the advisory committee determined that, even though the data to
> support Metrodin was sparse that, indeed, Metrodin should be approved.
>
> \[Slide.\]
>
> The next drug the I will talk about is Gonal-f. It is actually the
> first gonadotropin drug product for which the actual data was
> submitted to the FDA for review. However, we did not see the protocols
> prior to submission for the NDA, so we actually had no input into the
> study design and conduct of those trials.
>
> \[Slide.\]
>
> The efficacy and safety data was from four controlled studies. Two
> ovulation studies were open-label, active comparator to the drug
> Metrodin, phase III noninferiority studies in chronic anovulatory
> women. The primary endpoint was a cumulative ovulation rate,
> cumulative over three cycles of treatment. It was defined by a serum
> progesterone level greater than or equal to 10 nanograms per ml.
>
> The IVF indication was supported by two randomized, again open-label,
> active comparator, phase III noninferiority studies in normal
> ovulatory women. The primary endpoint was follicles on ultrasound
> greater than 14 millimeters.
>
> \[Slide.\]
>
> Both of these trials\--this is ovulation induction trials, now. One
> was conducted in the U.S. and one was conducted in Europe. As you can
> see, these, as I stated before, are noninferiority comparative trials.
> Both studies show that Gonal-f was no worse than Metrodin by 16 or
> 21 percent, so about 20 percent difference. The lower bound of the 95
> confidence interval suggests that it was no worse than about 20
> percent than Metrodin.
>
> \[Slide.\]
>
> There were, as I said, two IVF studies. One was conducted in the U.S.
> and one was conducted in Europe. This goes back to one of the
> questions that was asked earlier this morning. This was mean number of
> follicles. There was not much difference in the results between the
> U.S. and the European study. Again, the Gonal-f was no worse than
> Metrodin by about three follicles.
>
> \[Slide.\]
>
> The next drug was Follistim. It came in a little later than Gonal-f
> but received its regulatory review approximately about the same time.
> It was approved on September 29, 1997. Again, actual data was
> submitted for review to the FDA but we were not involved in the
> protocol in terms of study design endpoints.
>
> \[Slide.\]
>
> Efficacy and safety to support Follistim was from four controlled
> studies. One study supported ovulation. It was a single or
> assessor-blind study, active comparator to the drug Metrodin, phase
> III, noninferiority trial in chronic anovulatory women.
>
> \[Slide.\]
>
> The drug Follistim was actually better or superior to its active
> comparator in terms of ovulation rate with about 85 percent ovulation
> rate.
>
> \[Slide.\]
>
> Three randomized assessor-blind, active comparator to either Humegon
> or Metrodin, phase III noninferiority studies supported the IVF
> indication in normal anovulatory infertile women. The endpoint that
> was evaluated was the mean number of total oocytes retrieved.
>
> \[Slide.\]
>
> These three studies were all conducted outside of the United States.
> Most of these were European trials. The largest of the trials I have
> indicated as IVF Study No. 1 actually showed Follistim to be superior
> to its active comparator in the total number of oocytes retrieved. The
> point to bring out on this one is that this was a trial that was,
> indeed, powered to show a difference in pregnancy rate and it did,
> indeed, show that.
>
> I would just have you look at the numbers because that is a point that
> we will be coming back to.
>
> Now, the lower bound of the 95 percent confidence interval, as stated,
> showed that Follistim was either better or no worse than its
> comparators by about one oocyte.
>
> Now, at this point, the point I would like you just to take home is
> that we have been using various surrogate endpoints for pregnancy. Our
> sponsors and their advisors indicated to us that trials could not be
> powered to show pregnancy or would be difficult to power, and you do
> see what the magnitude of the sample size that would be needed to
> actually show pregnancy.
>
> We, then, as I said, looked a surrogate endpoints. Our question has
> always been what difference would be clinically meaningful in these
> surrogate endpoints; in other words, how do we make the interpretation
> of the difference between the drug and its active comparator.
>
> \[Slide.\]
>
> The safety evaluation on all the four examples of drug products that I
> gave you, the review looks strongly at ovarian-hyperstimulation rate
> and multiple-birth rate.
>
> \[Slide.\]
>
> As you have heard, since these selected gonadotropins were approved,
> IVF technology has been broadened to include adjunct procedures such
> as donor oocytes and intracytoplasmic injection and there are more IVF
> clinics available leading to a greater pool of patients for inclusion
> in studies.
>
> \[Slide.\]
>
> This brings me to the point in the presentation where we will put the
> questions up.
>
> DR. GIUDICE: Thank you.
>
> DR. SLAUGHTER: We will actually put these questions back up a little
> later, but just to have it, I will read through the questions for you.
>
> \[Slide.\]
>
> Please discuss what enrollment criteria should be used to adequately
> capture the population to be studied for ovulation induction and for
> assisted-reproductive-technology programs.
>
> \[Slide.\]
>
> Should enrollment criteria be stratified by age for ovulation
> induction and for ART? Should we stratify for use of adjunct
> procedures such as donor oocyte or ICSI?
>
> \[Slide.\]
>
> Should our studies be blinded or not and, if blinded, please discuss
> the merits of blinding the assessor, the patient or both. Discuss the
> merits of having placebo and/or active control arms in the studies. If
> an active control is used, discuss how you would define the
> noninferiority margin.
>
> \[Slide.\]
>
> Discuss the advantages and disadvantages of single versus multiple
> treatment cycles. Discuss the advantages and disadvantages of powering
> studies to detect a difference in live birth rate or ongoing pregnancy
> rate.
>
> \[Slide.\]
>
> If studies cannot be powered to demonstrate differences in live birth
> rate or ongoing pregnancy rate, please discuss the clinical relevance
> of the following surrogates; the rate of patients with a presence of a
> fetal heart beat, gestational sac, positive beta-hCG, ovulation rate
> or follicular development rate.
>
> \[Slide.\]
>
> Is an intent-to-treat analysis appropriate for ovulation induction? If
> you feel that it is not, should cycles by analyzed per patient given
> hCG? Likewise, for ART, is an intent analysis appropriate? If not,
> should cycles by analyzed per retrieval or per embryo transfer. Please
> discuss which safety endpoints should be evaluated.
>
> DR. GIUDICE: Thank you, Dr. Slaughter.
>
> **Questions from the Committee**
>
> DR. GIUDICE: Does the committee have any particular questions
> regarding Dr. Slaughter\'s presentation because we are going to wait
> to answer these questions or discuss these questions during the
> question discussion period later in the afternoon. Yes; Dr. Stanford?
>
> DR. STANFORD: I don\'t know if you know this stuff off the top of your
> head, but it would be helpful to me to know the GnRH agonists and
> antagonists, what were their endpoints when they were approved. What
> were the endpoints in those studies to approve those products?
>
> DR. SLAUGHTER: The agonists have never been presented to the agency
> for consideration. The antagonists also looked at oocyte retrieval.
>
> DR. STANFORD: On Repronex, which is another version of hMG, as I
> understand it, what was the endpoint on that because its indication is
> different. It lists with an agonist as opposed to the others don\'t
> list that.
>
> DR. SLAUGHTER: The history behind that is that Repronex was originally
> approved as a generic drug. They came back to the agency to ask for a
> change in route of administration and, at that time, they also
> presented new trials that utilized GnRH agonist for downregulation.
>
> Also let me say that the trials for Gonal-f, I believe, were not done
> with agonists. Two of the three trials for IVF for Follistim were done
> with GnRH agonists.
>
> DR. STANFORD: But they didn\'t put that in the labeling. So was the
> endpoint of Repronex the number of oocytes retrieved?
>
> DR. SLAUGHTER: Yes.
>
> DR. STANFORD: Okay.
>
> DR. GIUDICE: Yes?
>
> DR. EMERSON: In the Follistim IVF study, what was the patient
> population, what was the definition of infertility in the normal
> ovulatory?
>
> DR. SLAUGHTER: I believe that it included some male factor, I believe
> mild male factor, and unexplained and tubal factor.
>
> DR. EMERSON: And infertility was defined by one year of\--
>
> DR. SLAUGHTER: Yes.
>
> DR. EMERSON: Okay.
>
> DR. GIUDICE: Dr. Hager.
>
> DR. HAGER: Along that same line, is the reason that there is not
> consistency across the board is because you were not\--the agency was
> not involved in the protocols?
>
> DR. SLAUGHTER: Yes.
>
> DR. HAGER: You were not requested to be involved in the protocols?
>
> DR. SLAUGHTER: We did not receive those protocols ahead of time to
> participate in them. Subsequent to that, we looked at the trials for
> Follistim and made some recommendations about endpoints. Again, our
> recommendation, and Dr. Bennett is seated in the audience, was to look
> at take-home baby. We were told that that was not feasible and so we
> recommended oocyte retrieval and based our clinically meaningful
> difference on the trials that we had up to that point.
>
> DR. HAGER: So the use of oocyte retrieval was an FDA recommendation.
>
> DR. SLAUGHTER: Yes.
>
> DR. GIUDICE: I have a question following up on Dr. Hager\'s. Then, I
> guess for clarification of the advice that you would like from this
> committee, the immediate short-term goal is for us to answer these
> questions and so a guidance document would be developed for your
> interactions with sponsors before they design their clinical trials,
> when they have information that they are bringing to you? Can you shed
> some light on this, please.
>
> DR. SLAUGHTER: What happens, usually\--usually, at this point, what we
> have is the sponsors will come to us at a pre-IND stage and talk to us
> about the indications or applications that they would ultimately like
> to bring in. And we have ability to interact with them as they are
> opening their IND and study design and to make recommendations to them
> at that point.
>
> They generally do or do not take our suggestions and conduct their
> studies. They come in at the time that the studies have been completed
> at phase III and have another discussion with us before the NDA is
> submitted. There is also\--it depends on the stage of development they
> are with their drug. We can have meetings with them when they are very
> early at phase I, when they are at phase II or at the phase-III
> development.
>
> DR. GIUDICE: Thank you. Dr. Lipshultz?
>
> DR. LIPSHULTZ: Just for my own clarification, then, have the companies
> been coming to you at different stages in terms of where they have
> already gone with the product or do they all come to you prior to
> institution of a protocol?
>
> DR. SLAUGHTER: They have been coming at different stages. Sometimes as
> some of the examples I have shown you here, they never come to us
> until they are presenting their application. Sometimes, they come,
> depending on the drug product and I am just giving a general overview
> now at a very, very early stage before they ever go into humans, and
> then work with us all along the process.
>
> Sometimes they come in after they have already conducted some trials
> and to ask for further advice. When they don\'t come in at all, these
> are trials that have been conducted outside the U.S.
>
> DR. LIPSHULTZ: Do you foresee this process changing and that is why
> this document becomes important?
>
> DR. SLAUGHTER: The trend now is for most sponsors to come in with\--to
> us for advice, now.
>
> DR. LIPSHULTZ: Before they\--
>
> DR. SLAUGHTER: Before they submit the application. We still do have
> some who come in at a later stage, but we now have worked with a
> number of sponsors who are coming in early during their development
> and process. For the gonadotropins, they generally come in to discuss
> a phase III trial. There may be other drugs coming down the line that
> may come at an earlier stage, but, yes, the purpose is to give
> guidance to those\--to the industry conducing these phase-III trials.
>
> DR. GIUDICE: Yes, Dr. Crockett?
>
> DR. CROCKETT: I just have a question regarding these guidance
> documents and the past history and what you foresee in the future for
> them. This is kind of a new thing to me. I am interested in knowing do
> you have guidance documents in place already for other drugs through
> this division? Is this kind of a book that is being put together of
> guidance documents.
>
> Then my second part of the question is, as we have seen through these
> presentations, as our knowledge of science has grown, our
> recommendations probably would have changed over the last ten years.
> So my follow-up question is if we draft a guidance document today,
> when does this committee get to revise or look at it again and what
> does the division or the FDA plan to do with this?
>
> DR. SLAUGHTER: Okay. I will try to answer all those questions in
> order. This is not a new thing. Throughout the agency, we try to keep
> our recommendations as uniform as possible and, in order to do that,
> we do draft guidance documents. In our division, we have numerous
> guidance documents, some that, as you know\--some of the
> hormone-therapy guidance documents are now in draft on the web.
>
> What we intend to do with this guidance document, we do realize that
> things change over time which is why I am here today. But what we
> intend to do with this is take your recommendations, put a draft
> guidance together. That guidance will be approved internally and then
> will be put up on the web as a draft guidance for comment from the
> public.
>
> Our intent is not necessarily to bring that draft back to the
> committee but, certainly, the committee or anyone else would make
> comments to that document at the draft stage and we would take into
> consideration those comments.
>
> DR. GIUDICE: Dr. Hager?
>
> DR. HAGER: I\'m sorry; I hate to belabor this but it seems to me that
> what we are trying to determine is are we going to make a difference.
> I heard you make a comment earlier that the FDA recommended to
> pharmaceutical manufacturer X a change in protocol but that was not
> adhered to. At that point in time, then, basically you wait until the
> study is submitted without those changes in protocol and then
> reevaluate the data; is that correct? There is no intervention in
> between?
>
> DR. SLAUGHTER: Let me try to answer that. I put up these guidance
> documents are just that. They are recommendations. They are not
> binding. What we do in order to keep our recommendations uniform is to
> draft these guidelines, these guidances. If the sponsor chooses not to
> follow our recommendation, then that becomes an issue that we will
> look at in terms of whether it affected the outcome and we felt there
> was any effect on the outcome as we review the application for our
> regulatory decision.
>
> DR. HAGER: I understand that\--I thought there is some intervention
> process but I guess there is not. There are no regulations\--
>
> DR. SLAUGHTER: No. The guidances are not regulations. We would have to
> do that in order to make them binding. We can only make them as
> uniform as possible and give uniform advice and have the sponsor
> voluntarily adhere to those guidance documents.
>
> DR. GIUDICE: Dr. Shames.
>
> DR. SHAMES: The purpose\--we cannot, once we make recommendations for
> trials, compel anybody to do that particular trial. We can only stop a
> trial based on safety. So people are allowed to do essentially within
> certain parameters any trial they want to do. The guidance process is
> to make everything more efficient for the industry, for us, so that
> they know beforehand basically what we want. Then we do work with them
> and try to tweak their trials so that we, all along the process, know
> what is going to happen.
>
> Therefore, when we get the final information, we have the information
> we need so it is the most efficient way to get it done. Now, if they
> choose to do it some other way, it is still possible to get it
> approved but it is going to be\--it is a little riskier, certainly, on
> their part. So we are trying to get the word out of what is the best
> way to do it.
>
> Now, in this case, of course, we are not 100 percent sure what is the
> best way to do these trials so that is why we have convened this
> advisory committee. Of course, when we don\'t know what the best way
> and the company is telling us one thing and\--it makes the process
> less efficient.
>
> So if we can all sort of agree on some general parameters, then we can
> move forward faster.
>
> DR. GIUDICE: Thank you. Any additional questions? Yes; Dr. Emerson?
>
> DR. EMERSON: I am going back to these previous trials that have been
> done, and knowing that you gave us some background information that
> were chapters out of various gynecology and endocrinology books that
> gave estimates of the rates of\--pregnancy rates in infertile couples
> after a year, I think. Are those widely agreed-upon rates or are
> those, I guess they are quoting something 11 percent pregnancy,
> fecundity, rate after being infertile for twelve months. Is that a
> widely agreed-upon rate? Thank you.
>
> DR. GIUDICE: Dr. Stanford?
>
> DR. STANFORD: I guess it goes without saying that if there is a
> certain approach that comes out as recommended in a guidance document,
> that is basically what you are looking for in the actual approval. I
> mean, that is basically what you are saying is that if this is the
> endpoint you are asking for in the guidance document, that is also the
> primary endpoint you will look at when you are actually approving.
> That is a fair statement?
>
> DR. SLAUGHTER: Yes.
>
> DR. STANFORD: One other question. This may be a real\--there may be
> no\--I am just trying to understand, I guess, the details of the
> actual stated indications but I noticed that, for Follistim and
> Gonal-f, they are both indicated for both ovulation induction and ART
> but they list it in different order. Is there any significance to
> that, or is that just random?
>
> DR. SLAUGHTER: That was just how that fell out; yes. Let me just\--I
> had a little bit more on this I left off the questions, one of the
> things that I left off from these questions. So it will address one of
> your things.
>
> These are the indications; induction of ovulation or some of the
> labels do say induction of ovulation and pregnancy or marked follicle
> development and ART. We would like your comment on the appropriateness
> of these indications given all the discussions that hopefully you will
> have on the endpoints and analysis.
>
> Then, the last thing, and I apologize that I left off this at the end,
> this came up this morning about the SART data that is collected on
> pregnancy and about pregnancy registries with industry. We, as part of
> the process, can only recommend that they maintain a pregnancy
> registry. We would like to have your input on that, should
> manufacturers obtain approval for ovulation induction or ART who
> obtain approval maintain an pregnancy registry. If you do feel that
> they should, what information should be collected in that registry and
> at what point in time should the registry be terminated?
>
> DR. GIUDICE: I have a follow-up comment to Dr. Stanford and also Dr.
> Shames\' comments. Whenever a set of guidances are issued, not
> specifically to the FDA but by an organization or a body, very often
> they do not accommodate for the\--or they do accommodate for \"one
> size fits all.\" But, with the complexity of ART and ovulation
> induction, I think it is an important issue that this is another part
> of our discussion, that while these may be recommendations, clearly
> there should be some allowance for \"one size does not fit all\" for
> thee particular medications and indications.
>
> DR. SHAMES: It says in our guidances that these are only
> recommendations. In a field such as this, we often are open to adding
> to the guidance or changing the guidance periodically. We can keep it
> even as a draft guidance and still keep it public.
>
> And we certainly recognize that there are times when we\--there is
> more than one way of doing things. So that is a well-taken point.
> Absolutely.
>
> DR. GIUDICE: Thank you. Dr. Rice?
>
> DR. RICE: I am assuming that, when I look at Point 13, we would make a
> recommendation, if we decided to recommend this based on future
> products to be approved or is there any room for the current list of
> products that are approved for these indications to begin to maintain
> a pregnancy registry or are you only looking to us for guidance for
> future products that are going to be approved?
>
> DR. SLAUGHTER: I guess I would answer that as saying do you think
> these are necessary for these drug products and, if you believe they
> are, then I think we would certainly implicate them first with future
> products but would have further discussions on ART products that are
> already approved. Dr. Shames?
>
> DR. SHAMES: If the committee believes it is important to have that,
> that will add weight to our arguments to drugs that are already
> approved that they might investigate doing that. We have no way of
> compelling them to do that but we would be interested in your opinions
> about whether they should or shouldn\'t do it.
>
> DR. GIUDICE: Thank you. I think we can discuss that in more detail
> later this afternoon.
>
> I would like to move on now to the Open Public Hearing.
>
> **Open Public Hearing**
>
> DR. GIUDICE: Before starting this session, there is a statement that I
> have been asked to read, and that is that, \"Both the FDA and public
> believe in a transparent process for information-gathering and
> decision-making. To ensure such transparency at the Open Public
> Hearing session of the advisory committee meeting, the FDA believes
> that it is important to understand the context of an individual\'s
> presentation.
>
> \"For this reason, the 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 the 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 would not preclude you from
> speaking.\"
>
> So there are three individuals who have requested time during\--okay;
> are the three individuals who have requested time present? I see one
> hand, two hands. Two hands. Then let\'s begin with Dr. Kirsch, please.
> If you would introduce yourself, your affiliation and if you choose to
> make any comments with regard to the opening statement.
>
> DR. KIRSCH: Thank you. Good afternoon. My name is Robert Kirsch. I am
> a Director of Regulatory Affairs at Sorono. I would like to make a
> brief statement to the committee and we very much appreciate your time
> this afternoon.
>
> For more than 50 years, Sorono has been a global leader in the
> development of treatments for infertility and has been dedicated to
> helping couples realize their dreams of parenthood. Sorono is a
> company committed to cutting-edge research, high-quality products and
> patient care.
>
> Our complete portfolio of fertility drugs, including Gonal-f,
> Cetrotide, Luveris, Ovidrel and Crinone addresses patients\' needs at
> every stage of the reproductive cycle. Three of these products,
> Gonal-f, Luveris and Ovadrel are gonadotropin products manufactured
> using recombinant DNA technology.
>
> We appreciate the opportunity to provide comments on the following
> important issues raised by the FDA for discussion in consideration by
> the advisory committee. These issues are endpoints used in clinical
> trials;pregnancy as an endpoint, and clinical pregnancy.
>
> The design of clinical trials intended to support the registration of
> new products and indications is an important subject both to the
> sponsors of such clinical trials\--i.e., industry\--and the FDA.
> Equally important is to recognize that, although in certain patient
> populations for which the underlying cause of infertility has been
> clearly identified or which has already been extensively researched,
> it may be possible to agree on a single standard endpoint.
>
> However, it is imperative to avoid a \"one size fits all\" approach to
> research in the constantly evolving area of infertility and
> reproductive health. The first issue, endpoints used in clinical
> trials; for each population and indication studied, the endpoint
> chosen should reflect the primary pharmacological action of the drug.
> For indications involving ART, this may be development of multiple
> follicles which can be measured directly or indirectly as oocytes
> retrieved.
>
> In ovulation induction protocols, for example, patients defined by the
> World Health Organization as WHO2, an appropriate primary endpoint may
> be P4. Conversely, in patients defined as WHO1, P4 is not fully
> informative as it does not provide full visibility to other critical
> components of drug effect.
>
> Therefore, for this population, rate of follicular growth, estrogen
> production and endometrium receptivity are critical measures of drug
> efficacy and equally important to P4.
>
> The second issue, pregnancy as an endpoint. On the broader subject of
> pregnancy, this is the ultimate desire of every patient and her
> physician but does not necessarily reflect the primary pharmacological
> action of the drug. For those ovulatory patients whose cause of
> infertility remains unknown and unexplained, as many as 25 percent of
> all infertile patients, pregnancy may be an appropriate clinical
> endpoint.
>
> For patients undergoing ART, there are other pharmacological agents
> used during the treatment regimen as well as multiple additional
> confounding factors any of which may impact pregnancy. These
> additional factors which are beyond the control of any sponsor, must
> be considered.
>
> It is important to note, however, that information on pregnancy has
> always been collected and reported during gonadotropin clinical
> trials.
>
> The third issue, clinical pregnancy; regarding clinical pregnancy as
> an endpoint, the above considerations remain. Clinical pregnancy is
> defined be the National Registry, SART, by the presence of an
> embryonic sac. Patients realize that a pregnancy detected in its early
> stages is, indeed, a pregnancy even though it may not always proceed
> to a pregnancy confirmed by ultrasound or even a live birth.
>
> Beta-hCG is universally accepted as the diagnostic test for early
> pregnancy and the ultimate outcome of any pregnancy does not alter the
> fact that a pregnancy was established. Furthermore, in studies of our
> gonadotropin products, there are many instances where a clinical
> pregnancy has been confirmed by ultrasound with a fetal sac but
> without heart beat. Given that the majority of these same patients
> achieve a successful pregnancy outcome resulting in a live birth
> indicates that the most conservative approach, ultrasound with fetal
> sac and heart beat, could result in applying an excessively high
> standard in terms of product registration.
>
> In considering these types of endpoints, one must realize that, in
> order to ensure that a clinical trial is adequately powered to detect
> statistical differences between treatment arms, a primary endpoint of
> pregnancy, clinical or otherwise, will require large numbers of
> patients to be studied, potentially thousands per study, creating
> additional hurdles when conducting research in infertility.
>
> This, in fact, would serve as an additional deterrent to research in
> low-outcome patient populations and in those patients who suffer from
> rare conditions or diseases. Clinical development programs will always
> have constraints that are not present in routine clinical practice.
> Importantly, one must determine how much is too much to ask of a
> particular gonadotropin drug product.
>
> Ultimately, all divisions of the U.S. Food and Drug Administration
> must make decisions on approvability based on the overall benefit-risk
> profile of the proposed product in relation to treatment of patients
> and their respective underlying disease. These considerations are
> never black and white.
>
> Therefore, in making recommendations which may form the basis for a
> guidance-for-industry document, we encourage that maximum
> consideration be given to ensure adequate breadth and flexibility in
> aspects of study design. This will facilitate the introduction of new
> drugs, treatment of new indications and improvements in the scientific
> and manufacturing technologies employed in making these therapies
> available to patients in the most efficient manner possible.
>
> Sorono has been a leader in the field of research development and
> commercialization of products used in the treatment of men and women
> experiencing infertility for more than 50 years and we intend to
> continue this commitment. We request that the advisory committee
> consider carefully what recommendations can be made in order to
> facilitate the clinical development and availability of new and
> innovative products which are both safe and effective in the most
> expeditious manner possible for these patients many of whom are
> currently underserved.
>
> I would like to thank you all again for the opportunity to share
> Sorono\'s position with you this afternoon on some of these important
> issues. We look forward to hearing your recommendations and to
> receiving FDA\'s draft guidance for industry.
>
> Thank you very much.
>
> DR. GIUDICE: Thank you. The next speaker is Dr. Kurt Barnhardt.
>
> DR. BARNHARDT: Good afternoon. It is a privilege to be part of this as
> a public member. My name is Kurt Barnhardt. I am an Assistant
> Professor of Obstetrics and Gynecology, a reproductive endocrinologist
> as well as an epidemiologist at the University of Pennsylvania. I
> direct the Clinical Research Center in our department in the
> University of Pennsylvania and, as such, have contacts with many
> industry supports that sponsor our studies including, off the top of
> my head, Wyeth-Ayerst, Parke-Davis, Organon and Sorono.
>
> I wanted to talk briefly and add my comments on the idea of study
> design and outcomes. As I mentioned, in my capacity as doing clinical
> research, I have designed many of my own studies as well as
> participated in many industry-sponsored studies and I wanted to speak
> a little bit about outcomes and study design in that aspect.
>
> We all know, and we have heard some eloquent talks that infertility is
> a very complex subject and, often, I can have patients, I, in my
> practice, that I treat for infertility without gonadotropins and,
> oftentimes, I can treat them with gonadotropins concomitant with many
> other therapies as well.
>
> As I want to point out, and as you have heard before, there are many,
> many factors influencing the ultimate success of the treatment and it
> is not surely just the pharmacologic agent that I choose.
>
> I disagree with some of the verbiage that was used earlier and I think
> it was more a mistake that biochemical markers are surrogate markers
> of infertility treatment. I think that what I would like to say is
> that we would like to have, or, as a methodologist, you want your
> outcome to be as close to the direct action of the intervention as
> possible, in this case, drug therapy. The purpose of drug therapy is,
> again, in this case, for multiple follicle development or having
> someone ovulate that otherwise normally wouldn\'t.
>
> After that takes place, there are many factors that influence whether
> a women is going to get pregnant. There are many other therapies that
> we use allowing someone to pursue that goal. Some women get
> insemination. Some don\'t. Some get ICSI. Some don\'t.
>
> Age, obviously, as you know, requires a lot as the genetics of the
> woman, the receptivity of her uterus and such. But the further
> downstream we move from the use of the pharmacologic agent, the more
> determinants are going to affect that outcome. That makes it very
> difficult to design a study based on a downstream outcome.
>
> I mentioned that another reason that it makes it difficult for these
> outcomes is, again, the specifics of how we individualize treatment of
> the woman or the couple with infertility. It, again, varies very much
> on how we handle gametes, the quality of our laboratory and many other
> factors that are independent to the woman alone to try to stratify in
> these outcomes or to try and analyze these potential confounders
> afterwards, again, makes it very methodologically difficult.
>
> I guess the only analogy, as I was driving down, that I could think of
> would be if I was designing a new drug for the induction of labor, I
> would hope that this drug would be judged on its ability to induce
> labor, not on its C-section rates and not on its perinatal mortality.
> Of course, those are important aspects of the drug, but they are not
> the primary endpoints of the drug under study.
>
> Another issue I wanted to bring up was that the population is very
> specific and a very savvy population and that certain studies are
> going to be difficult to carry out practically in this population even
> though they might be a very good study on paper. A randomized, blinded
> trial, although certainly the Cadillac of studies, can have some
> difficulties in patients where high drop-out for not getting the
> treatment they want or for therapies that don\'t work is going to very
> much influence the outcomes and the validity of a study.
>
> The same could be said for the idea of trying crossover studies or the
> possibility of having multiple sequential cycles. Please recognize
> that this really is an individual population and the practicality of
> carrying out such studies should be taken into account.
>
> So the goal, really, was for me to say please maintain some
> flexibilities in your outcomes. I mean, currently we are talking about
> gonadotropins where the goal of the therapy is to induce ovulation in
> those that don\'t ovulate or to induce multiple ovulation in those
> that do.
>
> We could argue about what is the best test for ovulation. Currently,
> probably, the best compromise between reproducibility and invasiveness
> is a serum progesterone. But, as we change and that science advances,
> that also might change and we might adopt some other better marker of
> ovulation of follicular development.
>
> Indeed, as our drugs change, as we go into subpopulations of infertile
> populations, we might be talking about improving egg quality rather
> than egg number. If we are just talking about ovulation as an
> endpoint, we are going to lose the robustness of that additional
> information. Indeed, if we are talking about a new fertility drug
> that, for example\--and I just made this up\--maintains the miotic
> spindle, obviously, we can\'t have ovulation as an endpoint for that
> kind of drug. So we have to have flexibility on our study design to
> allow for the specific indication of that drug.
>
> So, obviously, as a clinician, I hope all of my patients get pregnant
> and I strive to maintain that. But I also know there is a lot more
> than the pharmacologic agent I choose and the dose that I choose that
> is going to influence that.
>
> So, of course, I suggest that you collect all pregnancy data as SART
> is collected and, of course, miscarriage rates, ectopic pregnancy
> rates and OHHS are important information. They are very valuable
> information to decide whether a drug is better or equivalent or no
> worse, and that is not what I am addressing in the study design. But
> that is information to compare and not, hopefully, the primary
> endpoint to power a study.
>
> So, thank you very much for the chance to speak.
>
> DR. GIUDICE: Thank you, Dr. Barnhardt. Are there any additional
> comments or any additional speakers for the Open Public forum? Yes?
>
> MR. TIPTON: I am Sean Tipton, Director of Public Affairs with the
> American Society for Reproductive Medicine. Our President Elect,
> Marian Dameler, was due to be here today and got detained in York,
> Pennsylvania which, unfortunately\--it is better for people who are
> flying from farther away because they are less likely to get hung up,
> I think.
>
> The ASRM does have a commercial relationship with a number of players
> in the pharmaceutical industry who may have an interest in the
> deliberations of this panel. Primarily, those will take the form of
> advertisement or sponsorship of ASRM programs.
>
> Thanks for the opportunity to offer our views on ovulation-induction
> drugs. The ASRM is a professional association of more than 8500
> members worldwide. Our members include the leading experts in the
> field of reproductive endocrinology and infertility many of whom are
> around the table and in the room today.
>
> As an organization, we have dedicated considerable time and resources
> to issues surrounding the use of ovulation-induction drugs. We have
> developed patient-education materials. Our practice committee has
> issued a number of related reports and in our journal, Fertility and
> Sterility, there are frequently works on ovulation-induction drugs and
> we feel uniquely qualified to offer a little insight and input into
> the topic.
>
> Ovulation-induction drugs are an essential component of the modern
> treatment of infertility with approximately one-third to one-half of
> all infertile women who are having ovulation problems. For many
> patients, ovulation-induction drugs help with their ovulatory problems
> and, for others, the drugs are used to maximize success of other
> treatments such as in vitro fertilization.
>
> Ovulation-induction drugs are used with great effect every day by the
> members of the American Society for Reproductive Medicine. However,
> like all physicians, our members are constantly seeking new and better
> ways to treat their patients. Like any medication, ovulation-induction
> drugs carry some risk, each specific product carrying its own
> particular risk, and we would support the approval of new products
> with lower-risk profiles.
>
> Many of the concerns, such as reports of increased cancer risk
> following the use of these products, have not stood up to increased
> scrutiny, but it is increased scrutiny, more research and better data
> that are essential for these products as they are for any medication.
>
> At present, one of the most serious potential risks from the use of
> these drugs is multifetal pregnancies. Multifetal pregnancies carry
> huge risk for the mother and the subsequent children. The ASRM
> practice committee has issues guidelines limiting the number of
> embryos to transfer in ART procedures to minimize the risk of
> multifetal pregnancy. This work was done with our affiliate, the
> Society for Assisted Reproductive Technology.
>
> In that case, the data were clear that the number of embryos
> transferred could be reduced without adversely affecting the prospects
> for a successful outcome. Unfortunately, the data are less clear on
> steps to recommend to prevent multifetal superovulation pregnancies.
> Writing in the January 2003 issue of Fertility and Sterility, the
> current chair of our practice committee and his immediate predecessor
> wrote, \"Specific guidelines for management of ovulation-induction
> cycles cannot be offered because neither sufficient evidence nor broad
> consensus exists. The ASRM practice committee has no valid basis to
> offer specific recommendations for cycle-cancellation criteria.\"
>
> In short, the data are not conclusive. Clearly, more data is needed,
> more research is needed, more and better medications to provide more
> and better options for the infertile patients in this country are
> needed.
>
> We look forward to the deliberations of the committee and thank you
> for the opportunity.
>
> DR. GIUDICE: Thank you. Are there any further speakers or comments?
> Okay; we have a choice, now, as a committee, either to take a break or
> to begin discussing one of the thirteen questions. Who would like to
> take a break? The hands are gradually going up around the table.
> Let\'s take a ten-minute break and then reconvene, please.
>
> \[Break.\]
>
> DR. GIUDICE: Before we begin discussion of the questions, there have
> been several committee members who have expressed an interest in
> finding out what input they may have with regard to the final
> document. Dr. Shames, if you would make some comments, please, as to
> what the process is.
>
> DR. SHAMES: Okay. The process\--in a general sense, the advisory
> committee literally advises us on certain issues, general issues,
> specific issues. Ultimately, however, your advice is advice. It is a
> recommendation. We have the authority to make the decision or write
> the guidance or whatever.
>
> What will happen in this situation where we are trying to write a
> guidance is, once we have finished this and we will look at the
> transcript\--everything you say is being written down. We will have a
> direct transcript of all this. Our staff will write a guidance. It
> will be called a draft guidance and will be posted publicly.
>
> You, everybody, anybody and everybody, will have a chance to make
> suggestions regarding our draft guidance including you. Now, you, as
> our advisors, have somewhat of a special status in that we can talk to
> you directly and you could recommend to us directly. We can speak to
> you on a more direct basis than other people.
>
> But the pharmaceutical industry will make recommendations.
> Public-interest groups will make recommendations. And then we will
> ultimately, if the process goes well, prepare a final guidance and
> that will go on the web. We may ask you, again, about the final
> guidance. We can do that. But, ultimately, we are the ones that have
> the authority to write the final guidance and put it out there.
>
> So, if that is helpful. But, as advisors, you have good access to us.
> So when the draft guidance goes up, you should feel free to be
> aggressive in telling us what you think. Okay?
>
> DR. GIUDICE: Thank you for that clarification. Dr. Slaughter, you have
> a comment?
>
> DR. SLAUGHTER: May I also just say we would like, also, that we will
> have access to you. So we may seek your input further after this
> meeting is over. So we would expect that we would have continued
> interaction on this.
>
> DR. GIUDICE: Thank you.
>
> **Presentation of Questions and Committee Discussion**
>
> DR. GIUDICE: The first question is a request to discuss what
> enrollment criteria should be used to adequately capture the
> population to be studied for ovulation induction and for ART. This is
> quite a loaded question. There are clearly two groups, the
> ovulation-induction group and the ART group, so, perhaps, we can start
> off with the OI group bearing in mind the WHO1-WHO2 and also the
> infertility population. So there are really three subgroups within the
> ovulation-induction group.
>
> So I open this discussion to the other members of the committee, if
> someone would like to begin to discuss the enrollment criteria for OI,
> initially. Dr. Keefe?
>
> DR. KEEFE: Rather than answer, I have a question about the role of the
> FDA in ensuring sort of the precision of a study, the
> generalizability. I think I alluded to it in my presentation. A few
> treatments in medicine today are applied to such a narrow band of the
> American population which is changing over time. But is it the role of
> the FDA or does the FDA feel responsible for questioning that?
>
> For example, I work in a state where my patients include sheet-metal
> workers as well as heiresses from Newport, and I see big variations in
> the way they metabolize drug, the way they\--they may be smoking or
> not, not telling you, body-mass index, weight. So there are enormous
> things that are tied, in part, to socioeconomic class, ethnic
> background and racial background.
>
> Should you be concerned that the studies are coming out looking at
> investment bankers from Manhattan and how they are going to apply to
> my patient population? Is there part of your deal or not? Do you care?
>
> DR. SHAMES: That is part of our deal. We do a lot to try to make sure
> that the clinical-trial results are generalizable to the general
> population. However, you can imagine that is very, very difficult. And
> so we do the best we can to make sure that the clinical-trial
> population reflects the general population or the population that is
> going to be using the drug. But it is something that we cannot do
> perfectly.
>
> DR. GIUDICE: Dr. Emerson?
>
> DR. EMERSON: This is just a question to cure my ignorance\--well, not
> cure it, but alleviate it. Ovulation induction, is that term ever used
> for the idea of induction of menses in amenorrheic women and would
> this indication be covered by that?
>
> DR. GIUDICE: Other colleagues are certainly welcome to respond. For
> women who are not interested in fertility who are anovulatory, there
> are other ways to either protect the endometrium or to promote monthly
> withdrawal bleeds, for instance, with oral contraceptives.
>
> However, to promote a monthly bleed, one would not use gonadotropins
> or antiestrogens, for instance.
>
> DR. EMERSON: So it is just that indication would not cover this.
>
> DR. GIUDICE: No. I assume the rest of the committee agrees with this?
> Thank you.
>
> DR. SLAUGHTER: Also, from the FDA standpoint, we do have indications
> for treatment of amenorrhea so this would not cover that. This is
> strictly for individuals seeking to become pregnant.
>
> DR. GIUDICE: Thank you. I hope all these questions have not had the
> major purpose of trying to avoid answering the first question. But I
> think it is time. So who would like to begin the discussion? Dr.
> Emerson?
>
> DR. EMERSON: So, on those grounds, then, it is very, very difficult
> for me to completely separate all of these questions and answer only
> one. So I do need to point out that I am going to be answering this
> question with an eye towards what I am also going to recommend as
> endpoints and that a concept of a noninferiority trial would be very,
> very appropriate in my mind for an endpoint of pregnancy.
>
> What that means is that when we are enrolling patients, we have to
> make certain that we have a patient population that is comparable to
> the ones in which we made the judgment that the existing active
> comparators are efficacious. So it obviously wouldn\'t do to be
> comparing a new therapy of ovulation induction in a population of
> women who are normal ovulatory. It is an idea that we have to apply
> some standards to say what is the level of infertility when we are
> trying to do ovulation induction in hypo-ovulatory women.
>
> If we are trying to do ovulation induction or hyperovulation induction
> in, for instance, egg donors or the normal ovulatory women, then it is
> important that we understand exactly what that background is and that
> the active comparator is working in that population, that we aren\'t
> ending up just testing the new therapy against something that is
> really acting as placebo.
>
> So that would be\--my most major criterion is how do you define the
> population to make certain that your comparison group is really
> gaining benefit from the treatment that it is on rather than it is
> just what they would be having otherwise.
>
> DR. GIUDICE: Thank you. That is very well taken. Dr. Rice?
>
> DR. RICE: I agree. I really do think that when you look at the
> differences between ovulation in patients who are presented for
> ovulation induction and what input you would use, that is typically
> different for us than a patient presenting for ART. I think it is very
> important for us to recognize that the criteria we set for a drug to
> be able to induce ovulation would probably be appropriate looking at a
> population who has hypo-ovulation.
>
> Some of our WHO criteria take that into consideration. Again, that
> population base is typically going to be different than an ART
> population who generally may\--a large percent of those patients are
> already ovulatory and we are trying to \"superovulate\" them.
>
> So I think that, when we look at this, we have to be cognizant of what
> our endpoint is. If it is a patient who doesn\'t ovulate, then,
> clearly, getting her to the point where she ovulates puts her on the
> same basis as that normally ovulatory person which is different than
> that person who is presenting for ART or IVF who ovulates but you want
> to increase your number of options when it comes down to the number of
> eggs you want to be able to\--particularly be able to select that one
> out that probably is going to go on to be a pregnancy.
>
> DR. GIUDICE: Okay. I think I am hearing basically the same thing. So,
> for WHO, we can either begin with WHO1, WHO2, or dive right into the
> infertility normal ovulatory group. Does someone want to begin,
> because right now these are the criteria for enrollment which is what
> the first discussion is on. Does someone want to address standard of
> care in terms of what we do in the office when someone walks in with
> infertility? Dr. Toner, are you going to rise to the occasion here?
>
> DR. TONER: I guess, for the anovulatory, apparently anovulatory,
> patients, we would want to know that that, in fact, is the case by
> measuring basal gonadotropins, by measuring progesterone, and the
> hypothalamic style patient will have very low FSH and very low LH at
> any old time you choose to measure and, in conjunction with a history
> of irregular absent menses, could probably be diagnostic of that
> circumstance.
>
> Progestin withdrawal? I guess you could consider it. Absence of
> bleeding after progestin is another hallmark of that circumstance.
>
> DR. GIUDICE: And after ruling out any organic causes, hypothalamic or
> pituitary. So that would be more in the exclusion criteria. Yes?
>
> DR. EMERSON: We would also need to talk about the criteria for
> infertility, how do we document the time period that the couple has
> been infertile with a way that we do that because, once again, we are
> dealing with active comparators that have not truly been tried
> head-to-head against placebo.
>
> So we don\'t know what those rates are.
>
> We are going to have to go on an understanding of what that is and our
> best guess so the best numbers that I gleaned from the background
> materials and what we have talked today is that a fertile couple, we
> would expect a roughly 20 percent fecundity rate and that, after a
> year of infertility, it is something down to 11 percent.
>
> Yet, we saw roughly 20 percent in the previously approved trial. So we
> are talking about roughly a 10 percent difference in the fecundity
> rate. As you are now going to look ahead trying to guess what
> difference we would tolerate in an active-comparator trial and still
> believe that we would have had efficacy against placebo, because that
> is sort of what a noninferiority or some one-sided equivalence trial
> is trying to do, is trying to guess what a placebo trial would have
> done to make certain that, when we go out there and say, this does
> work for ovulation induction and going on into pregnancy, we would get
> that.
>
> So, the mix of patients, if it is down to 11 percent after one year
> infertility, if it is down to, I can\'t remember the numbers, 4
> percent after two years of infertility or so on, that is going to be
> the criterion that we are using to base this.
>
> So we want to make certain that, as we compare the active comparator,
> they haven\'t snuck in a group that would actually have a lower rate
> or a higher rate, that we are accepting enough worse behavior that is
> actually taking us down to the level that it is an ineffective
> treatment.
>
> DR. TONER: Could I address that?
>
> DR. GIUDICE: Dr. Toner.
>
> DR. TONER: As a practical matter, though, if the clinician has a very
> confident idea that this is an anovulatory patient, we are not
> comfortable waiting a year, any clock to run. If we make the
> diagnosis, we want to treat now. So that interval, for this type of
> patient, isn\'t going to be appropriate and we won\'t get anyone
> enrolled.
>
> DR. GIUDICE: Thank you. Dr. Keefe and then Dr. Layman?
>
> DR. KEEFE: I was going to say the same thing, that we are trying to
> establish the diagnosis of an anovulatory infertility, the first is
> the diagnosis of infertility and I agree with Dr. Toner that you are
> not going to wait a year if somebody is documented to be anovulatory.
>
> But the documentation of anovulation, I think in the spirit of keeping
> things generic and broad, I would say clinically useful methods of
> diagnosis of anovulation and they would include periodic progesterone
> measurement, LH surge detection, presence of amenorrhea and the
> absence of uterine factor.
>
> As well, as was already mentioned, but just to include the importance
> of ruling other causes of anovulation such as hypothyroidism and
> hyperprolactinemia as well as primary ovarian failure.
>
> DR. GIUDICE: Dr. Layman?
>
> DR. LAYMAN: I was going to reiterate some of that as well. I think you
> need to exclude hyperprolactinemia in both Group 1 and Group 2. If
> somebody is amenorrheic and you think they have Group 1, then I think
> they really need a progesterone withdrawal to show that they are
> hypoestrogenic so that they don\'t bleed. Otherwise, it doesn\'t fit
> into hypogonadotropic hypogonadism. Gonadotropins can be low or normal
> in the face of that. Depending on what assay you use, that is going to
> make a difference whereas, in the other group, I think one thing we
> have to think about is the prevalence of both disorders. Group 2 is
> much more common so that I think the guidelines for Group 2 may\--for
> Group 1, you don\'t want to maybe be quite as stringent as Group 2 or
> you are just not going to get enough patients.
>
> DR. GIUDICE: Yes?
>
> DR. LEWIS: Also, although it may go counter to what you see in
> clinical practice, I think that the patients in either Group 1 or
> Group 2 or the ART population, for that matter, should pretty much be
> of relatively normal body-mass index.
>
> We know that extremes of obesity are quite common, or even just garden
> variety obesity, are quite common in the general population today but
> I think it is up to the clinician to adjust for that. When you are
> designing a clinical trial, I think it is useful to have patients just
> be relatively body-mass-index normal to glean the cleanest information
> possible from the study.
>
> DR. GIUDICE: Any comments about BMI for WHO2 type patients?
>
> DR. KEEFE: I have a question. I know what you are getting at, like try
> to reduce the variance and you would be able to better control the
> study, but it seems to me that that might lose some of the clinical
> value of the study. Those are precisely the ones that are the
> toughest, and so you get this beautiful result in the study.
>
> As you move into the clinic, you might bump up against some problems
> with that.
>
> DR. LEWIS: Well, of course. But, in any clinical trial, it is going to
> be quite different. What you see published in the literature and what
> it boils down to in clinical practice, we all know that. That is the
> practice of medicine. If you start out with a most difficult
> population, to design your clinical trial, you may mask an effect that
> might otherwise be quite useful to the rest of the population. So, I
> think if you start with a more ideal population and then try to apply
> it, see how far you can push it one way or the other, you are going to
> get a better result.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I think we know a lot more information about the impact of
> BMI on ovulation. So that may be something that you could consider for
> a stratification based on BMI. That is one of the things that I think
> would be very critical. If you have a product that is coming out
> looking an anovulatory patients that you want to stratify it, not just
> on age, et cetera, but you also want to consider BMI because I think
> that we all have instances where we have seen patients who lose weight
> who then become ovulatory. That is the only thing that they have
> really changed.
>
> So I think BMI could be used as a stratification.
>
> DR. KEEFE: I have a comment about the use of the
> progesterone-withdrawal test as an inclusion criteria. While clearly
> it is useful to test the integrity of the uterine tract and the
> vagina, you can have a negative progesterone withdrawal and still have
> an ovulation. It is just listed as sort of one sentence in Spiroff.
> But I have found it very frequently, patients that are hyperandrogenic
> will not withdraw.
>
> So you might have to give them steroid, presumably to decidualize
> their endometrium from the high androgens. It is not clear exactly why
> but it is very common that you will see that they will have a negative
> progesterone withdrawal and yet they are actually hyperestrogenic
> relatively and they have a completely intact tract.
>
> So, rather than say progesterone withdrawal, maybe a steroid
> withdrawal which would include the next step where you would probably
> give them estrogen and then progesterone.
>
> DR. GIUDICE: Dr. Layman and then Dr. Rice.
>
> DR. LAYMAN: I agree that some hyperandrogenic women won\'t bleed. But
> I don\'t see adding estrogen, how that will help, actually. But I
> think the way you get around that, and it is difficult in some PCOS
> women, to tell from hypogonadotropic hypogonadism whereas, if you look
> at hyperandrogenism, it may help you differentiate since
> hypogonadotropic patients usually have low testosterone. So that might
> be a way.
>
> But I agree. It is not black and white for the progesterone
> withdrawal. And it should be like a good bleed. It shouldn\'t just be
> spotting.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I would just caution that the ASRP Practice Guideline is
> probably going to be coming out very soon with the recommendation to
> remove progesterone withdrawal. So just before\--when you look at the
> draft document, make sure that the guidelines haven\'t changed and the
> utilization of progesterone withdrawal.
>
> DR. GIUDICE: Have they substituted something else for it?
>
> DR. RICE: No. Just making a comment.
>
> DR. GIUDICE: Thank you. Dr. Emmi?
>
> DR. EMMI: In light of what is being said about hyperandrogenicity and
> lack of withdrawal, frequently those patients will have fecund
> endometriums on ultrasound and that is a good way of differentiating
> sometimes. If somebody is hypoestrogenic, they don\'t have a lot
> lining as opposed to people who have 20 millimeters of lining on
> ultrasound. So that may be a point to look at.
>
> DR. GIUDICE: This is an interesting issue, whether or not ultrasound
> should be part of the enrollment criteria, whether it is for
> hypothalamic or Type 1 or for Type 2. Then, in looking for age and
> ovarian reserve, whether that is part of it.
>
> So we can get into the infertility side in just a moment, but I think
> also we do need to consider the cost perspective of putting
> ultrasounds in clinical trials which can be quite costly, but
> certainly is something that can be recommended. So what does the group
> think in terms of ultrasound used adjunctively for entry criteria?
>
> DR. EMMI: I don\'t necessarily think it would be necessary in all
> patients. It depends on what parameter you use to decide is a patient
> in Group 1 or Group 2. I mean, if you are going to use estrogen
> withdrawal, progesterone-withdrawal bleed, then, if they don\'t bleed,
> you are either going to look for hyperandrogenicity or you are going
> to look for some other reason why they haven\'t withdrawn and, at that
> point, perhaps, adding it might keep the cost down.
>
> DR. GIUDICE: Dr. Crockett?
>
> DR. CROCKETT: Yes. I just wanted to throw in my two cents about this
> whole question of the anovulatory versus the infertility patients in
> the enrollment. I think, as a group, when we are looking at making
> guidelines, the less specific we make the guidelines, the more
> applicable they may be down the line.
>
> If we are looking specifically at anovulatory women that have, by
> definition, whatever definition we come to, anovulation, we shouldn\'t
> include things that pertain to other parts of the fertility process in
> making inclusion criteria. For instance, if we start talking about
> endometrial lining, that is not necessarily an indicator of ovulatory
> function or dysfunction. It is more a function of fertility and the
> ability to implant and carry the pregnancy.
>
> So I would rather us kind of back up and say let\'s look specifically
> at ovulatory and anovulatory women for what they are and leave the
> whole fertility side out of it.
>
> DR. GIUDICE: Okay. Dr. Lewis?
>
> DR. LEWIS: Actually, I think the reason, the rationale, for bringing
> up endometrium was as a reflection of estrogenicity; that is, the
> endometrium would be thicker if there has been ongoing estrogen
> production thus separating Type 1 from Type 2. At least, I think that
> is why it was brought up.
>
> But the only\--well, another possible complication of using ultrasound
> to differentiate between the two is that you can see a multifollicular
> pattern in both types and so some centers, particularly in Europe,
> like to use ultrasound to diagnose polycystic-ovary syndrome.
>
> But that appearance can also be seen in Type 1 patients, especially if
> they are younger. So it is, I think, a little problematic to use
> ultrasound as a primary criteria. But, obviously, you have to use some
> sort of criteria to define that the patient has low gonadotropins and
> low estrogenicity. Maybe you could make it either/or, either a
> negative progesterone withdrawal or thin endometrium with a low
> circulating estradiol level. That might be an option.
>
> DR. GIUDICE: Okay. Yes; Dr. Keefe?
>
> DR. KEEFE: This is really halfway through the first question. Maybe we
> should just wrap it up and say something like the committee recommends
> that enrollment criteria include the presence of oligomenorrhea and/or
> amenorrhea with some evidence of lack of ovulation on the basis of
> blood tests, progesterone, urinary tests, LH surge or other methods
> which could include ultrasound.
>
> DR. GIUDICE: Thank you. Also, for Type 2 patients, there was recently
> a nonconsensus consensus conference in Rotterdam and I think, and you
> are absolutely right, we are only halfway through the first question,
> the whole Type 2 story is, again, very, very complicated. For us to
> put together today guidelines, I think, actually would probably
> consume the rest of the afternoon.
>
> So I would like to know from the group if, perhaps, looking at the NIH
> guidelines in terms of definition of PCOS which, then, could be
> applied to enrollment criteria, if you think that would suffice for
> the document.
>
> DR. KEEFE: Yes. Sounds good.
>
> DR. GIUDICE: Okay. Then, moving right along; No. 2, should enrollment
> criteria be stratified by age for\--I\'m sorry; we didn\'t finish ART
> inclusion. Let\'s go back to that. I thought we were out of No. 1.
>
> DR. KEEFE: We are only a third of the way through the first question.
> I forgot.
>
> DR. GIUDICE: No. We have done WHO1 and we have punted on WHO2.
>
> DR. KEEFE: Right.
>
> DR. GIUDICE: And now for ovulation induction for infertility, the
> enrollment criteria for that. This brings up many, many issues. If you
> have someone who is 42, you are probably not going to be doing this,
> or don\'t want them in a study for looking at a gonadotropin product.
>
> Also, if you have\--there is a whole series of things and people
> practice very differently. The criteria that are normally used when a
> couple comes in after twelve months, and, Dr. Emerson, this is to
> address your question about the definition of infertility, I think it
> is pretty standard that one takes the definition of twelve or more
> months of unprotected intercourse without a pregnancy, but then the
> age issue comes into it and whether\--if someone comes in at the age
> of 40, one doesn\'t usually ask her to go home and come back in a year
> and then we\'ll talk about pregnancy and fertility.
>
> So, we do need to discuss the issue of\--and this will, also, then,
> have some relevance for the second question. But, going to the first,
> for ovulation induction for infertility, I would like for the
> committee to address what types of enrollment criteria they think are
> appropriate for the FDA to have in trials. Dr. Layman?
>
> DR. LAYMAN: To start it, I would think you would have to pick some age
> group that would be agreeable to everybody, and I will throw out 25 to
> 34, but some age group that is reasonable would be one thing. The
> other would be maybe potentially eliminate ICSI with a severe male
> factor, to take ICSI out of it so that you are looking at fresh-cycle,
> first-cycle, patients.
>
> But I would think other diagnoses would be reasonable to consider. I
> mean, I don\'t think male factor would be unreasonable. But if you
> start putting in ICSI with it, then you are getting in more variables.
>
> DR. KEEFE: I am really uncomfortable with essentially disenfranchising
> a huge population, a growing population, of the infertile population.
> I don\'t think it is appropriate to, a priori, recommend that a
> certain age group be studied. It may well be that, in the future,
> pharmaceutical companies find it to their advantage to target certain
> drug regimens. I mean, from a financial standpoint, that is where the
> money is; right? That is where the growth is. That is where our
> demographics are pushing us.
>
> So you may want to, for a number of reasons, if you are trying to
> document the efficacy of ovulation, but, if we are looking at the
> clinical endpoint, I don\'t think we should box out this growing
> population right up front and recommend that they be excluded.
>
> I would say that we should tailor the inclusion criteria according to
> age and that we should include an age-specific diagnosis of
> infertility, six months, 35 and older, twelve months, younger than 35,
> which is sort of the standard.
>
> DR. GIUDICE: Dr. Emerson and then Dr. Emmi.
>
> DR. EMERSON: I think this idea that there would be other issues that
> come up after the therapy and all of the complicating things that will
> have an effect on the event rate, but it is randomized trial. I don\'t
> know of a disease that doesn\'t have ancillary treatments following
> the interventional treatment.
>
> So, while you have to give thought to whether your treatment might
> cause people to change the ancillary treatments and so on, it is not
> an issue. This just occurs in every single trial and, by randomized,
> it ought to be equal if it is not caused by the treatment.
>
> DR. GIUDICE: Dr. Lewis?
>
> DR. LEWIS: I think that, certainly, a clinical definition of one year
> of infertility is widely accepted and that is fine. But I think there
> ought to be exceptions for ART if the infertility is due to a tubal
> factor. If you have occluded fallopian tubes, there is no reason to
> wait one year.
>
> So I think you should have evidence of a normal uterus to be in the
> clinical trial and some documentation about the fallopian tubes. Some
> of the trials, I know, that have been done in Europe, have excluded
> patients with hydrosalpinges because that can have an impact on the
> trial and that might be something that is reasonable to exclude.
>
> You could exclude patients with ICSI. But, in the United States, about
> 60 percent of\--at least 50 percent of IVF cycles include ICSI. Even
> if the patient doesn\'t have proven fertilization, a lot of centers
> will recommend ICSI on at least some of the eggs.
>
> So, rather than exclude all ICSI, you might set some limits on it,
> ICSI with testicular sperm, perhaps. ICSI in particular cases\--maybe
> Dr. Lipshultz has some input here to give, but I don\'t think you
> would want to exclude all ICSI because I think that would limit the
> population too much.
>
> I agree that you have to have age limits and maybe 34 is a little
> Draconian, but maybe 38, under 38? And I don\'t think 25\--I think you
> could go younger than 25. There are some patients that would be
> reasonable to treat.
>
> DR. GIUDICE: Dr. Emmi and then Dr. Rice.
>
> DR. EMMI: I was going to make one of the points that she made which is
> that something like 60 percent of the cycles in this country are ICSI
> at this point so it is difficult to factor them out and why ICSI is
> being done in those cases.
>
> But I think, with the age matter, that may be something that might be
> nice to stratify. I think\--I mean, if you look at one of the studies
> that Dr. Toner was talking about with decreased follicular depletion
> over time, I think that the cutoff there is about 37 where you see a
> really rapid decline in the number of eggs in the ovary.
>
> Maybe you could make that, 37 and above\--I don\'t necessarily think
> that you have to stop at 38. I think you could go to 42 and just look
> at that group as a separate group.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: It is difficult for me to set up enrollment criteria if I
> haven\'t established what my endpoint is that I am going to evaluate.
> If I am going to evaluate number of oocytes for a different
> gonadotropin, then I pretty much know that, regardless of age, I can
> give probably most women enough medication and get equal number of
> oocytes. But if I am going to set up fertilization as my endpoint,
> then I would set my age of enrollment differently if I wanted to say
> whether Product A was better than Product B if I wanted to be able to
> answer that question.
>
> So you kind of got to say what your endpoint is. I think Dr. Toner
> showed us some data that says you can get a 42-year-old to act just
> like a 32-year-old when we are looking at the number of oocytes that
> are retrieved. But it really comes down to the bottom line, a
> 42-year-old doesn\'t get to take home a baby as often as a
> 32-year-old.
>
> So there are other confounders that come in there, but there are some
> variables that we may not have control over. So I kind of have to know
> what my endpoint is before I can say what my inclusion criteria are
> going to be on several of these issues.
>
> DR. GIUDICE: I think this is where we see one size does not fit all
> because, if you don\'t know what your goal is, it is very hard to set
> up the criteria.
>
> The other issue we may want to discuss, and perhaps not belabor the
> point, but is age really the issue that we want to talk about or is it
> ovarian reserve measured by other means, either ultrasound, complement
> of small antral follicles, ovarian volume, Clomid-challenge test,
> Day-3 FSH and estradiol. There is a whole series of things.
>
> These, again, I think one could put in, and certainly the committee
> should discuss this, but as we advise the FDA, these are all the
> things that we deal with clinically that, as clinicians, we are
> evaluating the performance of the ovaries in response to these
> medications.
>
> Dr. Toner?
>
> DR. TONER: I think, in that regard, you might want to set up sort of a
> stratification where you define upper limit of normal and then you
> define a borderline range, but then kind of a \"no-go\" range as well,
> for the purposes of studies.
>
> So, for instance, on the issue of age, you might say that there is a
> group that is under 38. Then there is a group that is from 38 to 41,
> 42. But we are never going to study people past 42 because it is so
> futile.
>
> On the ovarian-reserve side of the equation, you might say, we are
> going to consider normal, basal FSH under 10. 10 to 15 is the
> ambiguous area where we expect some diminished reserve but it may be
> okay. But we are not going to enroll anyone with an FSH of 16 or
> better. You know what I am saying? So there may be some advantage to
> demarcating where things start to get a little tough and where things
> become hopeless and break them out that way.
>
> DR. KEEFE: Can I comment?
>
> DR. GIUDICE: Dr. Keefe and then Dr. Crockett.
>
> DR. KEEFE: I don\'t think the FDA\--the advisory committee should be
> in the business of lowering our sites as a field. I mean, it is clear
> that there hasn\'t been a lot of progress in this area, but it is
> going to be the pharmaceutical companies\' problem if they don\'t
> account for these. Their bias is going to be already to exclude these
> patients.
>
> So I don\'t see the advantage. I mean, if you are trying to design the
> perfect study to show an effect, yeah; you, yourself, as an individual
> designing the study, would clearly want to narrow the variance by
> selecting a very carefully chosen population.
>
> But we, as the advisory committee, I don\'t think, should constrain
> the field by blocking that out. Let\'s say I move forward five years
> and I have come up with a new way of identifying that subset of 5 or
> 10 percent of the 42-year-olds who can get pregnant. Oh, but the FDA,
> though, has this thing where you have to be under 38 or 37. You know,
> that is not encouraged.
>
> So, while you might want to control for that, I think what we want to
> do is cast a broad net for this.
>
> DR. GIUDICE: Dr. Crockett and then Dr. Lewis.
>
> DR. CROCKETT: What he said. The other thing I had to add to that is
> that I think, once again, we are getting too narrow. What we couldn\'t
> do ten years ago, now we are talking about designing studies around
> today and, in ten more years, we are going to have so much more
> technology available that, for us to be talking about what we want as
> stratification for endpoints and inclusion criteria I don\'t, as a
> governing body, we should be doing that.
>
> DR. GIUDICE: Thank you. Dr. Lewis?
>
> DR. LEWIS: I don\'t think we are saying what population needs to be
> treated for infertility. That is not the mission of the committee or
> the mission of the FDA. It is simply to talk about what criteria would
> be useful in determining whether a drug is effective and safe or not.
> It doesn\'t mean that we are saying that this patient will never get
> pregnant. It doesn\'t have anything to do with that or with saying
> what the future of the field is going to be. It is simply to try to
> help the FDA come up with criteria that they can use with industry to
> design a study to say whether the drug works or not.
>
> I think if you start with a population where you might reasonably
> expect to see a better pregnancy rate, where it has been shown that a
> good pregnancy rate exists now, then you will go further. The trials
> will be more economical to devise. The drugs will get to market sooner
> so that we can use them in new populations who are more difficult to
> treat.
>
> So I think if you look at it that way, it, perhaps, might have some
> utility.
>
> DR. GIUDICE: Depending on the endpoint.
>
> DR. LEWIS: Yes.
>
> DR. GIUDICE: Dr. Crockett?
>
> DR. CROCKETT: With all due respect, I disagree with you a little bit
> on this. I think, from a standpoint of a regulatory agency, if we say
> to a drug company, we have a guidance that you can\'t enroll somebody
> over the age of 42 because it is futile, that we are going to severely
> limit the free market and the development of that research.
>
> I would rather not see that kind of cap put on either for ovarian
> reserve or age. I think it is too restrictive.
>
> DR. GIUDICE: Dr. Hager and then Dr. Dickey.
>
> DR. HAGER: It would seem to me that what we are saying is not to
> exclude but to stratify and that way those populations are included
> but the data are recorded accordingly. So I don\'t think\--I would
> agree that we would not want to exclude them but we certainly would
> want to stratify those populations.
>
> DR. GIUDICE: Thank you. Dr. Dickey?
>
> DR. DICKEY: I think David probably said it very well. If we stratify,
> you can always add new populations on either end or, for that matter,
> new enrollment groups. What you want to avoid, I think, is comparing
> apples and oranges. So, by stratifying, you can begin to do that and
> still push the edges of science as that opportunity comes along.
>
> DR. GIUDICE: Thank you. Dr. Rice?
>
> DR. RICE: I think, though, you capture all of this stratification if
> you begin to change your endpoint because, right now, you have it
> where all you have to do is show follicular development. All of them
> showed that pretty evenly across the board.
>
> If you take that 32-year-old and that 42-year-old and you say, my
> endpoint has to be fertilization, or it has to be live birth rate, in
> order to get said whatever indication they are going after, the
> stratification, then, begins and it really starts to really compare
> the gonadotropin compared to each other and compared to \"placebo.\"
>
> So I think you capture it. You keep your inclusion broad. And then you
> capture it by looking at your endpoints.
>
> DR. GIUDICE: Dr. Hager?
>
> DR. HAGER: Could we go to Question 8 and come back? I mean, it keeps
> coming up.
>
> DR. GIUDICE: Question 8.
>
> DR. SHAMES: Sure.
>
> DR. GIUDICE: I think we have pretty much completed No. 1 because the
> ART piece, from what I have heard, is very tightly connected to the
> infertility, ovulation induction and infertility. So we have done
> No. 1. And we can go to No. 8. We have also done No. 2. Maybe we can
> just go down some of the questions, here.
>
> Should we stratify for use of adjunct procedures such as donor oocyte
> or ICSI.
>
> DR. LAYMAN: May I?
>
> DR. GIUDICE: Yes.
>
> DR. LAYMAN: Just in terms of ICSI, I mean ICSI is not one thing. ICSI
> is many different indications and to have one category of ICSI is
> going to be asking for trouble because you are not going to get the
> same rates if you do ICSI in a program who does everybody because they
> are afraid of missing a cycle and opposed to another one who does
> testicular extraction because they have a lot of male factor.
>
> So ICSI has to be subdivided or else\--you know, when you are
> collecting data, or else you are going to lose the meaning of the
> outcome.
>
> DR. GIUDICE: So that would be stratified, also, then.
>
> DR. LAYMAN: Substratified.
>
> DR. GIUDICE: Or substratified; yes.
>
> DR. LAYMAN: But the answer would be yes to No. 3.
>
> DR. GIUDICE: Okay. Let me ask the FDA members if we need a formal vote
> on any of these. No. 1, we can\'t vote on. I think there is pretty
> much consensus, at least from the nods around the table, about
> criteria should be stratified by age and stratifying use of adjunct
> procedures, and then substratifying for ICSI.
>
> Now, this is a very interesting question; should studies be blinded or
> not and, if blinded, discuss the merits of blinding the assessor, the
> patient or both. Dr. Emmi?
>
> DR. EMMI: I just wanted to make one comment about Question 2 before we
> went on. Since, when we discussed ovulation induction, we actually
> discussed the difference in anovulators whether they were criteria 1
> or 2. Should that be for ART as well?
>
> DR. GIUDICE: Well, how about going around the table or at least\--how
> about if you rephrase what you would like for people to either agree
> or disagree with.
>
> DR. EMMI: Well, what I propose is that there is a difference in
> response in PCO patients and IVF and differences in LH and whatever
> your belief is whether it affects the endometrial development or the
> number of follicles and should they be stratified out as a separate
> group when you are looking at ART.
>
> DR. GIUDICE: I see nods.
>
> DR. HAGER: I thought, as we were talking about ART, that we were
> talking about those divisions anyway, tubal factor, PCO, et cetera.
> Was that not the consensus?
>
> DR. GIUDICE: I don\'t think we actually made it clear. But we should
> make it clear. The indications for ART, certainly, are several. One,
> with the PCO patient, in particular, is sort of an interesting
> situation, those who fail, essentially, monofollicular development or
> have had one or several follicles without a pregnancy who then may
> progress to ART is a very different population than the woman who
> walks in at the age of 39 for unexplained infertility where you start
> gonadotropins and then you go to ART.
>
> But it seems that the categories would stratify out. Or you can put
> them in. It depends on what the objective of the study is. But we have
> talked about male factor, anovulators and we didn\'t really discuss
> unexplained. But there is not really too much additional information
> that we would need to discuss unless someone has a burning issue.
>
> DR. KEEFE: One other diagnosis that may bear or may merit
> stratification would be severe endometriosis because there is growing
> evidence from split-donor cycles that the donor, if she has severe
> endometriosis, confers a reduced probability of success on the
> recipient. Meta-analyses have, I think, shown that there seems to be a
> fairly consistently lower pregnancy rate but only in severe
> endometriosis, as well as a low ovarian reserve. They start to
> resemble older patients.
>
> DR. GIUDICE: Dr. Brzyski?
>
> DR. BRZYSKI: In unexplained category, are we assuming that, as part of
> the screening for enrollment, that individuals that have some measure
> of ovarian reserve, because it is a fairly good likelihood that there
> could be impaired ovarian reserve in individuals with otherwise
> unexplained\--you know, patent tubes, normal male, ovulatory. There is
> still a pretty high yield of impaired ovarian reserve in that
> population.
>
> So we are assuming that, in that unexplained, that those would be
> screened and identified and stratified by that? Is that a true
> statement?
>
> DR. GIUDICE: What does the committee think?
>
> DR. TONER: As the advocate of ovarian-reserve screening, I think yes.
> You honestly just need to do it. I mean, you do a semen analysis to
> detect how many sperm are there. You have got no other way to assess
> how many eggs are there without looking, either in the blood or on
> ultrasound.
>
> DR. KEEFE: Can I answer? I agree completely with what Jim said. We
> would think of ovarian reserve as parallel to age. It is sort of like
> reproductive age. And, as Jim showed, there is an independent
> predictive value for each separately and, together, they interact. So,
> I would recommend we treat ovarian reserve like age, similarly. So
> even with the outcome of ICSI, in pure male factor, you can see a
> component of ovarian reserve.
>
> The question is how do you measure it because our radioimmunoassays
> vary from center to center. So you have to have either a central lab
> or some standardized method. There are also problems of the cycle
> dependency of it.
>
> There will be new ovarian-reserve markers coming out.
> Bularian-inhibiting substance has been recommended by Themin as a very
> useful cycle-independent marker secreted in the pre-antral phase of
> follicle development. So I think there will be, down the line,
> additional markers of ovarian reserve that will have to be considered.
>
> DR. SLAUGHTER: Just a comment. We do typically request these studies
> when they do these assays to be done in a central lab so that would be
> included.
>
> DR. GIUDICE: Thank you. Dr. Layman?
>
> DR. LAYMAN: I just have a statistical question to the statisticians
> here. If we get too many groups, is that going to reduce our power? I
> mean, that is why I was only saying a certain group. But, you guys
> have to be the people on that issue.
>
> DR. EMERSON: So I am completely unable to judge any of the criteria
> that you have just named of what they mean medically, but, again, the
> overarching principles here are in doing clinical trials it that the
> enrollment criteria should be as close as they possibly can be to the
> population that you are eventually going to use this in.
>
> That sometimes means that people that you don\'t really think the
> treatment will be all that beneficial in but it is going to be
> extrapolated to that population, you need to see the safety data. So
> you sometimes go ahead and include those patients but then say they
> are not really going to be in our efficacy population. We are just
> going to make certain that it is still safe.
>
> The other criterion is when you have an active comparator, what I
> spoke to at the very first. You need to make certain that it really is
> an active comparator and it is not placebo as you are setting those
> margins.
>
> Then, in the stratification question, the reason why we stratify is,
> first and foremost, to gain precision. But there comes some point
> that, if you are doing a multicenter trial, you can\'t do too many
> levels of stratification. If the trial is relatively large, you don\'t
> need to stratify and you can still get the precision by adjusting for
> it. It sometimes takes an argument to get it through the FDA, but that
> is what should be being done in those instances.
>
> The other aspect is scientific credibility of the results. If, by
> rights, by what we mean by statistics, you don\'t have to stratify on
> anything. But, if somebody sees that a large imbalance occurred on the
> trial, they aren\'t going to trust the trial. So those variables that
> are the most predictive but don\'t go to too many cells; just choose
> those that are.
>
> From what I have heard, mainly, it is this aging aspect, be it ovarian
> reserve or age as a surrogate for ovarian reserve, and then the
> various adjunct procedures, the indications for why we are going to
> that sound like the largest ones.
>
> And then you always have the site-specific issues that you want to do
> the stratification within site. That is going to be pretty much maxed
> out. Really, even if you are going to a thousand-patient trial, you
> don\'t want to stratify on much more than those things.
>
> That is my impression from what I have been hearing. As suggested, I
> probably wouldn\'t stratify on much more than that.
>
> DR. GIUDICE: Okay. Thank you. Perhaps we can now go to Question No. 4
> regarding blinding or not. Yes; Dr. Emerson?
>
> DR. EMERSON: Blinding; I am a statistician so you need a larger sample
> size and you need to blind yourself. But the issue here that I think
> is greatest is we have already heard aspects of the doctor effect in
> getting the follicles, that judgment goes into that concept.
> Obviously, if they know what the treatment is and, well, of course,
> this treatment produces more follicles than the other and, therefore,
> we will sample all of those more follicles that we see here.
>
> That is an issue. Also, the other thing that I worry about is
> canceling a cycle, to decide not to go with the stimulation. So I
> can\'t imagine many things that the patient would\--I think,
> otherwise, we are only talking about fairly objective criteria, so the
> patient we are not worrying as much about. But it is all the
> investigator, the clinician, that I would worry about.
>
> DR. GIUDICE: Dr. Emmi?
>
> DR. EMMI: I wanted to know why cancellation is such an issue.
>
> DR. EMERSON: We are back to my \"intent to cheat.\" If I have a really
> good therapy that I am sure works, but I start seeing a patient that
> it doesn\'t look like it works, or that I am not liking the way it
> goes, well, I will just not try that patient very much more.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I think we also have to remember that, particularly if we
> were looking at embryo quality as an endpoint, that we still don\'t
> have the most objective means for grading embryos. So it is clear that
> we must have our embryologists who are blinded as well so that we have
> some objective information that will come out of that if we are going
> to use embryology or embryo development as a criteria.
>
> DR. GIUDICE: That is a very good point. Other discussion? Yes?
>
> DR. EMMI: I think we are back to it is getting very complicated
> because not every institution uses the same criteria even for judging
> embryos. You know, then you would have to restrict, also\--if you had
> somebody who wanted to cancel, you would have to have cancellation
> criteria. I mean, I just don\'t know how you can\--
>
> DR. RICE: That is the benefit of blinding, that you can take care of
> some of these subjective issues.
>
> DR. GIUDICE: Dr. Hager and then Dr. Keefe.
>
> DR. HAGER: The only reason not to double-blind the trial, in my
> opinion, would be if you had a placebo arm because then there would be
> a distinct difference. If you did not have a placebo arm, would it not
> be more efficacious to double-blind rather than single-blind?
>
> DR. GIUDICE: Comments?
>
> DR. EMERSON: I guess my response would be that just purely
> logistically I think it is easier to maintain a blind from the patient
> and not the physician than vice versa. So I don\'t see any reason not
> to keep the patient blind in that instance, but it is just the
> assessor that I am most worried about.
>
> DR. KEEFE: Okay. Are we ready to move onto question No. 5? Here we
> come now to the placebo and active-control arms in the studies. If an
> active control is used, discuss how you would define the
> noninferiority margin. Dr. Hager?
>
> DR. HAGER: My feeling is that, from an ethical perspective, it is
> better to have an active control arm in this population of
> individuals.
>
> DR. GIUDICE: Other comments? Yes?
>
> DR. TULMAN: Just from the person you are trying to enroll is given a
> choice, a known choice, between a placebo or the new investigational
> drug, are you likely to get anybody to consent to be in it? So, from a
> very real patient enrollment point of view, if you are not offering a
> treatment that at least is one standard of care versus the new point,
> you are going to have a trial that will not get off the ground.
>
> DR. GIUDICE: That is a good point. Dr. Brzyski?
>
> DR. BRZYSKI: To my experience with clinical trials, or not even in
> clinical trials, I think patients tend to believe in technology and
> the newest technology and so that would be one reason to blind even in
> an active control arm, that patients may cancel themselves if they are
> randomized to the traditional therapy as opposed to the new therapy
> which everyone believes will be the better therapy. Otherwise, why
> would we be studying it; right? So, it just again supports the idea of
> blinding the patient.
>
> DR. GIUDICE: Thank you. One more comment? Yes, Dr. Keefe?
>
> DR. KEEFE: I would also support not using placebo and, instead, using
> a treated control group. We now have published literature showing the
> baseline fertility in untreated patients with unexplained infertility
> and recently a paper came out of Belgium where they looked at the
> spontaneous pregnancy rate after one failed cycle of ICSI. So these
> were people shown to have significant male factor and then,
> subsequently, there was a very low spontaneous pregnancy rate.
> Occasionally, people would get pregnant.
>
> So we have pretty good evidence that the untreated group, at least
> from observational studies, don\'t do well. So I agree; it is a little
> bit problematic ethically to deprive treatment through placebo. So
> control should include treatment.
>
> DR. GIUDICE: Okay. Thank you. No. 6 is, discuss the advantages and
> disadvantages of single versus multiple treatment cycles. Dr. Emerson?
>
> DR. EMERSON: There was a second part to Question 5.
>
> DR. GIUDICE: Oh, sorry. You\'re right.
>
> DR. EMERSON: Which is how\--using the active control, how do you use a
> noninferiority margin. The issue here, and I already alluded to this
> earlier and I am pretty much going to say the same thing but I will
> try to say it quickly, therefore, is that if we imagine that this
> 20 percent rate\--I mean, these are the criteria to use, whether we
> use other data to come up with this.
>
> But if we were having a 20 percent fecundity rate in the previous\--in
> what little data we have from the controlled trials, and if we believe
> that it should have been 10 percent or less in an infertile
> population, the idea is how much of a decrease will we accept. Making
> up a number of roughly a 6 percent decrease or an 8 percent decrease
> would be allowing for the idea that you might actually have a mix of
> patients who were a couple years out infertile and so that the 10
> percent or 11 percent I was quoting was from the 12-month infertile
> rate. So that would still be giving you this margin.
>
> So then a noninferiority trial is saying, we will feel confident at
> the end that, if we declare the new trial noninferior, it is not more
> than 6 percent noninferior. So we make a statement like that with 95
> percent confidence. But something in the 6 percent to 8 percent range
> would be what I would choose.
>
> The reason not to go all the way down to the boundary is, again, from
> the patient standpoint. Would you want to go on a clinical trial where
> you are saying that we are going to tolerate keeping on testing you on
> this treatment even when it is substantially below that level. The
> criteria of how far I regard substantially below is the secondary
> benefits the new treatment may provide, that there may be less pain
> involved, less logistical problems, whatever other conditions might be
> the secondary endpoints of the trial.
>
> DR. GIUDICE: Thank you. Dr. Rice?
>
> DR. RICE: It clearly depends on what you define as those secondary
> endpoints. If I look at the trial now, and my primary endpoint is
> ovulation induction and number of oocytes, my secondary endpoint is
> pregnancy, then I will tolerate a lot of inferiority dependent on the
> patient population that I choose. So it depends, again, on those
> clinical endpoints.
>
> DR. GIUDICE: Yes?
>
> DR. EMERSON: There is no question that I was giving, as my example,
> the pregnancy endpoints.
>
> DR. GIUDICE: Dr. Lewis?
>
> DR. LEWIS: Yeah; I agree that obviously it does depend on what your
> endpoint is. But also it is going to depend on the patient\'s age and
> their diagnosis and whether you are talking about ART or ovulation
> induction, even a difference in pregnancy rates because you are going
> to\--the variance is wider for some.
>
> DR. GIUDICE: Okay. Dr. Hager?
>
> DR. HAGER: Just a question. So are we recommending built-in alarms in
> the study so that, if we reach a noninferiority level of a certain
> percent, then the study will be broken, the code will be broken? Are
> we recommending that? Is that what I am hearing?
>
> DR. GIUDICE: Dr. Emerson?
>
> DR. EMERSON: That is an issue that can be really separated from\--if
> you decide what your hypotheses are that you want to test, then,
> building in a sequential monitoring plan so that, as early as
> possible, you identify whether you have met that, can be addressed
> separately and almost all IRBs are now demanding that be\--FDA and NIH
> are demanding that. It is my area of research so I would be glad to
> talk to you about it.
>
> DR. GIUDICE: Perhaps that line of communication to the FDA can be kept
> open, then. Dr. Toner?
>
> DR. TONER: I was going to ask of Dr. Emerson, I wonder whether\--is
> there any way to standardize or generate a rule for drug companies to
> understand what would constitute noninferiority based on expected
> percentages of success? I mean, even if we stick with your pregnancy
> rate endpoint and, let\'s say, nowadays, the pregnancy rate is 50
> percent, as the expected, would you still want to subtract the same
> absolute number of 6 percent or would you allow it to slip down to 20?
>
> DR. EMERSON: Would I want it to stay the same? Absolutely not. Is
> there any way that we can give some guidance? Well, the International
> Conference on Harmonization of Clinical Trials has a very long
> document on exactly this issue.
>
> Every case is different and a lot depends upon what the safety
> concerns are, what the secondary gains are that you are trying to
> anticipate. There may well be some people who are willing to accept a
> lower fecundity rate which might mean going through more implantation
> procedures if they only have to go through one ovulation procedure.
>
> So, under those considerations, as you design the trial, you have to
> consider all of the side effects, all of the anticipated adverse
> experiences, the gain that you might have, as you go through those
> trials and what\--we are back to this issue of are you going to get
> people to come on the trial. No trial is very efficient if no one will
> be on it, and so you don\'t do that.
>
> So it does have to be modified. The issues have to be broad guidelines
> but, to the extent that all the data that I have seen is the table in
> the background material about what the fecundity rates are, the longer
> you have been out of fertile, and then the one comparator trial that
> we had from the previously approved thing.
>
> And then you have to go with that. So it will change over time as you
> get more data.
>
> DR. KEEFE: Can I comment on that?
>
> DR. GIUDICE: Yes; one short comment.
>
> DR. KEEFE: I think the discussion should first focus on those cases in
> which there is no expected benefit and then could we then do sort of a
> power analysis with a two-tailed component in which we are looking not
> just whether\--you know, what is the size of the sample we would have
> to use to find a detrimental effect.
>
> I think, conventionally, with power analysis, you are looking at sort
> of 20 percent as a reasonable detection rate. Is that done? Could you
> do it that way where you are essentially\--because, otherwise, you are
> going to be encouraging companies to make very tiny little studies
> where there is no difference found and make the assumption of
> noninferiority.
>
> DR. EMERSON: Well, just to give you an idea because I did just look
> this up to see what it was. If you went, for instance, with the
> assuming that a 20 percent rate was the active effect, and you were
> willing to go down to a 14 percent rate and still call that not
> sufficiently inferior, that you do that, that would be about a 600
> patient, person, study, total, so 300 per arm.
>
> If you took it down to 12 percent, that would be about 150 or 160 per
> arm. So those are the sorts of numbers, and that is\--again, in a
> noninferiority trial, we don\'t go with that 80 percent power. We
> really need 97.5 power. We need to say, if it is below our threshold
> that we consider acceptable, we want to be 97.5 percent confident that
> we don\'t approve this thing that is inferior. So our standards have
> changed. This is the same thing, if we are using a 95 percent
> confidence interval to judge this and that is what those numbers are
> based on.
>
> DR. KEEFE: From the standpoint of the consumer, a lot of these people
> are paying out of their pockets for this. I don\'t know if that
> factors into it, but, as the patient advocates, they really want to
> know if something is inferior because this is coming right out of
> their pockets if not their hearts.
>
> So I would err on the side of caution before new drugs were introduced
> that this noninferiority has been established.
>
> DR. EMERSON: I think one of the things you will have is we are mostly,
> right now, talking\--or at least I am talking about\--maybe I should
> have clarified this\--but I am talking about the phase III studies,
> the very confirmatory studies. We have got, presumably, some phase II
> studies that are based on some of these surrogate endpoints to argue
> we have good reason to be going forward with this. And that is what
> you go forward with the patients.
>
> Again, it is the clinicians who are involved with that, them knowing
> what sort of enrollment they can get with the patient, what seems fair
> for the patient, in their best judgment, and then IRBs and DSMBs take
> on a role there, as well.
>
> DR. GIUDICE: That brings us right into the sixth question about single
> versus multiple treatment cycles. Any comments on that?
>
> DR. KEEFE: I\'d like to pick up where I left off in my talk. I
> proposed that we consider the advantages of a crossover design. I know
> there are a lot problems with that but it seems everyone agrees there
> are enormous patient-specific factors at play here. So, while there is
> clearly a problem and you have got a lot of people dropping out
> because they only got through the first treatment, especially if you
> have proper controls in terms of two different treatments being done,
> a crossover design would begin to touch on some of the enormous
> variability from patient to patient. What do you think, Scott?
>
> DR. EMERSON: That was an interesting proposal, as I talked earlier. I
> hadn\'t thought of that issue beforehand, of doing the crossover
> study, because I guess I had been thinking far more of some of the
> other issues. The biggest problem I would see with that is that
> patients dropping off the study not because they had pregnancy\--that,
> we could handle\--but more just the idea that we would have one period
> of treatment for them and not\--but I guess I tend to think that we
> would gain more power from actually taking multiple treatment cycles
> on the same arm or, certainly, from my endpoint of interest which
> would be more time until we had a pregnancy and taking advantage
> of\--again, some of these treatments that are going to be coming up
> will be trying to take advantage of cryopreservation, and what will
> define your cycle, only one fresh cycle or the idea that you might
> have four cycles from a cryopreservation.
>
> DR. GIUDICE: Dr. Hager, you had a comment?
>
> DR. HAGER: Merely, I was just going to say it would seem to me that,
> if we do multiple trials, you would need to quantify or in some way
> stratify for fresh cycle versus frozen cycle.
>
> DR. GIUDICE: Yes. Dr. Crockett?
>
> DR. CROCKETT: The other thing I like about the multiple cycles is, in
> the single-cycle studies, I think there is more of a temptation to
> blast the patient with as much as you can to get the highest pregnancy
> rate. I worry about safety in those patients. I think, if you allow
> for a multiple-cycle trial, you can be more judicious about your
> treatment options and maybe even start lower with your gonadotropins
> and not put the patient at as much risk in an effort to have a higher
> success rate in your study.
>
> DR. GIUDICE: We are talking, and I will address this to Dr.
> Emerson\--we are talking here for the phase III, so your dose-finding
> studies would have been done before then, I assume. Yes?
>
> DR. EMERSON: But I think there are many times that we, as a regimen,
> were testing the idea of the whole regimen. So it is not\--I mean,
> there are a lot of other ancillary things that are not related to the
> dose of this drug but the idea of what other ancillary treatments they
> might be doing or there are a number of implantations that they might
> do at a particular time.
>
> Again, if it is blinded, it is post-randomization, that is okay. If it
> is caused by the therapy, we would be doing that. So it is sort of a
> level of if you were using\--I am imagining that if fresh were as good
> as cryo and that you were more worried about multiple fetal
> gestations, that it might be reasonable to start out with two and see
> if that worked and then, the very next time, do more. And your
> facilitating that if you allow the multiple cycle whereas you aren\'t
> allowing it if you do the single cycle.
>
> DR. GIUDICE: Dr. Macones, Dr. Layman?
>
> DR. MACONES: I would just echo that. I think that, in my mind, in this
> case, I think we really want to try to test what people do in
> practice. Not being an infertility doc, but, as I see it, if you have
> a first cycle that fails, you go on to a second cycle. So to just
> limit it to a first cycle, to me, makes no clinical sense at all.
>
> DR. GIUDICE: That will stir controversy. Dr. Layman?
>
> DR. LAYMAN: I think, again, we have to get back to the statisticians,
> then, because you are going to have cycle dependency and that is going
> to have to be controlled for in the study, because if you have one
> person who has had four cycles and one person who has had one, or
> would it wash out in the randomization?
>
> DR. EMERSON: It washes out in the randomization. Particularly, again,
> if you are looking at an endpoint such as time to live birth, or time
> to pregnancy, viable pregnancy or whatever, that is a concept. People
> who go through more cycles, well, that is a deleterious effect, that
> they won\'t look as good as the arm in which it worked the first time.
>
> But, working on the fourth cycle is better than never working at all
> and so it will capture the endpoint you like.
>
> DR. GIUDICE: Dr. Toner and then Dr. Tulman.
>
> DR. TONER: My objection to the possibility of multiple cycles is the
> lack of generalizability. At least if you are living in a nonmandated
> state, as I am in, most patients get one try. And that\'s it because
> they are paying their own way. To then come in with an offer of four
> tries for free will induce different clinical behavior on the part of
> clinicians. They will maybe be more conservative. What you learn that
> way won\'t reflect what actually happens.
>
> So I would be very afraid of opening up a different kind of a
> treatment strategy than actually happens in practice.
>
> DR. GIUDICE: Dr. Tulman?
>
> DR. TULMAN: I just had two comments. One is, by having a crossover,
> would you, in fact, entice more people to enroll because, on some of
> the cycles, they might be getting what may or may not be perceived as
> the better treatment, although it may not be the better treatment.
>
> And the other question I had to respond to Dr. Toner\'s last comment/
> was that the current practice of allowing one cycle may be based
> somewhat on the scientific evidence, but if the scientific evidence
> changes, then that might also change what is allowable for
> reimbursement.
>
> DR. TONER: I was only making the comment that in Georgia\--
>
> DR. TULMAN: Okay; maybe I misread you.
>
> DR. TONER: Most people can\'t afford a second try. Even if it is to be
> encouraged on the clinical grounds, they can\'t afford it. So, to now
> offer it to a whole bunch of people who, in the real world, would
> never have gotten past a first try, introduces a different kind of an
> observed effect.
>
> DR. TULMAN: I guess I was just thinking further in advance in that, if
> we became better at doing this, and the cost were more allowable, and
> then the science would advance enough such that it might be that one
> trial might not do it but two might be good. But if you have the
> evidence that two is good, then that might eventually, somewhere down
> the road, become a more reimbursable, or a covered, benefit.
>
> DR. GIUDICE: Dr. Crockett and then Dr. Rice, Dr. Stanford and Dr.
> Lewis.
>
> DR. CROCKETT: I really get a little afraid when we start talking about
> letting finances dictate how we are doing our medical science. I
> understand completely what you are saying about the practicality about
> funding for cycles. However, the fact that a patient can\'t afford
> three cycles should not dictate how our physicians are treating those
> patients for infertility.
>
> For instance, you know, our natural fecundability rate is about 20
> percent. It takes most normal, healthy, fertile couples at least three
> cycles to get pregnant, and that is normal and healthy and okay. For
> us to be looking at a medical technique that pushes that to 50 or 60
> percent because that patient can\'t afford to come back for those
> three tries, I don\'t really, from a regulatory standpoint, want to
> encourage that type of behavior.
>
> So I would rather try to take that economic or that time pressure out
> of our recommendations for that kind of trial.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: Dr. Emerson, what does it do for the enrollment numbers if
> we use multiple treatment cycles and then you can change the second
> cycle based on information that you gather from the first. If some of
> you all remember some of the ovulation-induction trials with PCOS
> patients, if they didn\'t respond to a low dose that first month, the
> second month, you could bump it up, or you could bump it down,
> depending on what the trial was.
>
> So what does that do to your enrollment numbers?
>
> DR. EMERSON: Well, first, I should say that those numbers that I gave
> you on sample size were based more on a binomial proportion, just did
> they get pregnant or not, rather than what I would truly advocate
> which is time to pregnancy, which would be a more powerful idea.
>
> I am not, therefore, as worried about the multiple\--the
> nongeneralizability because that will fall right out from the
> analysis. You will see that the time to pregnancy was this many
> episodes and you would be able to judge that. If one arm had a higher
> overall rate over a six-month period but the other arm had a higher
> rate at the first cycle\--these are crossing survival curves and you
> can use statistics that will identify that if you want.
>
> But whatever it is, that will come out. So this idea of, then, your
> question of saying, now this idea that we might tailor treatment, that
> we would end up testing a treatment that allowed some tailoring. Of
> course, we do this all the time in diabetes. We don\'t prescribe a
> single dose of insulin. We give a constantly modifying dose.
>
> So it is possible to test such things if that is the strategy that you
> wanted to test and as long as it was blinded, it wouldn\'t hurt
> anything, that we would be doing the same modifications on both arms.
>
> So it is this idea of using these multiple times, we will be
> increasing our event rate, particularly if we can switch into
> something that is measuring the time as well as the probability of it
> occurring, we will be getting more useful information.
>
> DR. GIUDICE: Dr. Stanford.
>
> DR. STANFORD: I just want to comment first that the single versus
> multiple cycle advantages and disadvantages, again, depends on your
> endpoints, not only your endpoints but your adverse outcomes.
>
> For example, just an example, if you had two regimens and one got you
> pregnant faster in the first cycle, but the other one got you the same
> pregnancy rates or maybe a little more after three cycles but with a
> lower multiple-pregnancy rate, I think that would be a very important
> thing to assess.
>
> So my argument would be towards the total overall pregnancy rate for a
> course of treatment, whatever you determine that is, because then you
> can look at things like what is your overall multiple-pregnancy rate
> and maybe ovarian hyperstimulation, other things that really should be
> factored in.
>
> DR. GIUDICE: Thank you.
>
> Dr. Lewis? No. Okay.
>
> DR. KEEFE: I have a question.
>
> DR. GIUDICE: Dr. Keefe?
>
> DR. KEEFE: It seems to me that multiple cycles would be most helpful
> if our endpoint that we were looking at was pregnancy rate, but, we
> can all agree that that is an extremely expensive way to bring a new
> drug to market. If we are going to be using other markers, especially
> noninferiority, it seems like to be able to fund three, four, five IVF
> cycles\--because what is going to happen is a significant proportion
> of your patients are not going to get pregnant in either group, even
> after three and four cycles, particularly as you get into the mid-30s.
>
> So if we are going to use that, that is ideal. That is perfect. That
> is the gold standard. But, to have that burden, to put that burden, on
> a new drug entering, it is a little excessive, maybe.
>
> DR. GIUDICE: I think we will probably get into that discussion when we
> get to No. 8. Last comment on No. 6?
>
> DR. LAYMAN: I have one other quick question. I mean, does it make a
> difference when you are using multiple cycles? I have always been
> taught, you know, the patient is the experimental group if you are
> looking at the efficacy. Are you saying multiple cycles is reasonable
> to look at the time to event in addition to just efficacy? Is that
> what I understand? Is that what you are saying?
>
> DR. EMERSON: With the multiple cycles, we would have several choices.
> One is you could use the cycle as the denominator and just adjust for
> the fact that we have dependent observations, that we have measured
> some people more than one cycle and we would have to account for that
> in the variability.
>
> You might also have to decide how you want to weight the fecundity
> rate. When I have five observations on one person and two observations
> on another, do I want to weight that 5 to 2 or do I want to weight
> that, that is one person and here is another person, which is more
> important.
>
> But what I am suggesting is the time, measuring the time until they
> have a live birth, the fact that it is multiple cycles or not would be
> dealt with the exact same way. It is No. 9, but on an intent-to-treat
> analysis, the question is, once we have randomized you to this, just
> what is the time until you have had the live birth.
>
> For some people, it is going to be at infinity. It just never happens.
> But we know how to analyze that data and we find that same event, and
> then there is not this problem because that is the unit that we are
> interested in, the patient.
>
> DR. LAYMAN: So you are saying the key is you correct for the\--which
> has been the problem of some studies in the past where there are
> multiple cycles and there was no correction.
>
> DR. EMERSON: Yes; absolutely.
>
> DR. GIUDICE: Let\'s take Questions 7 and 8 together because they both
> have to with powering of the studies. We have been requested to
> discuss advantages and disadvantages of powering studies to detect a
> difference in live-birth rate or on ongoing pregnancy rate.
>
> Dr. Emerson, do you want to make a comment here?
>
> DR. EMERSON: I am not sure that the cost of this\--of the numbers that
> I have been bandying about are any greater than there are in a lot of
> other diseases. So I think the importance of answering the question
> that is the clinical outcome is not subservient to trying to choose a
> surrogate outcome that is not answering the question.
>
> In no clinical trials are we just looking for a pharmacological effect
> of the drug. There are plenty of examples in the history of clinical
> trials where the putative mechanism of the drug, the drug did it. The
> antiarrhythmia trials; we could give people drugs and decrease their
> arrhythmias. Unfortunately, we also killed them.
>
> The point was to find\--we are trying to treat a disease here. The
> disease is infertility. We aren\'t trying to just see how many eggs we
> can have from a particular ovulation. The people who are wanting this
> treatment goes there. With an infinite amount of money, I would love
> to study every single step in the whole mechanism that might lead from
> one particular treatment to a good clinical outcome.
>
> But no one is going to pay for it. Once they find out that it is a
> good clinical outcome, they are going to say, yeah, maybe you know the
> mechanism, maybe you don\'t. But I have got the outcome that I want.
> So we are at this stage now where there is plenty of reason to suspect
> that every treatment that we give may not have the same surrogate
> value, that we might be intervening on the whole endocrine pathway
> differently with one treatment than another, so the idea, here, is
> that if we stimulate ovulation or the additional ova that we are
> stimulating equally as fertile as those that we would get if we
> weren\'t stimulating as many. We don\'t know those answers, so it is
> the pregnancy rate that will answer it and, going in this sense, since
> you have the active comparator, that, by all appearances, works fairly
> well, it is not really that big of a burden to be able to demonstrate
> that you are not doing harm on the important clinical outcome.
>
> DR. GIUDICE: I think you have just opened Pandora\'s box. Dr.
> Lipshultz and then Dr. Rice and Dr. Stanford.
>
> DR. LAYMAN: I\'m sorry, but I have a question on just what you said.
> So what you are saying, then, is the only endpoint you think is
> significant is the pregnancy.
>
> DR. EMERSON: No. I think the primary endpoint of these trials\--for
> instance, I can imagine a scenario in which a new treatment is not as
> efficacious as another active treatment but has other advantages. For
> instance, there may be situations that I could imagine if you showed
> me one treatment that had a higher rate of pregnancy in the first
> cycle, and another treatment that had still an overall cumulative
> effect that was about the same, but in the first cycle, it wasn\'t, I
> can imagine many scenarios in which I would accept that.
>
> What I was, instead, talking about was the primary endpoint and
> ensuring that we do not have a treatment that is not efficacious
> against placebo. I mean, we are trying to estimate that in a
> noninferiority situation with an active comparator. The idea that we
> would not power a study so that you could even be sure that it was not
> doing as well as a placebo, I find not in good science at this point.
>
> You would like to make certain that, as we are going forward and might
> approve a therapy, that we would be certain that it is working better
> than placebo. We won\'t be certain that it is working better than the
> active comparator, necessarily. But then we have other secondary
> endpoints that I would certainly look at. It is just the guarantee
> that we aren\'t doing worse than doing nothing.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I guess my question is more so to the FDA. How do you
> maintain the equality if you have previously approved products based
> on one outcome and now, if this committee were to make a
> recommendation to say now we want to use a different endpoint. Someone
> new comes to the market, how do you maintain that level of equality?
>
> DR. SHAMES: Well, I think that we are here because we think, in fact,
> in the past, we have not\--let\'s say this. Sometimes science changes.
> Things change and we have to keep up with the science and do what we
> can\--do the best for the public in terms of having the science that
> we work with mimic the science in the community.
>
> It is not unusual for things to change and we are accused of being
> unfair. But this is not at all the only circumstance where that
> happens. This happens in other areas. Sometimes, we find safety issues
> that we didn\'t know about two or three years ago and we compel
> companies to do certain studies that we didn\'t compel other companies
> to do. We just find that we have to do that. We need to do the best we
> can at the moment based on the science, even though that is perhaps
> not what we did a number of years ago.
>
> DR. RICE: I think that, looking at gonadotropins\--I think you do
> reach a point with a certain class of products that what comes onto
> the market, there is a level of equality in effectiveness of an
> endpoint that you used to use but now the science has shown us that
> there are more variables that go into that ultimate outcome.
>
> I brought this up to hope that it was based on all of the science that
> is coming out even though our science in understanding ovarian
> reserve, et cetera, is still growing, but that the science perhaps
> does dictate that we look at different endpoints.
>
> DR. SHAMES: Absolutely, it should.
>
> DR. GIUDICE: I would like to ask the committee for some input in terms
> of what other primary outcomes\--does everybody agree, now, that the
> primary outcome for, for instance, gonadotropin therapy should be
> pregnancy? We have heard from Dr. Emerson and I think this is
> where\--and I think Dr. Lipshultz\'s question addressed this. Dr.
> Stanford?
>
> DR. STANFORD: I would just like to clarify. Are you talking about, Dr.
> Emerson, chemical pregnancy, clinical pregnancy, or live birth?
>
> DR. EMERSON: Well, I guess my top choice would be live birth. While I
> liked the suggestion earlier that it should really be live healthy
> birth, I think that there is trouble with healthy birth. So my first
> choice would be live birth and, if you have to take me to lesser
> things, it will be going backwards from live birth.
>
> DR. STANFORD: I would agree with that.
>
> DR. GIUDICE: Dr. Keefe?
>
> DR. KEEFE: If you looked at Dr. Toner\'s graph at the relationship
> between miscarriage and take-home baby, it seems to sort of parallel.
> So I think it is a crude but good indicator of what is going to
> happen. You could imagine a number of interventions that might
> selectively perturb the development of the embryo after that, but I
> think, in general, on balance, it is probably the best sort of
> practical measure we have short of live birth. This would be clinical
> pregnancy or with a heartbeat.
>
> DR. GIUDICE: Dr. Toner and then Dr. Lipshultz, and I saw another hand
> down here. Dr. Hager.
>
> DR. TONER: I would still vote for some measure of follicular response,
> the primary pharmacologic action of the drug in question. I think, if
> we choose pregnancy, as I said this morning, if a drug these days
> proved more potent in egg production, it would be invisible to the
> fresh pregnancy rate. So an apparent benefit is completely invisible.
>
> Now, sure; it could go the other way. But we clinicians are actually
> in the business of trying to get pregnancies and not trying to get
> eggs despite what I might say otherwise and it wouldn\'t be too long
> before an inferior product with respect to the ultimate endpoint would
> come to light and change practice.
>
> Already, all the studies that have focused on egg-production capacity
> have disclosed pregnancy rates. So it is not like the data would be
> unavailable if we stuck with the same endpoint as has been used
> heretofore.
>
> DR. GIUDICE: Dr. Lipshultz?
>
> DR. LIPSHULTZ: It\'s really not a question for you because, I mean, I
> am coming from a specialty where we don\'t have such a long delay in
> waiting for an outcome. But if you are a company developing a drug and
> your outcome is nine months after you start giving the medicine in
> question, the drug in question, let alone the start-up time and
> getting your patients enrolled, what are you looking at,
> realistically, until you get something\--data together that is going
> to be significant enough to present and, in the meantime, science is
> changing and you are taking three years to do a study, with the
> numbers you talked about.
>
> I mean, if you just use live birth as an endpoint, I am questioning
> just how long such a study would have to take.
>
> DR. EMERSON: In a time-to-event analysis, you actually measure the
> amount of data you get by the number of events. So the question is how
> long do you have to go until you have so many events, and you power it
> according to that. Of course, cancer in clinical trials routinely
> takes years and years and years. So this isn\'t anything that is out
> of the ordinary in the experience of clinical research.
>
> DR. KEEFE: Can I respond to that one?
>
> DR. GIUDICE: Yes; Dr. Keefe?
>
> DR. KEEFE: There is a real practical issue as well. People disappear.
> They got their babies; like, sayonara, they are out of there. I mean,
> the person who is treating for infertility is not the one who is going
> to deliver the baby. So it is really hard just to find these people.
> They move. They go to different places. They deliver at another
> hospital. So you can\'t get the data, even in a really carefully
> controlled study.
>
> One other point, though, about using the egg number or follicle
> number, there are precedents in which you get more eggs but there is a
> worse outcome. Klaus Dietrich, for example, just looking at a subset,
> those with lower response, has shown that the flare, the old-fashioned
> flare, actually gives you more eggs. It gives you higher estradiol
> response, but a lower pregnancy rate than some of the other methods.
>
> So it is a little tricky just to look at egg and follicle number. So I
> would say clinical pregnancy is kind of a middle ground.
>
> DR. GIUDICE: Dr. Hager?
>
> DR. HAGER: I understand the pharmaceutical perspective, the research
> perspective, of power and design in trying to get as many positives,
> if you will, regarding follicular development, regarding oocytes. At
> the same time, my patient population, they are not interested in a
> chemical pregnancy test. Their perspective is that they want to get
> pregnant.
>
> At the same time, given my understanding that if we have a gestational
> sac with fetal heart motion, there is a 95 percent chance of carrying
> that pregnancy. Then, I think that gives that patient the same odds as
> a patient who conceives outside of an assisted-reproductive-technology
> situation.
>
> So my perspective is that my endpoint would be fetal heart motion. I
> realize that we would all like to have a live baby but I don\'t think
> that is the endpoint that I would like to see with these medications.
> I would like to take it to fetal heart motion.
>
> DR. GIUDICE: Dr. Layman and then Dr. Brzyski.
>
> DR. LAYMAN: I think, to me, it is different depending upon the
> implication. Like, for ovulation induction, for Class 1 patients
> versus Class 2 versus using for ART, for ART, it seems more clear to
> me that it should clearly be pregnancy. But, at the opposite extreme,
> I think Class 1, I think it is not practical to use pregnancy as the
> endpoint. You will never get enough patients to do it.
>
> So I think you have to sort of bear in mind how common it is. I think
> Class 2 is a tougher one. It is sort of in between and I don\'t view
> all three of those the same.
>
> DR. GIUDICE: Dr. Brzyski.
>
> DR. BRZYSKI: I think I brought this up earlier but especially in the
> PCO population, there is a real problem with miscarriage rate and also
> in infertile populations, not only in advanced but just the infertile
> puts you at increased risk of miscarriage even after the documentation
> of cardiac motion on ultrasound.
>
> So I think you do lose something, and you can imagine an intervention
> that\--I mean, there is some scientific evidence now for an off-label
> use of a ovulation-induction medicine that is used to induce ovulation
> in PCOS patients. One of the attractions to that is, because of the
> lower miscarriage rate in PCOS patients. So that becomes an important
> endpoint that you might lose if you focus on cardiac motion or
> positive pregnancy test.
>
> DR. GIUDICE: That does bring us into Question 8, but I think Dr. Rice
> had a comment.
>
> DR. RICE: I was just going to say, I agree with Dr. Layman. I think it
> really does depend on the type of patient you are looking at. If I
> have an anovulatory patient, then I may have a trial that really just
> looks at getting that patient to ovulate as the endpoint. In that
> patient population, that would be adequate because of what the patient
> came to the table with.
>
> But when you are looking at ART patients, I think that it should be
> fetal-cardiac activity on a ultrasound because, again, as Dr. Hager
> was saying, there is 95 percent chance of success once you have that.
>
> I also would say to Dr. Keefe, I can bet you, and I don\'t think I am
> wrong about this, that most of the pharmaceutical companies know
> whether or not those women that had a positive pregnancy test
> delivered that baby. They track that information. I would be surprised
> that they didn\'t track some of that information.
>
> The FDA sort of alluded to it earlier, that they know they report some
> of that information. At least, there is some information regarding it;
> is that correct? So I would be surprised that they don\'t know some of
> the outcomes of that data. So I think that data is obtainable.
>
> DR. GIUDICE: That I think we can get to in Question 13. Let\'s move
> on. With regard to the pregnancy or the outcome, we have already
> discussed, not really follicular development rate but follicle
> development. As you can see from Question 8, the issue is, if you
> can\'t power to demonstrate differences in live birth, or ongoing
> pregnancy rate, then discuss the clinical relevance of these surrogate
> markers. Dr. Crockett?
>
> DR. CROCKETT: I just have a question concerning our discussion of
> these endpoints. In my mind, it seems like it would be easier to
> separate out what we look at as endpoints for efficacy versus
> endpoints that I would consider for safety considerations.
>
> For instance, for efficacy of an ovulation drug, I think follicular
> development is an acceptable endpoint. But I might want to know more
> about that drug such as does it cause teratogenesis of some kind. I am
> not aware of that being a problem with any of our current medications,
> but it is conceivable that, in the future, there could be drugs that
> do that.
>
> So it would probably be helpful for us, from a safety standpoint, to
> follow out those patients to a pregnancy or even beyond pregnancy
> endpoint since we know that genetic factors can carry even beyond
> birth. So I just wanted to raise that question.
>
> DR. GIUDICE: Thank you. Other comments? Going through the list here, I
> think we have heard, with anovulatory patients, that follicular
> development\--we haven\'t really defined follicular development,
> whether we mean follicles of a given size or estradiols over a given
> level or endometrium over a given thickness. Would someone like to
> make some comments about that? Or should we include those as
> possibilities for recommendations as we advise the FDA? Okay.
>
> DR. KEEFE: In each of these, it seems that, as you push back further,
> it makes it easier to do and you need less power, but it always raises
> the question of is there a downside to the treatment later in
> development.
>
> So, just to balance these\--some, for example, have argued that for
> ovulation induction, all we need to do is show that they have
> ovulated. But there are many ways to make people ovulate that almost
> guarantee there would be a miscarriage. You could drive the LH level
> so high that they may ovulate but it is not going to develop.
>
> So I would say that, in general, for most of these things, to try to
> paint with broad strokes, would be that these are useful indicators of
> efficacy unless there is some scientific evidence to suggest a
> detrimental impact at later stages of development. So that would open
> the door to concerns of\--for example, we had an intervention that
> drove up LH levels too high\--that maybe, in that, there might be a
> little bit more concern about showing more than just ovulation,
> ovulation with development of fetal heart, and then, if there is some
> evidence of a treatment causing higher rates of miscarriage after
> fetal heart, that efficacy should be determined at a later stage of
> development.
>
> DR. GIUDICE: Okay. Yes; Dr. Emmi?
>
> DR. EMMI: I remember reading a study a couple of years ago that showed
> that it wasn\'t just fetal heart. It was when, in the first trimester,
> fetal heart was obtained, whether the pregnancy would continue to go
> on. And that was based on age. The older patients, if they didn\'t
> have the fetal heart at about eight to ten weeks, had more chance of a
> miscarriage.
>
> So I don\'t think that you can just go clinical pregnancy. I think you
> have to pick a parameter. If you are going to pick clinical pregnancy,
> you have to pick a time in the first trimester for that ultrasound to
> be performed to establish it.
>
> DR. GIUDICE: Dr. Emerson?
>
> DR. EMERSON: I have already stated that I sort of wouldn\'t go beyond
> the presence of the gestational sac, personally, and I would prefer
> not stopping before fetal heartbeat. I do want to point out that if
> your whole goal is that you think that they can\'t get a sample size
> large enough to detect this, you are also guaranteeing absolutely that
> you won\'t have a large enough sample size to be able to detect a
> meaningful rate of fetal abnormality or miscarriage because if you
> don\'t even have a large enough sample size to observe that you have
> got a difference in pregnancies, by the time you have reduced that
> sample size, you have got a very small sample size of pregnancies to
> work for.
>
> Seeing zero events, zero events, your confidence bound on a bad event
> rate is roughly 3 over n. The space shuttle went off 24 times without
> a catastrophe and the next one blew up and we now know that that rate
> is actually far higher than you might have thought with just 24 no
> failures.
>
> So we are making a decision truly as you want to power this down for
> the clinical endpoints of interest is also we won\'t be able to detect
> meaningful adverse-event rates.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I can\'t see why we would think we would not be able to
> enroll enough patients in, say, a trial because if you look at, just
> from the Follistim data she showed, what was it, under a thousand
> patients in those two arm, to detect a difference. We had
> approximately 160,000 people maybe last year who used\--maybe 100,000
> who used gonadotropins, 40 percent of that for IVF, the other percent
> just with ovulation induction.
>
> So you are talking about 100,000 people in a given year and we can\'t
> come up with 2,000 to detect a difference in a product? That would
> seem unreasonable. I can\'t imagine that.
>
> DR. GIUDICE: That may be true for pregnancy, for infertility, but if
> you get the Kallmann\'s patient, for instance, there you probably will
> not\--I think what Dr. Layman was referring to was the WHO Type 1 and
> even subsets within that where getting enough patients for power is
> nearly impossible with a few thousand worldwide.
>
> DR. RICE: Clearly, there are going to be some limitations when we get
> to specific disorders like that. And we have all seen, in some of
> those studies, you change your endpoint because you recognize that the
> disease is so rare that you could not potentially use pregnancy as the
> outcome.
>
> But if we were looking at infertility, and I would even venture to say
> we were just looking at \"anovulation,\" the anovulatory patient, that
> there may potentially still be the opportunity with the incidence we
> see the disease process in to enroll enough patients.
>
> DR. GIUDICE: I would like to ask the committee, in terms of pregnancy
> rate for the list here, what the consensus is in terms of
> recommendation to the FDA, if pregnancy is going to be an outcome. Is
> it positive beta-hCG? Is it a sac on ultrasound? Is it a sac with a
> heartbeat? Is it a sac with a heartbeat at six weeks or eight weeks?
>
> Are we going to give a definitive recommendation or leave the list and
> have that open for interpretation and discussion at the FDA by the
> FDA? Dr. Keefe?
>
> DR. KEEFE: I would advocate, as was argued very persuasively, that a
> fetal heart is a big quantum leap, once you have the fetal heart
> detectable conventionally around six weeks. So I would vote for the
> fetal heart. You know, on balance, it is practical, doable, and it is
> a big hurdle that the embryo has overcome.
>
> DR. GIUDICE: Dr. Hager?
>
> DR. HAGER: I think the other advantage is that it is a reproducible
> event to measure.
>
> DR. KEEFE: It is under the control of the clinic that is doing the
> study.
>
> DR. GIUDICE: Can we take a vote on this one? Okay. Who is in favor in
> the definition of pregnancy as the outcome for sac and fetus with a
> heartbeat. Anyone opposed? Dr. Stanford.
>
> DR. STANFORD: I would think that you could set it as a minimum
> standard. That is what I would be comfortable with. I think, in some
> cases, where there may be safety concerns that go beyond that, you
> would want to allow for having a higher standard in some cases where
> there is a reason to do so.
>
> But, if you state it as a minimum standard, I think I would be happy
> with that.
>
> DR. GIUDICE: Okay. Yes; Dr. Hager?
>
> DR. HAGER: Just a comment. I would think that there would be a strong
> emphasis for follow up and tracking, et cetera. I think we have
> already conveyed that. So this would be a part of that is what is the
> ultimate outcome and, also, I would hope that we would encourage
> follow up regarding anomalies and aneuploidy, et cetera.
>
> DR. GIUDICE: Thank you. Let\'s move on to Questions 9 and 10 regarding
> intention to treat. So the first one; is an intent-to-treat analysis
> appropriate for ovulation induction and, if not, should cycles be
> analyzed per patient given hCG? Any comments on that?
>
> We have heard Dr. Emerson. Perhaps he would like to restate his
> statement.
>
> DR. EMERSON: You know, randomization\--you are only protected by
> randomization if you do intent-to-treat. Otherwise, you are not.
>
> DR. GIUDICE: Yes. Dr. Lewis?
>
> DR. LEWIS: I think you have to use intent-to-treat for both ovulation
> induction and ART because also cancellation rates are very important
> and, if a given drug is associated with a higher cancellation rate for
> whatever reason, you want to know about it. So I think the other
> endpoints are really not so meaningful, or the other denominators are
> not so meaningful, I should say.
>
> DR. GIUDICE: Yes; Dr. Toner?
>
> DR. TONER: I would concur. I would just argue, hopefully, for
> flexibility in the stimulation arm because, if you constrain every
> patient to get the same dose, and you are under on some and over on
> some, you are going to get hardly any to the finish line. And you will
> look like you didn\'t do well, but it is because you had your hands
> tied behind your back.
>
> So I think that was the problem with some protocols that have been
> done to date and would need to be changed.
>
> DR. GIUDICE: There seems to be pretty good consensus among the group
> about intent-to-treat. Going on to No. 11, to discuss safety endpoints
> that should be evaluated. Dr. Stanford?
>
> DR. STANFORD: I will just say, again, I think multiple gestation
> definitely ought to be on the list. Certainly, there are others that
> we have talked about, ovarian-hyperstimulation syndrome, obviously
> ought to be on the list.
>
> DR. GIUDICE: Others? Yes; Dr. Crockett?
>
> DR. CROCKETT: I have a lot of concern about this. I, in particular, am
> concerned about the risk to the mother being given these drugs or
> hyperstimulation, not just the immediate effects of the
> ovarian-hyperstimulation syndrome but are there oncogenic effects
> further down her lifetime. So, while it may not be a factor that we
> need in order to make a decision about certifying a drug for use, it
> may be important to us, as an agency, to know how those patients, both
> the maternal side and the fetal side, progress 20, 30, 40, 50 years
> out.
>
> And we ought to consider having a registry of adverse events just like
> we do for many other drugs, far out.
>
> DR. GIUDICE: Thank you. Any other comments? Dr. Hager.
>
> DR. HAGER: Bringing up the clomiphene situation long-term, I think, as
> Dr. Crockett has said, there needs to be a definite registry not only
> for immediate disease but also the long-term oncologic effects. I
> would hope that would be designed into all of these trials so that we
> not only follow the infants but we also follow the moms.
>
> DR. GIUDICE: I think you both make very important points and I think
> one of the major questions is\--actually, there were several
> questions\--who would run and have control over a central registry.
> Would it be one individual pharmaceutical company? Would it be the
> FDA? Would it be the CDC? Would it be SART? Would it be ASRM?
>
> Complementary to that is the whole issue of cost, who would fund the
> registry. These are issues that I don\'t know that our committee can
> solve, but I think, and this certainly bears very much on Question No.
> 13\--but this is something that I think we need to at least discuss in
> a little bit more detail because I think we are all aware of these
> issues but, perhaps, we can be of some help to the FDA in making some
> recommendations.
>
> Dr. Lipshultz?
>
> DR. LIPSHULTZ: Just a comment because I randomized up against this
> recently. Apparently, as physicians, we all have the duty to report to
> the pharmaceutical company any adverse event we find in a patient, no
> matter what they are taking, related to that drug. I just don\'t think
> we, as physicians, do that.
>
> We find things. We have patients who develop malignancies and we think
> it might be related to something, and we never let the company know
> because we are not part of a study. I mean, these people, after they
> go through IVF are no longer going to be part of a study, or part of a
> group. They are going to move on with their lives but they will all
> have doctors.
>
> So I don\'t know whether it is anybody\'s, any agency\'s or any
> subgroup\'s responsibility, as it is the medical community\'s
> responsibility to make sure that all adverse events are reported to
> the pharmaceutical companies if you think there is a connection.
>
> DR. GIUDICE: Dr. Crockett and then Dr. Keefe.
>
> DR. CROCKETT: I think this is a public-health problem. I don\'t think
> this is a pharmaceutical-industry thing. Frankly, no disrespect to our
> pharmaceutical people that are in the audience, but I don\'t trust the
> drug companies to take the whole public interest to heart. I think
> that is why we have agencies like the CDC that track other
> public-disease problems.
>
> I would suggest that should become part of our responsibility in that
> regard.
>
> DR. GIUDICE: Okay.
>
> DR. KEEFE: I agree. If you really want it to work, you don\'t go to
> the pharmaceutical companies. You don\'t depend on doctors. You put it
> out there, maybe foundations, CDC, a number of sort of public-interest
> groups, and the patients will help us because they will start calling,
> they will start reporting. They will say they have a friend who had
> this or that, and all the chat rooms. That is how to make it work.
> Then you really have data.
>
> There are registries available. The Australians have a registry. They
> have published extensively on long-term outcomes and they are not
> finding a lot. But they are looking more at cancer, I think the
> developmental anomalies, aneuploidies, other issues regarding the
> offspring and potentially other issues regarding the patients.
>
> But I think it has to be outside everyone and of its own domain funded
> externally. Then it will work.
>
> DR. GIUDICE: Dr. Dickey, you had a comment? And then Dr. Hager?
>
> DR. DICKEY: Judging from some of the other things that we fund
> externally to keep registries, that doesn\'t work so well either. They
> are dependent on state funding which comes and goes. But I do think
> the whole conflict of interest thing that we are so attuned to here
> suggests, in fact, that it would probably be better if it came from
> some centralized entity as opposed to expecting the pharmaceutical
> industry to track that.
>
> I don\'t have a great deal of faith that either doctors or patients,
> in fact, do a very good job long after the fact of trying to correlate
> back what happened. So I think you have to have a little more specific
> guidance out there of who you need to report to you and what kinds of
> things you want reported and, perhaps, then chat rooms and things can
> do it.
>
> But very few of us, in fact, correlate something back to something
> that happened twenty years ago or thirty years ago. And I am not sure
> how you get somebody to fund it.
>
> DR. GIUDICE: Dr. Hager?
>
> DR. HAGER: There is precedent. When metronidazole was approved by the
> FDA as an antianaerobic agent, there was some rodent data at the time
> that indicated the potential for some problems. I was at the CDC. We
> began a registry at that time looking at deleterious effects in
> newborn infants.
>
> As you know, we have discontinued that registry because there are
> none. But, there is precedent for cooperation between the two agencies
> to develop a registry and to follow that, and it is a public-health
> measure.
>
> DR. GIUDICE: Dr. Macones, Dr. Lewis and Dr. Brzyski.
>
> DR. MACONES: I agree that I really see this as a domain of the
> pharmaceutical company to put together a registry for this. I think I
> could see this discussion happening with the NIH coming up with,
> developing a long-term follow up for a cohort of people who were
> exposed to ART drugs. I think there is some precedent for a very
> successful long-term follow-up physicians health study, nurses health
> study, that have been remarkable.
>
> I just can\'t see how a 40-year follow-up study is going to be the
> responsibility of a pharmaceutical company. I think this needs to be
> independently funded and I think the NIH would be very receptive to
> something like this.
>
> DR. GIUDICE: Dr. Lewis?
>
> DR. LEWIS: A registry could provide enormously helpful information. I
> think you have to be very careful about privacy concerns of patients,
> particularly in this day and age with HIPAA regulations. So it would
> have to be, obviously, voluntary. I don\'t think it is realistic to
> think the pharmaceutical industry is going to pay for it.
>
> One thing about patients recollections, it has been shown quite
> clearly that if a patient develops a disease, they recall very clearly
> every single thing they ever took. So recall bias could be quite a
> problem so you really do have to think about doing it prospectively.
> But it is very expensive and there are a lot of obstacles in the way.
>
> DR. GIUDICE: Dr. Brzyski?
>
> DR. BRZYSKI: One point I would like to raise is the issue that we
> really don\'t have good information about complications, first of all,
> even in the general population. There is a quote\--I tried to track
> down a reference for the commonly cited rate of 2 to 4 percent for
> severe birth defects. I can\'t find it. It is on the CDC website, but
> there is no citation for, like, where that rate comes from.
>
> If you look\--well, anyway. And then if you look at infertile
> individuals who may have other predispositions, genetically or
> epigenetically, to have complications or problems down the line,
> really, we have no information on that population compared to, say,
> the ART population where there is concern about, for instance, birth
> defects in the children.
>
> So when we look at a registry, if all we have is a registry of people
> exposed to fertility medications, I am not sure how to put that in
> perspective in terms of the general population or in terms of
> infertile individuals who were not exposed to fertility medications.
> So now you are doubling or tripling your effort to collect the data on
> those other populations so you can make some comparison about, well,
> is the rate of 2 per 10,000, is that bad or good compared to other
> individuals.
>
> DR. GIUDICE: Thank you. Another question also is what type of
> information would be collected for this type of registry. I think,
> certainly, now that there are potentially three populations to collect
> information on. This does bring up even yet again a larger database
> but I would like to hear\--perhaps we can discuss, as a group, some
> potential entries into this hypothetical database. Dr. Crockett?
>
> DR. CROCKETT: Well, let\'s start at the lowest end which would be
> adverse events during the pregnancy that you wouldn\'t have otherwise
> expected. So I would want to know fetal anomalies identified by
> ultrasound and a fetal-loss rate beyond the first trimester, perhaps.
>
> Beyond that, after birth, then tracking out the infant or the baby, I
> would want to know about specific diseases, particularly oncogenesis,
> learning disability, diseases which we are concerned about now with
> other drugs that we are introducing into our pregnancy women. From the
> maternal side, I have already mentioned, oncogenesis, also.
>
> DR. GIUDICE: Thank you. Dr. Toner?
>
> DR. TONER: I was just going to mention, kind of following up with what
> Bob had said, that every state in the country has its own rules about
> how to do birth-defect reporting. There is no consensus about what is
> in the list, what is off the list, who collects it, when it is
> observed. So that is partly why Dr. Brzyski can\'t find a reference,
> because it is done a hundred different ways.
>
> Probably the most simple thing to do would be to go into a state that
> already does it across the board and then parse them up by, are these
> IVF babies or are these not so you don\'t focus undue scrutiny on the
> IVFs and don\'t apply that same scrutiny to everybody else.
>
> As I understood the CDC, they were trying to get such a thing to
> happen in Massachusetts where there is potential for linkage. But in
> most states, because of privacy concerns, you can\'t know who the baby
> is, who the mom was and who got treated. So it is going to be very
> tough, I think, except in a state potentially like Massachusetts.
>
> DR. GIUDICE: Dr. Keefe?
>
> DR. KEEFE: The Dutch have done that, of course, published. They looked
> at one particular outcome which is adverse neurological sequelae and
> found huge increases. Those were in group homes where the most
> severely impaired live. And so there is much less detection bias.
>
> It is true there are problems, but there is such precedence for it
> being such a large impact and the vast majority of the abnormalities,
> by the way, were linked to multiple births and prematurity, as you
> would expect.
>
> So now it looks like I think 2 percent of all births in Sweden come
> from IVF babies. It is going to grow in the United States. I think we
> should start planning now. I think it has got to be done. I mean, look
> at DES, diethylstilbesterol. This was the previous generation\'s new
> technology. It was some well-meaning, brilliant Harvard professors of
> biochemistry and GYN who had this tremendous theory of the value of
> estrogen in early pregnancy which made a lot of sense then but, in
> retrospect, is laughable, how naive it was and led to some really
> adverse outcomes.
>
> So I think it is way too big and way too important to say it can\'t be
> done. It is just a question of how, really.
>
> DR. GIUDICE: But the specific question from the FDA was whether the
> pharmaceutical companies would need to be responsible for these
> registries. What I think I have heard from the group is that this is
> way bigger than any one pharmaceutical company. Dr. Rice and then Dr.
> Stanford.
>
> DR. RICE: I agree with Dr. Keefe. I think just because it is hard
> doesn\'t mean that we shouldn\'t do it. I think we need to do it. I
> think it is going to be valuable information that is going to find
> invaluable as we look at long-term outcomes. And I do think it is
> bigger than the pharmaceutical companies. So I don\'t know if I would
> put, per se, the burden on them to do it.
>
> I don\'t know where the burden, per se, falls but I think it
> definitely needs to be done because we are treating too many women at
> this\--we are treating so many women at this point that, at some
> point, we are going to get to a point where we can actually detect
> some differences, and those differences may be very significant in
> looking at not only fetal outcomes but maternal outcomes, also.
>
> DR. GIUDICE: Dr. Stanford?
>
> DR. STANFORD: Just a comment. It is probably stating the obvious but
> maybe just a comment that the FDA would welcome the assistance or
> cooperation of the drug companies in these efforts as opposed to you
> should do this, or this has to be done somehow, and stating that that
> is a desirably\--obviously, that doesn\'t have any teeth, regulatory
> teeth, but just as a statement of policy that they would appreciate
> cooperation or assistance in terms of tracking people from trials or
> whatever that may come up.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: And we are talking about a registry for ovulation-induction
> patients and ART patients because we get caught up in the ART part of
> it but the ovulation induction is mostly what we see. Our
> gonadotropins are usually patients who use insemination or time to
> intercourse, et cetera, and that. So we want to make sure that we are
> talking about areas.
>
> DR. GIUDICE: Yes; I am glad you clarified that. Thank you. Dr.
> Brzyski?
>
> DR. BRZYSKI: One comment, one recommendation, I would have is I hear
> from my colleagues that there is concern, and we have talked about it
> here, concern about privacy. I mentioned, myself, the stigmatization
> of offspring. There are, perhaps, educational efforts that need to be
> made in the patient populations and that would be the efforts that
> professional societies could make, patient-advocacy organizations
> could make. Even the FDA might be able to inform the public regarding
> the relevance of\--you know, if a registry is established, the
> importance of participating in that and educating patients and
> families and physicians about the public-health impact of that
> registry.
>
> DR. GIUDICE: Thank you. Yes; Dr. Crockett?
>
> DR. CROCKETT: I just wanted to add one more thing to that. A registry
> is really helpful but the other part of this is informing the patient
> about what knowledge is available concerning the medications that they
> are taking and what knowledge is not yet available.
>
> For instance, on the product labeling, there probably should be a
> statement that makes the patient aware of the safety data and efficacy
> data that has been looked at and the terms of those studies and the
> limits of those studies. If we had done that with hormone-replacement
> therapy twenty years ago, then we may have had a little less trouble
> dealing with the questions of that whole breast-cancer issue.
>
> I think people, when the FDA says something is approved, they have the
> assumption that it is safe and it is efficacious for the nth degree.
> If we are establishing safety for a short period of time that we are
> looking at, it needs to be made clear in the literature to the
> patients.
>
> DR. GIUDICE: That is a very good point. Dr. Rice?
>
> DR. RICE: I think we ought to be very careful about that because we
> can only use the information that we have currently to make those
> limited statements on safety. So we don\'t want to be using level 2 or
> 3 evidence to say what safety is. So you want to be using\--you want
> to be very careful about that because, when you used the hormone
> therapy as an example, based on when the information was presented to
> the FDA, when they wrote those guidelines, that was the best
> information they probably had then.
>
> It changes over time. So I think that is the key thing. You ought to
> keep the flexibility so that you can change it as more\--as the best
> evidence becomes available.
>
> DR. CROCKETT: So that again. That is exactly right.
>
> DR. RICE: I don\'t know how I said it.
>
> DR. CROCKETT: The patient needs to know that, though.
>
> DR. RICE: Right. The patient clearly needs to know this.
>
> DR. CROCKETT: That this is based on our best information right now and
> that it may change over time.
>
> DR. RICE: But I think there are different\--there is different quality
> of evidence. If that was the case, then, we could take some studies
> now and put a potential oncogenic risk to taking infertility drugs.
> But many of us would say that that evidence is not based on anything
> prospective. And so you wouldn\'t want to put that on the label to
> unduly scare the patient at this point.
>
> DR. CROCKETT: You misunderstood what I said. Let me clarify.
>
> DR. RICE: Okay.
>
> DR. CROCKETT: I didn\'t want to say specifically that there may be a
> risk of X, Y and Z that has not been discovered yet. I mean merely
> that we would tell the patient what has been discovered and what the
> time frame is of that discovery and that there may be, in a general
> way\--like you previously stated, there may be risks in the future
> that are undisclosed at the time that the drug was approved.
>
> DR. RICE: But then you have to ask the question which risk. You know,
> that is the thing, which risk. There are several possible risks that
> could be there.
>
> DR. CROCKETT: There are a million possible risks.
>
> DR. RICE: So your possible risks needs to be based on some good
> evidence.
>
> DR. CROCKETT: No. There are a million possible risks that we take with
> anything that we take into our bodies, but the patients, when they see
> something from the FDA that says it is approved, the patient and the
> public think that that means it is safe forever and ever. And we ought
> to be able to tell them, no, we have looked at the safety and efficacy
> regarding these things in this short period of time, and there may be
> things that we don\'t know about yet.
>
> We don\'t have to list what those things may be but we need to at
> least disclose the limitations to what we know.
>
> DR. GIUDICE: I think it is an obligation of clinicians who are
> prescribing medications to inform patients about risks and benefits
> and also to give them the package insert so that they read all of the
> information. But I think what you are getting at is, in the package
> insert, some statement should be made, perhaps more clearly, that
> there are limitations to the evidence.
>
> DR. CROCKETT: Yes. The whole reason I thought to bring this up is
> because, if we are talking about a registry, it would be helpful for
> the patient, when they get that medicine, to know that, if they have
> an adverse effect that was not discovered at the time the drug was
> approved, that they need to report it to somebody.
>
> DR. GIUDICE: Yes. Thank you. We have one more question to do and that
> is No. 12. Oh; there was part of 13. At what point should a registry
> be terminated. I think, perhaps, Dr. Hager described quite well the
> CDC experience that if there is no difference, then why continue to
> have a registry and spend the money, et cetera.
>
> Unless others have additional comments on that.
>
> Okay. It states here that drug manufacturers conducting studies for
> female infertility currently obtain the following indications;
> induction of ovulation in pregnancy and multiple follicle development
> in ART. Please comment on the appropriateness of these indications
> given your discussions of endpoints and analyses.
>
> I would like some clarification on exactly what the question is. Are
> you asking us to comment on other potential studies or are these the
> only indications that should be sought?
>
> DR. SLAUGHTER: These are the current label indications that are either
> induction of ovulation or induction of ovulation and pregnancy or
> multiple follicular development and ART. Would you comment on whether
> or not you would modify, given all the discussions that you have had
> on the endpoints, et cetera.
>
> DR. GIUDICE: Dr. Emerson?
>
> DR. EMERSON: I\'m in favor of an indication that indicates it is
> pregnancy when that is the endpoint. So the only way that I could
> imagine that the multiple follicular development and ART indication
> should go forward is at the point that we did develop the technology
> for cryopreservation of oocytes. Well, then, that would become the
> endpoint in itself. But I would imagine that should happen when we
> also feel more comfortable that that is the ultimate goal.
>
> So I would want to add pregnancy on the follicular development and I
> would like to make it that it is induction of ovulation and pregnancy
> not just induction of ovulation.
>
> DR. GIUDICE: Dr. Stanford?
>
> DR. STANFORD: I would support that. It seems to me what we are
> basically saying is that some drugs have been approved for ovulation
> induction and pregnancy outside the IVF setting and then other drugs
> in the IVF setting have been approved, or sometimes the same drugs,
> simply for follicular development.
>
> It seems like make it the same standard. Make it pregnancy across the
> board is what we are saying, it seems to me. Now, I would also say,
> though, that if we talk about some potential exceptions to that, I am
> still\--if there is some kind of rare condition where there are not
> enough numbers to do that, I think that may be another discussion. But
> I think whenever you have got the potential\--I agree that the basic
> gold standard should be the same across the two types of therapy.
>
> DR. GIUDICE: Other discussion? There may be rare instances where
> individuals may have ovulation induction and even oocytes retrieval
> but then elect not to have embryos transferred for the purpose of
> establishing a pregnancy such as an ongoing malignancy.
>
> But, again, these are very, very rare. So I don\'t know how that would
> be handled. I guess one can certain prescribe medications off-label or
> at least not for these indications but the issue is really for the
> study. Yes; Dr. Emerson?
>
> DR. EMERSON: But in that instance, wouldn\'t they be doing this in
> order to have a later pregnancy? The indication why they were doing
> this for in the case of the cancer therapy was to protect the idea
> that they might later want a pregnancy.
>
> DR. GIUDICE: Yes; but for a pharmaceutical company, if the endpoint is
> pregnancy and your patient population is a cancer population, that may
> be a very long time before you end up with an outcome.
>
> DR. EMERSON: So I guess I am saying that I wouldn\'t imagine them
> running a clinical trial specific to cancer patients just prior to
> chemotherapy. But, once you are confronted with facing chemotherapy,
> it seems quite reasonable to pursue something that would preserve your
> childbearing potential and, if there was a drug that did that, we have
> got that indication.
>
> DR. GIUDICE: Other comments? Dr. Keefe?
>
> DR. KEEFE: If we added that to the indication, doesn\'t that sort of
> lock in pregnancy as the only outcome that would be permitted in terms
> of the acceptability of a new drug? It seems to me that we just had
> that discussion earlier and there was a little bit of debate about
> that. So I am just a little bit concerned that that goes into the
> indication.
>
> We have a chemotherapy drug and we are saying that life is the
> outcome. You might be able to cure a cancer, but these are in
> 90-year-old patients. It seems that multiple follicular\--it is very
> clearly connected to the outcome. I am sort of voting for flexibility
> in that and I am just afraid that we may lose flexibility if we put it
> into the indication.
>
> DR. SHAMES: Some companies could elect to have pregnancy the outcome
> and some people could elect to have follicular development. I mean\--
>
> DR. RICE: But if you were a company, which one would you select?
>
> DR. SHAMES: Depending on how the trial is run, you need to match the
> trial to the indication. To use your oncology analogy, we don\'t
> expect everybody to get pregnant. It is a proportion of people that
> get pregnant. Generally, we try to match the indication to the
> clinical trial and what is important. If pregnancy is important, that
> would be the endpoint in a particular trial and that would be the
> indication they got.
>
> It is possible, under certain circumstances, for some unusual
> circumstances, that there would be others and that would be the
> indication that they would get.
>
> DR. GIUDICE: Dr. Toner and then Dr. Slaughter.
>
> DR. SLAUGHTER: I guess the only comment I would have is that, as we
> talked about, should the science advance to the point that we have a
> surrogate that we really do think is a predictor. It is possible to
> modify the guidance document at that time.
>
> DR. GIUDICE: Thank you. Dr. Toner, you had a comment?
>
> DR. TONER: I was wondering whether sort of a hybrid indication such as
> follicle development for pregnancy might better capture what the
> gonadotropin part of this process is about. And to say pregnancy would
> apply for any of the components in the whole process that would
> pertain to the progesterone we are using or the hCG we are using. Why
> are we using it? For pregnancy. So maybe we want to be a little more
> specific than pregnancy undefined.
>
> DR. GIUDICE: Dr. Rice?
>
> DR. RICE: I guess I am confused. Didn\'t we discuss this already? I
> mean, what did we vote on? I guess I am confused about why we are
> backtracking here back down this because I thought that the
> whole\--when everybody was polled, we were saying fetal cardiac
> activity, et cetera.
>
> DR. KEEFE: Since I am the one who brought it up, let me explain why.
>
> DR. RICE: Okay.
>
> DR. KEEFE: I think once you put it in\--it is a different level. It is
> a different burden. It is one thing to recommend that it be used as
> the outcome. It is another to put it as an indication. To me, it is
> another level of\--another burden that you are incurring. That is why
> I brought it up. Not so much that we hadn\'t discussed it. think we
> did almost ad nauseam. But the question is do you want to kick it up
> to this next level where it actually enters the indication.
>
> I agree with Jim. If you say \"for\" pregnancy instead of \"and\"
> pregnancy, that one word makes it so that you have the wiggle room
> that you need to keep it an open shop and, at the same time,
> reasonable. That\'s all.
>
> DR. RICE: I think you are leaving a lot of flexibility because if I
> was a pharmaceutical company and I had the option, I would go for just
> the follicular development and \"for pregnancy\" sounds like my
> secondary endpoint which I am already looking at.
>
> So I guess I don\'t distinguish between the two. I mean, either you
> are going to look at pregnancy as your outcome by some measure or you
> are going to continue to look at follicular development. If we are
> going to continue to look at follicular development, are we really
> going to be ever distinguish between Product A versus Product B versus
> anything else that comes on the market if they only have to look at
> follicular development, because we have pretty much shown that, when
> you look at the different products, there is not a great deal of
> difference in follicular development.
>
> You would have to decide, are we going to raise the level of rigor
> here or are we not.
>
> DR. GIUDICE: Dr. Stanford?
>
> DR. STANFORD: It just seems to me the main indication\--and if the FDA
> staff disagree with that, I would like to know, but it seems to me
> they are the same.
>
> DR. GIUDICE: Dr. Shames?
>
> DR. SHAMES: The primary endpoint is the indication. So if we decide
> that pregnancy is the primary important endpoint, then it should be
> the indication.
>
> DR. GIUDICE: Dr. Layman?
>
> DR. LAYMAN: I just have a point for clarification. We said we agreed
> that fetal heart beat was the indictor for pregnancy. But, in that
> Question 8 that says, if we are not taking live birth or ongoing
> pregnancy rate, is the way that question reads. Did we mean\--I\'m not
> clear whether we meant we want to say for pregnancy all of them or
> just in that question, I mean, because it is not clear.
>
> I didn\'t get the feeling we agreed on what was the best pregnancy to
> consider. It just says, if you can\'t have enough power for live birth
> rate or ongoing, which one. And we said heart beat.
>
> DR. GIUDICE: Right. That was what we had discussed. Now, there seems
> to be some ambiguity, though.
>
> DR. SLAUGHTER: I don\'t believe so. The question was worded is live
> birth or ongoing pregnancy to suggest something further along than
> gestational sac with a heart beat. So I think we clearly understand
> that that is what we are talking about now, that we want gestational
> sac with heart beat.
>
> DR. GIUDICE: Right.
>
> DR. LAYMAN: Right. I agree, but does that mean for every study that is
> what we are requiring? We are not requiring live birth or farther on.
> That is what I am asking. Did we agree to that?
>
> DR. GIUDICE: We agreed to that. Dr. Lewis?
>
> DR. LEWIS: I thought the only exception was for Type 1 anovulation
> where we agreed it would be very difficult to power a study to look
> at\--okay.
>
> DR. GIUDICE: Right. Dr. Stanford, you had a comment?
>
> DR. STANFORD: Sort of the next question; it is sort of like there is
> an 8A question that is, if the study cannot be powered for presence of
> fetal heartbeat, and that might be the Type 1, then what is an
> acceptable outcome in that case. It sounds like that is the question
> you are putting on the table.
>
> DR. LEWIS: I wasn\'t really putting it on the table because I thought
> we had already discussed it. I thought we had already agreed that it
> would\--ovulation. I\'m sorry; follicular development.
>
> DR. STANFORD: So, I guess, then the issue is under what\--if we all
> agree that fetal heart beat is a reasonable standard in general, then,
> under what conditions do you accept something else as a main outcome,
> something less than that as a main outcome, then, as an indication. We
> are saying that Type 1, WHO Category Type 1, anovulation would be one.
>
> DR. GIUDICE: Right. Are we all clear on that? Any further discussion?
> It is amazing we got through all those questions. I would like to
> thank everyone for their participation today. Tomorrow\'s session
> begins at 8:30 in the morning and the discussion will be NDA 21322 on
> Luveris. For members of the committee, please bring your green FDA
> binding document and your gray Serono briefing documents.
>
> \[Whereupon, at 4:39 p.m., the meeting was recessed to be resumed at
> 8:30 a.m., Tuesday, September 30.\]
>
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