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Improving the efficacy, safety, cost-effectiveness and acceptability of gonadotropin administration prior to in vitro fertilization
presented by William Keye, MD
 
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Thank you, Dr Hatoum. I am the third and final speaker in this morning’s program. I am currently Director of Obstetrics Reproductive Endocrinology and Infertility at William Beaumont Hospital in Royal Oak, Michigan, with a Clinical Appointment with the Department of Obgyn at the University of Michigan in Ann Arbor. Prior to coming to Beaumont Hospital, I was on the faculty at the University of Utah for eleven years, past President of the American Society for Reproductive Medicine and, during the last six years, I have been actively engaged in designing and conducting clinical trials looking at the efficacy and safety of various gonadotropin preparations.

What I would like to do is discuss with you this morning in the hopes that you can use these gonadotropin preparations in the most efficacious and safe way. A series of studies we have conducted over the last eight years comparing and contrasting a variety of different protocols so that you can make the best clinical choices on your own. 

I would like to begin by talking a little bit about the sort of factors that are important to both clinicians and to patients in selecting their protocol for either controlled ovarian hyper-stimulation prior to IUI or, more specifically in this series of studies, prior to in vitro fertilization.

In evaluating protocols using a variety of gonadotropins, as clinicians, we usually look at these variables. We ask how effective is the protocol or the drug, how affordable, how simple is it to use, how safe is it to use, how predictable from cycle to cycle and how will different patients of differing backgrounds respond to the medication?

Let’s look at effectiveness, for example. If one looks at it from the standpoint and perspective of the clinician, one tends to look at follicular growth, estradiol production and, to some extent, oocyte maturity. The embryologist looks at oocyte maturity, fertilization rate, cleavage rate and implantation rate. Both the embryologist and the clinician fully look at and evaluate a protocol on the basis of continuing pregnancy rates, it is the patient who looks at the live birth rate. So each of us has his own perspective and in choosing the protocol, these are the issues we usually consider.

In terms of cost-effectiveness of a specific protocol or medication, there are a number of considerations that will be used. For example, in constructing cost-effective analyses in comparing two different drugs, one may look at only the cost of the drugs, one may look at the cost of just the gonadotropins, one may look at all the medical costs in the IVF cycle or one may look at all the medical costs of not only the IVF cycle, but also the care of the children and of the pregnancy itself. The denominator one may use when the cycle starts, one may use completed cycles, pregnancies, live births. The selection of the specific items in the construction of the cost-effective analysis really depends on the perspective of the individual doing the cost-effectiveness analysis. If you are a patient doing a sort of crude cost-effectiveness analysis, in her mind, it will depend on and be influenced by whether or not she has some insurance coverage for her drugs because she is only interested in the out-of-pocket expenses. So she will construct in her simplistic way, a cost-effectiveness analysis based on how much out-of-pocket expenses. On the other hand, if one is a health care insurer and you are paying for the IVF cycle, then you are going to be considering different costs that will be well beyond those of just the drugs, and if you are a country that provides a national health insurance and coverage, one wants to consider perhaps the cost of the on-going care of children born after IVF given the use of a given protocol or different medication. So the term perspective is important and really does dictate exactly how one looks at the affordability of the given protocol.

Patients tend to look at the simplicity of a variety of protocols. My nurses look at the simplicity of various protocols because those are the ones who have to answer the questions of the patients if a protocol or medication is not simple to use. Patients look in terms of the number of injections of medication every day, the number of doses or days that they will be taking the medication and also the route of administration.

In terms of safety, it is we the physicians who generally are most concerned with the possibility of hyper-stimulation syndrome. The patients are concerned with the amount of pelvic discomfort that she may have during the course of the cycle and then any local injection-type reactions that may occur.

In terms of predictability, it is nice to have enough experience as a clinician with a given protocol that one has a bit of history with the drug or protocol and knows how predictable it will be from cycle to cycle and from woman to woman.

If one looks at the medical literature to try and predict the outcome of a particular drug protocol or a particular medication, one finds that almost all of the studies published use good candidates. They are usually young, they don’t have complicating factors, such as other endocrine pathologies, they have regular menstrual cycles. So it is somewhat difficult to take the medical literature and to predict exactly how well a protocol or drug is going to work in your patient population because your patient population, like mine, is more heterogenous than the patient population studied in most of the investigative reports that make it into the literature. So one wants in their own clinical experience to see if the given protocol will work equally well and be safe and cost-effective in a group of patients with irregular menstrual cycle and polycystic ovary syndrome, and they would in a group of women who are good candidates for success with regular menstrual cycles. The other group we are concerned with are those who are typically poor responders, perhaps with limited ovarian reserve or advanced age. So independent validation of the protocols into those groups is important and usually done in the clinic by each one of us in our practices.

How do we as clinicians generally make our decisions about the use of specific protocols? Well, we do it on the basis of three things. One is the published scientific studies we can read from the literature. Except for the reasons I just pointed out, those are somewhat limited because they usually only study a very small homogenous group of patients. We take the opinions of experts as we make decisions in the clinic and we also then use our own clinical experience. Because the types of patients we see in our own practices are going to vary and be different from the types of patients seen in another practice, we have to take our clinical experience into account. Since 1998, Ferring has funded a series of studies designed to aid the physician in trying to understand how best to use the medications that are currently available on the market. Remember only we as physicians can prescribe infertility treatments and protocols and Ferring nor I are really advocating a specific gonadotropin preparation or specific regimen today, that really is for you as clinicians to decide.

At the beginning of this series of studies, in the late 1980s, following the introduction of highly purified forms of FSH and recombinant FSH which provided patients for the first time, the opportunity to administer gonadotropins subcutaneously, which gave them a great deal more freedom than the use of intra-muscular injections because they could self-inject the medication and therefore were not dependent upon finding someone else to administer the medication.

There has been a typical reluctance over the years to administer hMG as a subcutaneous dose for historic reasons: fear of local reactions, allergic reactions and the lack of FDA approval. This is why we designed a series of studies to address the issues of the efficacy and safety of subcutaneous administration of hMG.

Again, the subjects in this study are much like those you will see in most of the studies in the literature. They were good candidates for success in IVF. They had regular ovulatory menstrual cycles, they were below the age of 40, they were not obese, they had normal day 3 FSH and estradiol levels, and normal ovarian reserve, so it was unlikely that they had decreased ovarian reserve or polycystic ovary syndrome on the basis of these selection criteria.

The protocol we used to test the safety and efficacy of subcutaneous administration of hMG did not include a cycle of oral contraceptives prior to the stimulation cycle. It did use a reasonably high dose of leuprolide acetate beginning with 1mg in the late luteal phase of the previous menstrual cycle and given daily until hCG. hMG was administered 225 international units either IM or subcutaneously for five days and then the dose was varied, depending upon the clinical response of the individual. Patients entering this study were randomized and they were entered and the study was double-blinded in terms of, it was not double-blinded, it was randomized. hMG was administered when there were at least three follicles equal to or greater than 16 mm in diameter and progesterone was administered at 50 mg a day IM, beginning on the day of oocyte retrieval.

If you look at the data on this slide, you will see that, in terms of the mean days, the gonadotropin therapy, the total dose, the mean number of vials, cycles undergoing oocyte retrieval and the number of cycles in which there was embryo transfer, there was no significant difference in any of those parameters between subcutaneous and intramuscular administration of hMG.

One looks at the number of oocytes retrieved and while this bar is somewhat difficult to see, you can at least see the numbers. On average, about 14 oocytes retrieved in both of the groups. In terms of the number fertilized, again, about 8 to 8.5. The number of embryos transferred was 3. The state of the study that was initiated in 1998, six years ago.

If one looks at pregnancy rates, beginning with chemical pregnancy rates, clinical pregnancy rates would be the presence of a sac and cardiac activity, and for live birth rate one finds a trend but a non-statistical difference between the subcutaneous group on the one hand and the intramuscular group on the other hand, with a trend toward a higher success rate using the subcutaneous administration of hMG.

So, in summary, this first study demonstrated that subcutaneous administration was just as effective as the intramuscular administration of hMG using any of these end points.

It wasn’t long after the initial study that physicians more and more began to use what we call mixed protocols; that is, the administration of FSH and the administration of hMG to the same patients during the same protocol. The rationale for the mixed protocol was the fear that in those patients who were down-regulated, there might not be adequate amounts of LH to stimulate good follicular development and oocyte production. On the other hand, there may be too much LH for some patients and that might be counter-productive. So physicians began to experiment with these mixed protocols in which they would give some purified FSH and some hMG in amounts that they generally decided upon simply on their own experience.

The problem is that that then meant that patients were often getting two injections a day, one of the purified FSH and one of the hMG, and that was an inconvenience for the patient because they now had to have two injections of gonadotropins rather than one a day, so we did a study looking at the mixing of the human purified FSH and hMG into the same syringe to see if there would be any alterations in the bioactivity of the FSH or the LH activity when mixed together.

We used a series of solutions, a standard bioassay which I will describe in just a minute, and then compared the results to known standards.

We used the Steelman Pohley assay that Dr. Chappel talked about earlier today, using female rats and looking at the ovarian response.

We used as an LH bioassay male rats and looked at the increased growth of the seminal vesicles.

What I would like you to do is concentrate on just these two columns which demonstrate the fact that there was no loss of bioactivity when these two preparations were mixed in the same syringe and administered together. Here is the theoretical bioactivity for FSH and here is the actual bioactivity; this is showing LH activity and the actual bioactivity of LH. 

So one can safely mix these two products together in a single syringe without altering the bioactivity. It is important to remember, however, that these drug products were obtained from the same manufacturer, used in the same diluent and there were really no results available drawing the same conclusions if one takes an FSH product and an hMG product from different manufacturers and mixes them together in the same syringe.

As I mentioned before, the mixed protocols became increasingly popular and they grew in popularity despite the relative paucity of any data in the scientific literature to demonstrate which approach or which mixed protocol would be the most efficacious and safest.

We again designed a study that looked at three different types of mixed protocols to see if there were any inherent benefits of one versus another in, again, reasonably young, good candidates. After surveying clinicians in the field, decided there are really three patterns of mixed protocol use around the United States. One was those clinicians who felt it was important to have some LH activity early in the follicular phase and therefore they would use hMG early and generally if there was a need to increase medication or increase the FSH component as opposed to hMG. There were those who felt the patient should receive largely FSH in the beginning of the follicular phase, and later during stimulation the addition of hMG. Another thought there should only be a very low dose of hMG and that was kept constant throughout the stimulation cycle.

So we looked at three different protocols that emphasized either early exposure to LH activity, late exposure to LH activity or low, constant exposure to LH activity and this group of subjects, again, matched those I described before: reasonably young, good candidates without evidence of polycystic syndrome or reduced ovarian reserve.

This is the first group that had the administration of hMG early in the stimulation phase. That is the early LH activity group. This is the group that had no LH activity in the form of hMG in the early part of the stimulation protocol and hMG was added only after they fixed. In this group, there was a constant low dose presence of hMG.

We looked at a randomized group of individuals for these three protocols and looked to see what differences in efficacy or safety there would be. We looked at the duration of treatment. You see it was the same at about 9.5 days of gonadotropin therapy prior to hCG administration. We looked at the total dose of FSH and we see there was no significant difference. We looked at the number of vials; no significant difference. The percentage of patients who met criteria of hCG also was similar and over 90% for all three of those protocols. So, from a clinician’s standpoint, it appeared as though all three approaches for the use of mixed protocols were equally effective.

We looked at the mean number of oocytes retrieved and here you will see a few more in the group that received hMG early but, again, no significant difference among these three groups.

Now if we look at any of chemical, clinical, continuing or live birth rates as a reflection of pregnancy rates, here you see again no significant difference but a good pregnancy rate in all three of these, with again no significant differences among them.

Therefore, it appears that a variety of mixed protocols can be used with relatively equal efficacy. Now, those patients had the administration of leuprolide acetate, a long protocol in which indigenous gonadotropins were suppressed, but more and more physicians were beginning to switch to units of GnRH antagonists as opposed to GnRH agonists.

So again we did a study looking at the effectiveness of a mixed protocol when used with a GnRH antagonist. The question we designed the study to answer was in women who are receiving GnRH antagonists, is a mixed protocol of human FSH and hMG more effective than a protocol simply using recombinant FSH alone?

These subjects, like the subjects in the other study, also were good candidates for success without evidence of decreased ovarian reserve or polycystic ovary syndrome.

The protocol included in this case a month of oral contraceptives, the administration of either recombinant FSH, 225 IU per day or a mixed protocol which had a total of 225 units with FSH activity with hCG administration and at least two follicles which were 16 mm or greater and, again, progesterone administered 50 mg a day intramuscularly beginning on the day of oocytes retrieval. 

If you look at the days of stimulation, there is no difference between the two groups. The total mean dose of FSH in terms of IUs was slightly less than the group receiving the mixed protocol, the number of vials was fewer, the number of oocytes retrieved were identical.

If you look at the estradiol levels, here you see on the first day of administration of the GnRH antagonists for the group receiving recombinant FSH, there was a little bit of a plateauing of the E2 level which gradually then began to rise more rapidly by the second day. There was no increase in the estradiol level following the administration of GnRH antagonists in the group receiving hMG, as well as FSH, an observation made by other people, as well.

We looked at the chemical pregnancy rate. Here is the group receiving the combination of FSH and hMG, plus the GnRH antagonist, with a pregnancy rate of slightly higher but not statistically different from the group receiving the recombinant FSH alone.

So, it appears on the basis of the studies that I just reviewed, we can draw several conclusions. One is that subcutaneously administered hMG is as effective as intramuscularly administered hMG. hMG can be mixed in a single syringe with human FSH and administered as a single injection with no impact or effect on bioactivity. There are several mixed protocols of hMG and FSH that are effective for control of ovarian hyper-stimulation in IVF cycles. In the presence of a GnRH antagonist, the mixed protocol of hMG and human FSH and a protocol using recombinant FSH alone were equally effective. Again, the disclaimer I want to leave you with is we are not advocating one particular drug or protocol today simply providing information that will make it easier to each one of you to use these medications in the most efficacious, the safest, the most acceptable and most cost-effective fashion.