A Comparison of Urinary and Recombinant Gonadotropins: An Audit of 8 Years of Clinical Practice

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Hans van der Slikke, MD, PhD: “It’s July of 2002, we’re at ESHRE in Vienna, and next to me is Dr. Sharma. Dr. Sharma, welcome, you’re a consultant obstetrician in Leeds and you presented a huge amount of research concerning urinary versus recombinant FSH in stimulation. You did a retrospective analysis, now why did you do this because there already were some meta-analyses that were available?”

Vinay Sharma, MD: “First of all, at the time of setting up the retrospective analysis not all of the information that we have currently was available; we did have some meta-analyses available and there was some discordance with information that we had. The problem with prospective randomized studies have always been that multi-center, multi-country, large projects with an endpoint to show a difference in the live birth rate per cycle using different forms of treatment would have in fact involved recruiting something like 2,100 couples. It would have been an extremely large study and such a study has not been done. These studies that are available are powered to look at other endpoints, which are not directly correlated with live birth outcome although there would be some influence of them on the live birth rate outcome. So we looked at our data primarily because this is an observational work, it wasn’t set up as a research trial. We realized that it might be useful information because our protocol hasn’t changed. We have been consistent in what we’ve been doing and the only factor that had influenced which gonadotrophin was prescribed to the patients was patient’s choice and which was then based upon cost and route of administration and efficacy, of course. So the information that we had about all three of these issues was passed on to the patients and when choices became available - urinary preparations or the recombinant preparations - these choices were passed on to the patients and they made the choice of which preparation they wanted.”

Hans van der Slikke, MD, PhD: “So from what time period did you collect your data?”

Vinay Sharma, MD: “The data has been collected on the day that we presented at the conference, with convective cycles performed between April 1, 1992 to March 31, 2000. All cycles conducted in that period were included.”

Hans van der Slikke, MD, PhD: “So there were no missing cycles at all, it’s all included.”

Vinay Sharma, MD: “It’s all convective cycles, it’s an outcome of clinical practice. This was a service delivery program and we looked retrospectively because we had the data and we had this variable.”

Hans van der Slikke, MD, PhD: “How many cycles are you talking about?”

Vinay Sharma, MD: “We’re talking about 2,288 IVF cycles and equally 750 plus ICSI cycles and about 954 frozen embryo transfer cycles.”

Hans van der Slikke, MD, PhD: “You had several arms, retrospectively?”

Vinay Sharma, MD: “Retrospectively, we divided the groups into urinary HMG, urinary FSH, and recombinant FSH groups.”

Hans van der Slikke, MD, PhD: “Is there a trend in the time period between the two?”

Vinay Sharma, MD: “A time trend in terms of usage of preparations?”

Hans van der Slikke, MD, PhD: “Yes.”

Vinay Sharma, MD: “With the use of preparations there would be a time trend because in the earlier years, 1992-1993 recombinant preparations weren’t available and purer forms of urinary FSH also became available in 1994-1995 so the trend would be based on availability of drugs. In the UK we’ve also had other marketing and other forces with new developments dictating what we had available for use so we would have trends in that respect but in terms of overall success rate of the program there has been no change between April of 1992 and March of 2002.”

Hans van der Slikke, MD, PhD: “That may be even surprising.”

Vinay Sharma, MD: “The live birth rate per cycle has been static, there’s been no difference annually and at the conference I presented data on our program which showed there was statistically no significant difference between any of our years. We did not fluctuate in terms of effectiveness so that, again, we thought made our data a little bit unique. Even though it is not a prospective randomized it was billed a control trial it was a clinical observation of a program with convective cycles and it’s a record of outcome of clinical practice.”

Hans van der Slikke, MD, PhD: “You had more than 2,000 cycles and you divided them between ICSI and IVF. How were the results comparing the urinary FSH to the recombinant FSH in those groups?”

Vinay Sharma, MD: “Urinary HMG and urinary FSH consistently performed better than recombinant FSH in our clinical practice. Our protocols were not any different for any of the three preparations, and the clinical protocols in terms of GnRH analogues used or the methods by which we decided when to give HCG were no different. They have not changed in the last ten years; we use long protocol for all patients. In our analysis we control for age, etiology, number of eggs collected, the total amount of gonadotrophin used, the number of days of stimulation required to meet our criteria for HCG, number of eggs that were viable, number that fertilized, cleaved, proportioned that fertilized, the number of embryos we put back, the type of solution support we gave, and the type of GnRH analogue we used to down-regulate the patients before we started. So all of that was controlled for in both IVF cycles and in ICSI cycles.”

Hans van der Slikke, MD, PhD: “Then the result of the urinary preparations was better for the continuing pregnancies.”

Vinay Sharma, MD: “In our analysis in fresh IVF cycles looking at first attempts alone the 2,288 cycles that I mentioned were all first attempts in fresh IVF cycles. We did have 2.2 or twice as great of chance of getting a live birth with urinary HMG and 1.8 times good a chance of getting a live birth with the urinary FSH as compared to the recombinant preparations in our program.”

Hans van der Slikke, MD, PhD: “You said you did this calculation not only on outcome but also took into account the financial aspects of it.”

Vinay Sharma, MD: “The financial aspects were what dictated what I think was one of the biggest messages perhaps from our work and that was the patients in the United Kingdom and in the area that I practice already cost ???? and the NHS service delivery is limited and it is more restrictive in terms of cost that you can undertake for treatment. On top of that, the vast majority of the patients, about 75% of our patients in my practice, have to pay for their own treatment, which is unlike the rest of the National Health Service where everything else is available. As a result, the patients would want to know whether the cheaper preparations would deliver the same effective outcome as compared to the more expensive preparations.”

Hans van der Slikke, MD, PhD: “After your presentation you were asked the same question about the purity, can you comment on that?”

Vinay Sharma, MD: “I think the questions about purity are not for me to really comment on. To be honest, I think it is something that perhaps in terms of purity the manufacturers should have a position on how pure the preparations are in proportion to each other.”

Hans van der Slikke, MD, PhD: “I agree with you but as a doctor you have some responsibility about the things you tell your patients about this.”

Vinay Sharma, MD: “At the conference I did mention the safety record that at least from what we know from the urinary preparations being around forty plus years there aren’t any recorded cases of complications with urinary preparations which perhaps in terms of the microanalysis that we do less bill than recombinant preparations.”

Hans van der Slikke, MD, PhD: “Do I understand that you’re saying that in theory there might be a difference but in practice we never actually see it.”

Vinay Sharma, MD: “The concern that is theoretically raised on these grounds is a justifiable concern to raise for the medical profession. It would be irresponsible not to be concerned about these things because safety is an important issue and evidence of safety comes with time, and all we can do at this time is observe and look at the record and look at the safety profile information that we have. On that basis we can advise our patients, and when we don’t know we should also tell the patients that we don’t know.”

Hans van der Slikke, MD, PhD: “How did the result of your study influence your policy in your clinic?”

Vinay Sharma, MD: “It hasn’t influenced in any way because we still use recombinant preparations, we still give patients the choice because the route of administration is also an important issue for the patients, and patient acceptability in that regard is important. We haven’t been directional with our patients, and we still tell our patients although our analysis in our hands suggest that we get a better pregnancy rate with HMG we have not used that to influence patients decisions. We still tell them that the information is being gathered and the question is under investigation. While we wait for more prospective adequately powered randomized trials to conclusively answer this question the inference that we can draw from the current literature is the two preparations are at least equally effective and, therefore, you can choose on the basis of how you administer the drugs and what cost there will be to you.”

Hans van der Slikke, MD, PhD: “Thank you very much.”

Vinay Sharma, MD: “Thank you.”