1 Organon Laboratories Ltd, Science Park, Milton Road, Cambridge CB4 0FL, UK, and 2 NV Organon, Oss, The Netherlands
The debate on the clinical benefits of recombinant gonadotrophins (Meniru, 1999) addressed various aspects of recombinant follicle stimulating hormone (FSH) in general, and follitrophin ß (Puregon®; NV Organon, Oss, The Netherlands) in particular, and has prompted us to participate in this discussion. Although, as manufacturers of this preparation, we do not wish to interfere in a scientific debate amongst clinicians on the value of this compound, we feel the need to put a number of the issues raised by Meniru in the right context. Balen et al. (1999) and Bergh (1999) have already addressed many of these issues in reaction to the leading article (Balen et al., 1999
; Bergh, 1999
). We would like to add the following remarks.
Firstly, in order to gain a marketing licence of a new drug, regulatory authorities require extensive clinical trials to be carried out to demonstrate clinical efficacy and safety. For that reason, Puregon has been tested in the largest trial programme ever done for the evaluation of a new fertility drug. The comparison was made with the only urinary FSH preparation available at that time (Metrodin ; Ares-Serono, Aubonne, Switzerland). In these studies, patients underwent an experimental treatment for which Ethics Committee approvals were obtained. We feel it is an ethical obligation to publish the results of these human experiments. The publications of the results were not `ebullient' reports, as Meniru states, but merely a reflection of what has been performed and found. The fact that these studies were set up, co-ordinated, analysed and reported by ourselves, does not mean the results are not reliable, as Meniru suggests. The trials were performed according to the strictest `good clinical practice' guidelines applicable at that moment ensuring optimal validity and transparency of the data, and protection for the patients (CPMP Working Party on Efficacy of Medicinal Products, 1990). These data are open for inspection by regulatory authorities and in fact audits were done by the Food and Drug Administration (FDA).
Secondly, an important issue raised by Meniru is the difference between findings in randomized clinical trials and in daily life clinical practice. Randomized controlled trials (RCT) are the only way to prove whether an intervention works (Mant, 1999). In our view, results of a (small) series of patients treated outside an experimental control, but representing a particular clinical reality (as for example, done by Jacob et al., 1998
), should not be used to validate the conclusions derived from properly designed controlled trials. Previously, a paper was published by Vandekerckhove et al. (1993), entitled: `Infertility treatment: from cookery to science'. This overview of controlled randomized trials in the infertility field indicated that trials using randomized methodology (including studies comparing effectiveness of gonadotrophins) were relatively few in comparison with other branches of medicine. In addition, most studies suffered from unrealistically small sample sizes, inappropriate use of cross-over design or pseudo-randomization (Vandekerckhove et al., 1993
). Apparently, there is a need for properly designed studies in the area of infertility, as we implemented in the assessment of the efficacy and safety of recombinant FSH. All of these randomized studies have been included in the Cochrane controlled trial register.
Thirdly, the quote by Meniru: `Another unsettling issue, especially for rFSH neophytes like me, has been the suggestion that the potency of Puregon is such that the 50 IU ampoule should be regarded as being equipotent to the 75 IU ampoule of the uroG (Out et al., 1995)' is wrong. We have never made such suggestions in peer-reviewed publications. In individual contacts with infertility specialists, we did make similar practical recommendations, merely because clinicians were asking us how to dose with Puregon in the absence of 75 IU ampoules. The reason to abandon the 75 IU presentation was, in our view, valid and was related to the observed higher potency of the recombinant preparation, our fear of overdosing and was relevant in view of the medical obligation to always use the lowest possible dose of a drug to obtain a wanted effect.
Fourthly, the price of Puregon is a reflection of >10 years of research and development , increased file requirements from authorities, the quality of the product and a limited patent life, during which time the extensive investments (>$200 million dollars) have to be recouped. This price is not `punitive' and inhumane as Meniru says, but the mere result of an economical calculation needed to guarantee our long-term survival in a highly competitive market. However, we do understand that the price may be a limiting factor to its use. For that reason, we have set up clinical trials to investigate the possibility of achieving at least comparable results with lower dosages (Devroey et al., 1998; Nyboe Andersen et al., 1998
; Out et al. 1999
; H.J.Out, D.D.M.Braat, B.M.E.Lintsen et al., unpublished). Three of these studies were randomized including two double-blind trials, which is unique in gonadotrophin clinical research. These studies show that many patients could benefit from starting doses as low as 100 IU of recombinant FSH. Bergh (1999) described a 46% ongoing pregnancy rate per started cycle using only 1217 IU of Puregon in 26 women using a 100 IU fixed-dose protocol! Many in-vitro fertilization (IVF) centres now routinely and successfully start with 100 IU of recombinant FSH in patients with prognostically favourable markers.
There is no doubt about the fact that at Organon world-wide we are enthusiastic and proud about our recombinant FSH preparation which is shared by many others. McDonough in a comment in Fertility and Sterility refers to the recent availability of recombinant products as the `coming of wonders' (1997). Our enthusiasm should not be interpreted as marketing of a `super drug', as Meniru feels. Recombinant FSH is an improvement in the treatment of infertility and hopefully we will be able to develop further new (recombinant) medicines that will increase the convenience of the treatment and the chances for success. A close collaboration between industry and clinicians is mandatory to achieve these goals. We hope the above-mentioned considerations will contribute to a better understanding of our role in developing new medicines, which we consider to be a `scientific business'.
Notes
1 To whom correspondence should be addressed
This debate was previously published on Webtrack 73, June 21, 1999
References
Balen, A.H., Hayden, C.J. and Rutherford, A.J. (1999) What are the benefits of recombinant gonadotrophins? Clinical efficacy of recombinant gonadotrophins. Hum. Reprod., 14, 14111417.
Bergh, C. (1999) What are the benefits of recombinant gonadotrophins? Recombinant follicle stimulating hormone. Hum. Reprod., 14, 14181419.
CPMP Working party on efficacy of medicinal products (1990) Good Clinical Practice for trials on medicinal products in the European Community. Pharmacol. Toxicol., 67, 361372.[Medline]
Devroey, P., Tournaye, H., Van Steirteghem, A. et al. (1998) The use of a 100 IU starting dose of recombinant FSH (Puregon ) in in-vitro fertilization. Hum. Reprod., 13, 565566.
Jacob, S., Drudy, L., Conroy, R. and Harrison, R.F. (1998) Outcome from consecutive in vitro fertilization/intracytoplasmic sperm injection attempts in the final group treated with urinary gonadotrophins and the first group treated with recombinant follicle stimulating hormone. Hum. Reprod., 13, 17831787.[Abstract]
Mant, D. (1999) Can randomised trials inform clinical decisions about individual patients? Lancet, 353, 743746.[ISI][Medline]
McDonough, P. (1997) The coming of wonders. [Comment]. Fertil. Steril., 67, 411413.[Medline]
Meniru, G.I. (1999) What are the benefits of recombinant gonadotrophins? Is Puregon a `good' or `super' drug? Hum. Reprod., 14, 14091411.
Nyboe Andersen, A., Loft, A., Leerentveld, R. et al. (1998) A prospective trial comparing Puregon 150 IU and Metrodin-HP 225 IU as a fixed-dose regimen in IVF treatment. Hum. Reprod., 13 (Abstr. Book 1), 185.
Out, H.J., Mannaerts, B.M.J.L., Driessen, S.G.A.J. and Coelingh Bennink, H.J.T. (1995) A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle-stimulating hormone (Puregon vs Metrodin) in in-vitro fertilization. Hum. Reprod., 10, 25342540.[Abstract]
Out, H.J., Lindenberg, S., Mikkelsen, A.L. et al. (1999) A prospective, randomised, double-blind clinical trial to study the efficacy and efficiency of a fixed dose of recombinant follicle stimulating hormone (Puregon ) in women undergoing controlled ovarian hyperstimulation. Hum. Reprod., 14, 622627.
Vandekerckhove, P., O'Donovan, P.A., Lilford, R.J. and Harada, T.W. (1993) Infertility treatment: from cookery to science. The epidemiology of randomised controlled trials. Br. J. Obstet. Gynaecol., 100, 10051036.[ISI][Medline]