Joan-Carles Arce, MD, PhD, Chief Scientific Officer, Ferring US, Parsippany, USA.
Bjarke Mirner Klein, PhD, Director, Biometrics, Ferring Pharmaceuticals, Copenhagen, Denmark.
We thank the Global Medical Affairs executives at Merck (EMD Serono) for their interest in our trial. We strongly refute the claim that the trial does not provide evidence of non-inferiority with respect to the co-primary endpoints. As it is well-known to those involved in the development of new medicines, there are rigorous and highly regulated processes in place. The trial protocol was specifically designed and powered to demonstrate non-inferiority for ongoing pregnancy and implantation in discussion with regulatory authorities. The protocol was reviewed and approved by health authorities in 11 countries and independent ethics committees covering 37 clinics. Finally, the trial conduct and results have subsequently been inspected and assessed by the European Medicines Agency, leading to the approval of follitropin delta (REKOVELLE®) based on established non-inferiority. Ferring continues to incorporate innovative concepts and emerging technologies in clinical development programs with the purpose of providing recommendations in the product labellings of new gonadotropins on how to improve patient safety without compromising efficacy. We are grateful to the many investigators and health care professionals who collaborate with us in this scientific endeavor.
The Merck executives state that the starting dose of 150 IU follitropin alfa (GONAL-F) used in our trial is “inappropriate”. While the European Summary of Product Characteristics (SmPC) for GONAL-F mentions a starting dose range of 150-225 IU, there are other regions where Merck recommends 150 IU as the only starting dose in non-suppressed cycles, such as in the United States (1, 2, 3) and also Canada (4) where trial participants were included. We are therefore surprised given their own prescribing documentation that the Merck executives suggest that 150 IU is “inappropriate”. Further, one can hypothesize that higher starting doses of follitropin alfa up to 225 IU would have led to even greater differences in safety profile between the two treatment groups in a high-risk population, where the incidence of early moderate/severe OHSS and/or preventive interventions for early OHSS was 7.7% with follitropin delta and 26.7% with follitropin alfa at a starting dose of 150 IU (5).
We agree with the Merck executives that it is of benefit to use clinical markers (body weight) and biomarkers (AMH) for determination of the starting dose. The clinical development program for follitropin delta (REKOVELLE®) has prospectively incorporated these parameters as part of the evidence base gathered during phase 2, leading to the establishment of an individualized dosing regimen with documented efficacy and safety during phase 3. It is suggested that follitropin alfa should have also been dosed by AMH and body weight, but this is clearly not a viable option given the above prescribing information for follitropin alfa. The suggestion to have used both gonadotropins at a fixed starting dose is contradictory to the clinical objective of follitropin delta (REKOVELLE®) which is individualized dosing, and the view point that new innovative treatment modalities should be forced into the old/current way of thinking is certainly counterproductive for any new scientific developments and innovations.
Non-inferiority between follitropin delta (REKOVELLE®) and follitropin alfa for ongoing pregnancy rate and ongoing implantation rate was designed to be assessed for the overall trial population (N=1,326 patients), not in sub-populations characterized by age or other parameters. For the readers not familiar with the style of Assessment Reports prepared by the European Medicines Agency, these documents summarize the findings and questions raised during the review process, the corresponding responses provided by the Sponsor (in this case Ferring Pharmaceuticals) and finally the conclusions. Merck makes reference to a sentence on “some heterogeneity of responses” in the Assessment Report (6) made early on by the assessor when reviewing the data. Despite what seems to be an intense and detailed reading of the Assessment Report, the Merck executives appear to have overlooked that the European Medicines Agency assessor four lines further ahead states that “complementary information… was provided” and concludes “non-inferiority of FE 999049 over Gonal-F was accepted” (note: FE 999049 being the internal compound name for follitropin delta) and finally “In conclusion, the CHMP considered the efficacy of follitropin delta established” (CHMP: Committee for Medicinal Products for Human Use) (6). Furthermore, it is unfortunate that this evaluation and conclusion went unnoticed, as this would have saved Merck bringing forward hypotheses or claims based on a phase 2 trial with merely 43 patients exposed to GONAL-F.
We find the reporting of secondary outcomes, including the ones pointed out by the Merck executives, i.e. live birth, ovarian response, embryology data, and early and late OHSS and/or preventive interventions for early OHSS, appropriate and clinically relevant. Live birth rates are critical to patients and clinicians and presenting data on this provides reassurance that unforeseen events have not occurred during the second and third trimester. The dosing algorithm for follitropin delta was specifically designed to modulate the ovarian response, so naturally these data are presented. Embryology data are informative to clinicians and other laboratory members of the multidisciplinary team, hence them usually being included in publications on gonadotropin trials. It is important to report the safety profile associated with this new treatment modality, including the frequency of early and late OHSS and/or preventive interventions for early OHSS.
Finally, we must once again stress that non-inferiority of follitropin delta versus follitropin alfa has been established for ongoing pregnancy and ongoing implantation, as concluded by the European Medicines Agency. Regulatory bodies governing the health care profession hold the highest authority in assessing new medicines, and we are disappointed that the Merck executives aim to undermine rather than respect such evaluations.
Ferring will continue its pursuit to expand the knowledge on gonadotropins by investing and conducting clinical trials compliant with the highest regulatory and scientific standards and to publish our research in peer-reviewed journals and thereby to bring forward safe and efficacious medicines within reproductive health.
1. EMD Serono. Full prescribing information for Gonal-F® RFF Redi-ject™. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_RFF_Redi-ject_PI_tcm115_140008.pdf?Version=
2. EMD Serono. Full prescribing information for Gonal-F® Multidose. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_Multidose_PI_tcm115_140005.pdf?Version=
3. EMD Serono. Full prescribing information for GONAL-F RFF. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_RFF_75_IU_PI_tcm115_140009.pdf?Version=
4. EMD Serono. Product Monograph for Gonal-f® Pen.
5. Ferring Pharmaceuticals. Summary of Product Characteristics for follitropin delta (REKOVELLE®). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003994/WC500220235.pdf
6. European Medicines Agency. Assessment Report for follitropin delta (REKOVELLE®). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003994/WC500220237.pdf
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