Drug Discovery Discovery Today Today dd Volume Volume xxx, Number8xxd August 27, Number d xxxx 2022 2022 PERSPECTIVE PERSPECTIVE FEATURE Feature Overlapping biosimilar and originator follitropin alfa preparations: How much closer can they get? ⇑ Fernando de Mora a, , Colin M. Howles b Unfounded skepticism relating to biosimilars, arising from the assertion that they are not molecularly Feature  PERSPECTIVE identical to their original counterpart, fails to acknowledge that no biological medicine, including Gonal-fÒ (from Merck Serono) is identical to itself. Molecular differences between the biosimilar and the reference medicines are irrelevant and clinically undetectable as long as they are contained within the accepted variability for the original medicine. Accordingly, the minor differences in ‘ongoing pregnancy rate’ and ‘live birth’ rate reported in a recent meta-analysis of biosimilars of Gonal-fÒ from Chua et al. are probably driven by product-unrelated factors, notwithstanding the fact that of the four products under analysis, only OvaleapÒ (from Theramex UK Ltd) and BemfolaÒ (from Gedeon Richter Plc) can unambiguously be considered to be biosimilars. The EU Biosimilars model has proven successful, but some healthcare professionals, building on highly arguable premises, voice a distrust in biosimilars. Only if such scientifically unfounded distrust is reverted, the full promise of rFSH alfa biosimilars for reproductive medicine patients is likely to be fulfilled. Keywords: BemfolaÒ; Biosimilar; Follitropin alfa; Gonal-fÒ; OvaleapÒ; Recombinant follicle-stimulating hormone; Reproductive medicine; rFSH; Follitropin beta Biosimilars are biological medicines that Serono). These two biosimilars were autho- of a biosimilar and its original counter- have been shown to be essentially the rized in the European Union (EU) in 2013 part,3 doubts still remain regarding the same as an original reference product, and 2014, respectively, and elsewhere, and therapeutic performance of follitropin- according to stringent regulatory stan- were rapidly shown to increase access to alfa biosimilars, as revealed by a very dards. Such products have brought infertility treatment for women.2 In paral- recent paper.4 By discussing and updating demonstrable value to patients.1 Notably, lel, early skepticism about rFSH biosimilars the scientific evidence, this feature article OvaleapÒ (from Theramex UK Ltd) and was exhibited by some healthcare profes- refutes the view that the authorized rFSH BemfolaÒ (from Gedeon Richter Plc) are sionals (HCPs). Despite efforts by the refer- biosimilars exhibit clinically relevant dif- two biosimilars of the recombinant ence regulatory authorities and academics ferences with Gonal-fÒ; a view that, in follicle-stimulating hormone (rFSH) or fol- to reassure HCP on the science of biosimi- the authors’ opinion, is built on question- litropin alfa product Gonal-fÒ (from Merck larity, and on the interchangeable nature able premises. 1359-6446/Ó 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.drudis.2022.04.022 www.drugdiscoverytoday.com 2071 PERSPECTIVE Drug Discovery Today d Volume 27, Number 8 d August 2022 The science of rFSH biosimilar products: intrinsic structural variability of the origi- heterogeneity of the original product, as Learning from Gonal-fÒ nal medicine. Indeed, extensive analytical reported for OvaleapÒ.13. Skepticism about biosimilars of Gonal-fÒ comparisons can identify molecular fluctu- from some HCP arose from the assertion ations that would otherwise remain clini- Biosimilar-to-originator rFSH: No that “biosimilars are not exact copies” of cally undetected because of inter-patient evidence of clinical divergence their original counterpart.5 Such a state- variability in treatment response. There- In light of the above, a recent meta- ment is taken out of context, however, fore, the common claim that the pre- analysis conducted by Chua et al.,4 which since even original biological medicines authorization clinical comparability led the authors to conclude that biosimilar are not ‘identical to themselves’. Indeed, assessment needs to be extended lacks sci- versions of Gonal-fÒ exhibit lower rates of in 2003, the developers of Gonal-fÒ6 had entific foundation. The understanding ‘ongoing pregnancy’ and ‘live birth’ than already disclosed the inherent batch-to- that close analytical comparability predicts the reference medicine, warrants further batch structural heterogeneity of the origi- clinical comparability was obtained from scrutiny. On the basis of the scientific nal rFSH product. Expectedly, the Gonal-fÒ studies of the unwanted intrinsic hetero- principles summarized above, the clinical batch-to-batch variation in sialylation was geneity of original biologics. Indeed, com- differences reported between biosimilars not paralleled by variation in the clinical parability is a well-established scientific and Gonal-fÒ are very unlikely to be dri- behavior, and did not trigger discomfort principle that has been used for decades ven by the clinically acceptable minute among HCP. The fundamental scientific to evaluate changes in manufacturing, or molecular differences that were observed, principle that clinical ‘sameness’ between composition, that occur during the com- as their analytical attributes essentially two versions of a given biological medicine mercial life cycle of biotechnological overlap. Instead, the clinical differences may arise despite non-molecular identical- medicines.11. are more likely to be attributable to ity is well established. Notably, in a 2017 In reality, the development of an orig- product-unrelated factors. Indeed, multi- paper,7 Merck, the current marketing inal candidate product and the replica- ple factors, such as the hCG dose given authorization holder (MAH) for Gonal-fÒ, tion of an existing product, for which to trigger final follicular maturation, the acknowledged that “variability of product extensive knowledge has accumulated, time interval between oocyte collection characteristics is intrinsic to complex living logically should not follow the same and fertilization subsequent to intracyto- cell production processes, and acceptable experimental path. Randomized clinical plasmic sperm injection (ICSI), the labora- changes in quality attributes have been trials (RCTs) are advocated as the gold tory procedures followed, and even the described”. Accordingly, despite broader standard for demonstrating the therapeu- individual embryo transfer operator,14 molecular differences between them, the tic benefit of new products, but they among others, probably do impact the first-to-market original rFSH preparations have very limited value in showing the analyzed endpoints. Consequently, in the Feature  PERSPECTIVE Gonal-fÒ (alfa) and PuregonÒ (beta) exhi- comparability of highly similar biologic context of the confirmatory nature of a bit no evidence of significant clinical medicines. Accordingly, industry repre- clinical comparability exercise, the ‘ongo- divergence.8,9 All this shows that compar- sentatives from Merck, a company active ing pregnancy’ or ‘live birth’ endpoints isons in a clinical setting are therefore in the reproductive medicine field are of reduced value in confirming much less sensitive than analytical com- declared7: “Much greater analytical scrutiny biosimilarity. parisons for picking up minute differences and in-depth functional characterization are Ovarian stimulation is the well- between versions of a given biologic, given required for the approval of a biosimilar. . .as characterized mechanism of action of the fact that those minor differences are these are the foundations for comparable rFSH, which gives rise to the drug’s clinical often irrelevant from a therapeutic safety and efficacy performance in the effect. Thus, the recommended primary perspective. clinic.” The questionable value of RCTs marker of efficacy, the number of ‘oocytes Because of the reliance on the certainty in demonstrating biosimilarity has retrieved’, is the most reliable product-to- that function follows form, biosimilarity recently been stressed by the UK Medici- product comparability endpoint because needs to be demonstrated through a com- nes and Healthcare Products Regulatory it minimizes the bias introduced by the prehensive comparability analysis that Agency (MHRA)12: “. . .an efficacy trial in secondary factors mentioned above. In ascertains the essential molecular overlap patients is not expected to show differences fact, the interpretation of the meta- between the biosimilar candidate and the undetected by extensive analytical testing” analysis results challenges the well- reference medicine (as we have extensively and “. . .comparative efficacy trials are nei- established functional connection reviewed for rFSH products10) The accept- ther an effective discriminating tool for the between ‘oocytes retrieved’ and ‘preg- able level of difference between a biosimi- comparison of the biosimilar with the refer- nancy rate’ or ‘live birth’ rate.15 One could lar candidate and its reference medicine ence product, nor an efficient use of limited infer that, although the number of oocytes is determined by a thorough assessment resources”. Experts from the European remains statistically equivalent, their qual- of multiple batches of the reference bio- Medicines Agency (EMA)3 endorse the ity may differ owing to physicochemical or logic. Consequently, the most sensitive concept that RCTs are only confirmatory, functional differences among the prod- way to demonstrate that rFSH biosimilar rather than key to substantiating biosim- ucts, such as differences in biological activ- preparations and Gonal-fÒ have equivalent ilarity. Therefore, the optimal approach ity or glycopattern. This seems very efficacy and safety is to show that their dif- to uncovering biosimilarity is to demon- improbable in light of both the thorough ferences in critical structural and func- strate that differences in critical analyti- analytical comparative assessment of the tional attributes do not exceed the cal attributes do not exceed the intrinsic biosimilar candidates (including isoforms 2072 www.drugdiscoverytoday.com Drug Discovery Today d Volume 27, Number 8 d August 2022 PERSPECTIVE TABLE 1 Key evidence from clinical studies required for authorization of rFSH alfa-bearing biosimilars, from real world therapeutic performance of biosimilars, and of the value of biosimilars to reproductive medicine patients. Scope Study Observations and conclusions Safety and efficacy (Real Rettenbacher et al.16 Safety and efficacy of BemfolaÒ (biosimilar follitropin alfa) for up to two treatment World Evidence (RWE)) cycles in infertile women using assisted reproductive technology. The Phase III open label study demonstrated that BemfolaÒ and Gonal-fÒ have similar clinical efficacy and safety profiles. Strowitzki et al.19 Safety and efficacy of OvaleapÒ (biosimilar follitropin alfa) for up to three cycles in infertile women using assisted reproductive technology: a Phase III open-label follow- up main study. European Medicines Agency & Document made public by the European healthcare authorities essentially for European Commission20 prescribers, in which the biosimilar concept is thoroughly revised. The EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicine. Sydow et al.21 Study in 34 reproductive medicine centers in Germany, in which the effectiveness and safety of ovarian stimulation with OvaleapÒ in a gonadotropin-releasing hormone (GnRH) antagonist protocol was extended for the first time to real-world practice in assisted reproductive technology (ART) clinics. Griesinger et al.27 Study in 24 reproductive medicine centers in Germany and Austria, in which the effectiveness and safety of ovarian stimulation with BemfolaÒ in a GnRH antagonist protocol was extended to real-world ART clinical practice. Ferrando et al.28 Study in 26 ART centers in Spain, in which the effectiveness and safety of ovarian stimulation with BemfolaÒ in four distinct patient populations were recorded. The four populations studied were poor responders, suboptimal responders, normal responders and oocyte donors.  Sprem Goldstajn et al.29 Single center study evaluating the efficacy of OvaleapÒ with reference to Gonal-f Ò in a GnRH fixed antagonist or flexible antagonist protocol. Essential sameness Cruz et al.22 The use of any follitropin alfa version (whether original or biosimilar) does not impact the number of oocytes retrieved from women. Van den Haute et al.23 Clinical outcome is not influenced by the product given—OvaleapÒ (follitropin alfa) or PuregonÒ (follitropin beta)—as had been shown in earlier studies comparing Gonal-fÒ and PuregonÒ. Kaplan et al.24 Phase III trial comparing OvaleapÒ and Gonal-fÒ in ART in a prospective cohort, Feature  PERSPECTIVE showing that ovarian hyperstimulation syndrome (OHSS) and OHSS severity, as well as pregnancy and live birth rates, are similar for OvaleapÒ and Gonal-fÒ. Bosch et al.25 BemfolaÒ (biosimilar follitropin alfa) has clinical efficacy similar to those of established recombinant follitropins in ART (either alfa or beta). Strowitzki et al.26 Safety and efficacy of OvaleapÒ (biosimilar follitropin alfa) compared to Gonal-fÒ in the first ART treatment cycle. This Phase III open label study demonstrated that OvaleapÒ and Gonal-fÒ have similar clinical efficacy and safety profiles. Value substantiation QuintilesIMS2 Early impact of the launch of rFSH alfa biosimilars: (i) increased patient access to fertility treatment measured in number of treatment days; and (ii) reduced overall cost of fertility treatment. and biological activity studies), which by pooling data from homogeneous trials, folaÒ and data from products whose showed that the minute differences in crit- the authors themselves admit to the mod- development may not have followed the ical attributes are contained within the erate quality of their study. It is worth same scientific standards (potentially sub- batch-to-batch variability found for underlining at least three relevant standard biologic products). This would Gonal-fÒ, and the fact that markers of methodological issues. put the validity of the authors’ conclu- oocyte and embryo quality are examined First, of the four products included in sions into question, as homogeneity is a during the development of biosimilars, as the analysis, only OvaleapÒ and BemfolaÒ key principle in meta-analysis methodol- per EMA guidance. Accordingly, no differ- can unambiguously be considered biosim- ogy. Indeed, as also stressed by the cur- ences in oocyte quality were uncovered ilars on the basis of the regulatory frame- rent Gonal-fÒ marketing authorization by a head-to-head study comparing the works used in the regions where the holder7, notwithstanding the fact that effects of biosimilars and original products have been approved. Many less stringent requirements may consti- products.16 agencies are not compliant with the tute a risk for patients, one should refer Alternative interpretations of the meta- evidence-based principles followed by to a product as a ‘biosimilar’ when there analysis4 may also be provided. Could the the World Health Organization (WHO)- is certainty that it has been developed fol- unexpected results be linked to the designated stringent regulatory authori- lowing the scientific criteria pioneered by methodology? In spite of the usefulness ties.17 This signifies that the authors have the EMA. Reference regulators themselves of a meta-analysis meant to provide power gathered data from OvaleapÒ and Bem- have warned about the need for utmost www.drugdiscoverytoday.com 2073 PERSPECTIVE Drug Discovery Today d Volume 27, Number 8 d August 2022 rigor in designating a medicine as a folaÒ or OvaleapÒ and the original prod- foundation, the promise of rFSH alfa ‘biosimilar’.18 ucts Gonal-fÒ or even a follitropin beta biosimilars is unlikely to be fulfilled. Second, disregarding the probable dif- (PuregonÒ) (Table 1).19–29 ferences in development standards (and References possibly in the standard operating proce- Conclusions 1. F. de Mora, Biosimilars: a value proposition, BioDrugs 33 (2019) 353–356. dures (SOP) of the centers involved), the The lack of an accurate understanding 2. QuintilesIMS. Impact of Biosimilars Competition in number of patients (n) attained by com- regarding the science of biosimilarity Europe. https://www.medicinesforeurope.com/wp- bining the studies may be statistically may foster distrust in biosimilars among content/uploads/2017/05/IMS-Biosimilar-2017_V9. pdf. Published May, 2017. Accessed February, 2022. acceptable, but it still seems too low to HCPs, whereas knowledge of the well- 3. E. Wolff-Holz, K. Tiitso, C. Vleminckx, M. Weise, allow an undisputable conclusion to be established scientific principles that guide Evolution of the EU biosimilar framework: past and reached, which may partly explain the the development of biosimilars raises con- future, BioDrugs 33 (2019) 621–634. 4. S.J. Chua, B.W. Mol, S. Longobardi, R. Orvieto, C.A. moderate quality of the study undertaken. fidence. Further to pre-launch evidence, Venetis, M. Lispi, et al., Biosimilar recombinant On the other hand, only data from three of as stated by the European Commission follitropin alfa preparations versus the reference the four pre-authorization RCT (one of in a 2019 guide20: “. . .the EU monitoring product (Gonal-FÒ) in couples undergoing assisted reproductive technology treatment: a systematic them with an overly low number of system for safety concerns has not identified review and meta-analysis, Reprod Biol Endocrinol patients) have been pooled to conduct any relevant difference in the nature, severity 19 (2021) 51. the calculations, which certainly does not or frequency of adverse effects between 5. D. Santi, M. Simoni, Biosimilar recombinant follicle stimulating hormones in infertility treatment, Expert comply with what a standard meta- biosimilars and their reference medicines”. Opin Biol Ther 14 (2014) 1399–1409. analysis would require under the stated The EU biosimilars model has thus pro- 6. A. Gervais, Y.-A. Hammel, S. Pelloux, P. Lepage, G. conditions. ven successful and cost-effective. The Baer, N. Carte, et al., Glycosylation of human recombinant gonadotrophins: characterization and Third, an additional hurdle in our opin- most notable impact of such cost- batch-to-batch consistency, Glycobiology 13 (2003) ion is that the authors draw their conclu- effectiveness is the potential for health- 179–189. sions by assessing the endpoints ‘rates of care budgetary redistribution, which, for 7. L. Magnenat, A. Palmese, C. Fremaux, F. D'Amici, M. Terlizzese, M. Rossi, et al., Demonstration of ongoing pregnancy’ and ‘live birth’ rate, instance, has increased early patient physicochemical and functional similarity between in spite of the fact that the RCT that are access to fertility biological therapies. Fur- the proposed biosimilar adalimumab MSB11022 and included in their analysis were not thermore, the reallocated funds may be HumiraÒ, MAbs 9 (2017) 127–139. 8. G. Horsman, J.A. Talbot, J.D. McLoughlin, A. Lambert, designed to detect differences in such end- used to improve healthcare services, to W.R. Robertson, A biological, immunological and points. This is because, on the basis of the acquire technologic upgrades or innova- physico-chemical comparison of the current clinical scientific principles described above, tive medicines, or to initiate biological batches of the recombinant FSH preparations Gonal- F and Puregon, Hum Reprod 15 (2000) 1898–1902. ‘oocytes retrieved’ is the endpoint of therapy at earlier stages of a given disease. Feature  PERSPECTIVE 9. R. Orvieto, R. Nahum, J. Rabinson, Follitropin-alpha choice for regulatory authorities because Stakeholders must acknowledge, however, (Gonal-F) versus follitropin-beta (Puregon) in it minimizes the interference of confound- that the advantages of biosimilars are controlled ovarian hyperstimulation for in vitro fertilization: is there any difference?, Fertil Steril 91 ing factors in a clinical comparability exer- more than monetary and have been bol- (2009) 1522 cise. Even though a meta-analysis is meant stered by empirical validation throughout 10. F. de Mora, B. Fauser, Biosimilars to recombinant to overcome the limitation imposed by Europe since their inception in 2006.1 human FSH medicines: comparable efficacy and safety to the original biologic, Reprod Biomed low numbers of participants in each indi- The creation of patient registries that Online 35 (2017) 81–86. vidual study, qualitative limitations, allow more data to be amassed through 11. L.-F. Rojas-Chavarro, F. de Mora, Extrapolation: including the lack of a double-blind greater access will help to gauge the experience gained from original biologics, Drug Discov Today 26 (2021) 2003–2013, https://doi.org/ approach to evaluate the targeted clinical long-term effects of biosimilars on disease 10.1016/j.drudis.2021.05.006. outcome, do remain. progression. Legal provisions also exist to 12. M.C. Bielsky, A. Cook, A. Wallington, A. Exley, S. All in all, the interpretation of Chua encourage innovation within the biosimi- Kauser, J.L. Hay, et al., Streamlined approval of biosimilars: moving on from the confirmatory et al.4 that “treatment with biosimilar lars themselves, leading manufacturers to efficacy trial, Drug Discov Today S1359–6446 (20) preparations of follitropin alfa is likely to aim for greater stability, less immuno- (2020) 30343–30353, https://doi.org/10.1016/ result in lower probability of life birth, clin- genicity, or easier and more efficient j.drudis.2020.09.006. 13. R. Winstel, J. Wieland, B. Gertz, A. Mueller, H. Allgaier, ical and ongoing pregnancy compared with modes of delivery, as has been the case Manufacturing of recombinant human follicle- the reference product” is questionable for follitropin alfa-bearing biosimilars.30 stimulating hormone OvaleapÒ (XM17), and, at the very least, should be put Physicians should be reassured that comparability with Gonal-fÒ, and performance/consistency, Drugs R D 17 (2017) 305– on hold. Instead of re-visiting pre- EMA-approved follitropin-alfa-bearing 312, https://doi.org/10.1007/s40268-017-0182-z. marketing clinical data, in the light of biosimilars, such as BemfolaÒ and Ova- 14. F. Cirillo, P. Patrizio, M. Baccini, E. Morenghi, C. the extensive experience with the leapÒ, are a high-quality alternative to Ronchetti, L. Cafaro, et al., The human factor: does the operator performing the embryo transfer biosimilar preparations, the outcomes Gonal-fÒ. The merits of original biologics significantly impact the cycle outcome?, Hum observed in clinical practice could now are not disputed, but biosimilars con- Reprod 35 (2020) 275–282 provide more conclusive evidence. tribute principally to the sustainability of 15. S.K. Sunkara, V. Rittenberg, N. Raine-Fenning, S. Bhattacharya, J. Zamora, A. Coomarasamy, Indeed, real-world evidence (RWE) from healthcare systems, thus ensuring that Association between the number of eggs and live thousands of patients treated with present and future patients are properly birth in IVF treatment: an analysis of 400135 high-standard follitropin-bearing prod- served. But as long as there is a scientifi- treatment cycles, Hum Reprod 26 (2011) 1768–1774. 16. M. Rettenbacher, A.N. Andersen, A. Garcia-Velasco, ucts has been published to support the cally unjustified resistance to the use of M. Sator, P. Barrie, S. Lindenberg, et al., A multi- clinical sameness of the biosimilars Bem- biosimilars that is built upon a biased centre phase 3 study comparing efficacy and safety 2074 www.drugdiscoverytoday.com Drug Discovery Today d Volume 27, Number 8 d August 2022 PERSPECTIVE of BemfolaÒ versus Gonal-fÒ in women undergoing in infertile women undergoing superovulation for Prof. Fernando de Mora is full ovarian stimulation for IVF, Reprod Biomed Online 30 assisted reproductive technologies: a multinational professor of pharmacology at the (2015) 504–513. comparative, prospective cohort study, Front Universidad Autonoma de Barce- 17. World Health Organization. List of Stringent Endocrinol 12 (2021), https://doi.org/10.3389/ lona, where he obtained a PhD in Regulatory Authorities (SRAs). https://www.who.int/ fendo.2021.632674 632674. immunopharmacology. He initiatives/who-listed-authority-reg-authorities/SRAs 25. E. Bosch, C. Howles, No difference in clinical worked as a postdoctoral fellow Accessed February, 2022. outcomes using follitropin alfa (biosimilar) at Harvard Medical School, and shortly after obtained an MBA 18. M. Weise, M.-C. Bielsky, K. De Smet, F. Ehmann, N. compared to follitropin alfa or follitropin beta for from the University of Chicago. Ekman, G. Narayanan, et al., Biosimilars—why controlled ovarian stimulation (COS) in oocyte Fernando is principal investigator terminology matters?, Nat Biotechnol 29 (2011) donation-recipient cycles, Fertil Steril 110 (2018) in government-funded research 690–693 e336. projects on both the identifica- 19. T. Strowitzki, W. Kuczynsky, A. Mueller, P. Bias, Safety 26. T. Strowitzki, W. Kuczynski, A. Mueller, P. Bias, tion of new targets in asthma and and efficacy of OvaleapÒ (recombinant human Randomised, active-controlled, comparative phase novel approaches to biosimilar characterization. He acts as an follicle-stimulating hormone) for up to 3 cycles in 3 efficacy and safety equivalence trial of OvaleapÒ academic consultant and speaker in biosimilar science and in infertile women using assisted reproductive (recombinant human follicle-stimulating hormone) the sphere of regulation and marketing in the biopharma- technology: a phase 3 open-label follow-up to in infertile women using assisted reproduction ceutical industry, working with healthcare administrations main study, Reprod Biol Endocrinol 14 (2016) 31. technology (ART), Reprod Biol Endocrinol 14 (2016) and with public and private organizations. 20. European Medicines Agency, European Commission. 1, https://doi.org/10.1186/s12958-015-0135-8. Biosimilars in the EU: Information Guide for Healthcare 27. G. Griesinger, T. Schill, M. Sator, M. Schenk, J.S. Colin M. Howles is the founder Professionals. https://www.ema.europa.eu/ Krüssel, Clinical efficacy of follitropin alfa in GnRH- of ARIES Consulting, based in en/documents/leaflet/biosimilars-eu-information- antagonist protocols: a prospective observational Geneva, Switzerland. ARIES Con- guide-healthcare-professionals_en.pdf. Published phase IV study on the use of biosimilar follitropin alfa sulting has been active since 2019. Accessed February, 2022. r-hFSH in assisted reproductive technology in a 2013 and provides services to 21. P. Sydow, N. Gmeinwieser, K. Pribbernow, C. Keck, I. routine care setting, J Reprod Infertil 22 (2021) 116– companies in the Fertility thera- Wiegratz, Effectiveness and safety of follitropin alfa 124, https://doi.org/10.18502/jri.v22i2.5798. peutic area as well as working (OvaleapÒ*) for ovarian stimulation using a GnRH 28. Ferrando M, Coroleu B, Rodríguez-Tabernero L, directly with in-vitro fertilisation antagonist protocol in real-world clinical practice: a Barrenetxea G, Guix C, Sánchez F, Jenkins J; BIRTH (IVF) clinics across the world. He is multicenter, prospective, open, non-interventional study group. The continuum of ovarian response also an Honorary Fellow in the ART study, Reprod Biol Endocrinol 18 (2020) 54. leading to BIRTH, a real world study of ART in Spain. Deanery of Biomedical Sciences, 22. M. Cruz, V. Vergara, A. Requena, Type of follitropin Fertil Res Pract 2020;6:13. doi:10.1186/s40738-020- University of Edinburgh where he alfa for ovarian stimulation with 00081-4. participates in the undergraduate medroxyprogesterone acetate does not affect 29. M.  Sprem Goldstajn, S. Dumancic, M. Mikus, teaching program and research supervision. Dr. Howles has clinical outcomes in a donor-recipient program P- Retrospective analysis of the use of two worked for 44 years in the field of Reproductive, Endocrin- nology and Medicine. He obtained a PhD from Nottingham 857, Fertil Steril 114 (2020) e455–e456, https://doi. recombinant follitropin alfa injections in patients University, UK and started working at the first human IVF org/10.1016/j.fertnstert.2020.08.1316. undergoing in vitro fertilization treatment with the clinic in the world, Bourn Hall Clinic, Cambridge UK in the 23. L. Van den Haute, P. Drakopoulos, G. Verheyen, M. De gonadotropin-releasing hormone antagonist early 1980’s. He then spent 25 years in the biopharmaceutical Vos, H. Tournaye, C. Blockeel, Follitropin alfa protocol, J Obstet Gynaecol Res 47 (2021) 992– industry and was involved in the development and world- (OvaleapÒ) compared with follitropin beta 1001, https://doi.org/10.1111/jog.14626. wide clinical introduction of the first recombinant h-FSH (PuregonÒ) in women undergoing a first GnRH 30. G. Foxon, P. Mitchell, N. Turner, A. McConnell, H. (follitropin alfa), h-LH (lutropin alfa) and hCG (choriogo- antagonist cycle for ICSI: a retrospective cohort Kendrew, J. Jenkins, Bemfola Ò fixed dose pens nadotropin alfa). In total, he had experience of introducing Feature  PERSPECTIVE study, Fertil Steril 114 (2000) e324. potentially reduce drug wastage and associated costs into clinical use six recombinant gonadotrophin preparations. 24. S. Kaplan, R. Levy-Toledano, M. Davies, D. Roy, C.M. of infertility treatment, Hum Fertil 21 (2018) 275–280, Howles, A. Lass, Safety of OvaleapÒ (follitropin alfa) https://doi.org/10.1080/14647273.2017.1328131. ⇑ Fernando de Mora a, , Colin M. Howles b a Departamento de Farmacología, Terapéutica y Toxicología, Universidad Autónoma de Barcelona, 08193 Bellaterra, Barcelona, Spain b ARIES Consulting, Ch du Barbolet 5b, 1213 Onex, Geneva, Switzerland ⇑ Corresponding author. www.drugdiscoverytoday.com 2075