Biosimilar FSH preparations- are they identical twins or just siblings?

Abstract

As patents expire on innovator products, there is increasing interest in developing biosimilar products globally. Biosimilars are not exact copies and are not considered generic versions of the reference product. They may differ in strength, purity and contain different composition of isoforms and/or various glycosylation profiles, with the consequent alterations in clinical efficacy or safety. Recently 2 new recombinant FSH preparations were introduced to clinical practice following randomized controlled, phase 3 clinical trials. Both, Bemfola and Ovaleap® were referred to the FSH innovator product Gonal-f™ (Follitropin alpha), and were found to yield an equivalent number of oocytes (primary end-point), following a long GnRH agonist suppressive protocol in “ideal” patients, i.e., young, normal responders. However, a closer look at these RCTs reveals a non-significant 4 % difference in clinical and ongoing pregnancy rates, in favor of Gonal f over the biosimilar products, accompanied by half the incidence of OHSS (2.9 vs 5.2 %, respectively). These studies were underpowered with reference to pregnancy rates, Thus, we believe that further comparative studies are needed in additional patient populations, e.g.,older,, poor responders, patients with repeated IVF failures and/or polycystic ovary syndrome, before the universal implementation of biosimilar products for clinical use. Biosimilars are actually a regulatory synonym, facilitating a fast track introduction of a FSH preparation to the COH armamentarium. We therefore recommend against interchanging or substituting innovator and biosimilar agents in clinical practice, and believe that the decision whether to use an innovator or a biosimilar product, should be reserved to the discretion of the treating physician. Furthermore, we believe the time has come that the measurement of the biological activity of FSH in humans should require other methods rather than the Steelman-Pohley assay, such as the determination of dose–response curves in defined populations of women with well-defined outcomes during COH in preparation for ART.

In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f)

“…This suggests that there may be clinical differences between Bemfola and GONAL-f. The factors responsible for these differences include the different glycosylation profiles [ 40 ] that may potentially affect ovarian response and the subsequent competency of the oocytes.…”

In vitro fertilisation/intracytoplasmic sperm injection beyond 2020

“…62 An option for affordable stimulation protocols involves use of cheaper biosimilar FSH preparations that are now emerging as patents expire on innovator products, although questions remain regarding their efficacy and safety profile. [63][64][65] Other low-cost protocols such as natural cycle IVF, low stimulation regimens, use of oral ovarian stimulants such as clomiphene citrate, and single embryo transfer (SET) can not obviate the necessity for a quality good laboratory. [66][67][68] Possibly in the future we will see further innovations to help overcome high laboratory costs, such as advances on prior work using the vaginal cavity of the patient as a substitute embryo incubator, with reported single live birth rates of up to 24%.…”

“…Low‐cost IVF focuses on affordable stimulation protocols, clinical judgment rather than excessive investigations, limited use of disposable materials, and clear and simple laboratory protocols, all of which ensure that low cost does not jeopardise quality . An option for affordable stimulation protocols involves use of cheaper biosimilar FSH preparations that are now emerging as patents expire on innovator products, although questions remain regarding their efficacy and safety profile . Other low‐cost protocols such as natural cycle IVF, low stimulation regimens, use of oral ovarian stimulants such as clomiphene citrate, and single embryo transfer (SET) can not obviate the necessity for a quality good laboratory .…”

Urinary versus recombinant gonadotropins for ovarian stimulation in women undergoing treatment with assisted reproductive technology

“…[ 37 ] They may differ from the original product in composition, strength, and purity. [ 38 ] The manufacturing process of biosimilars is complex, unlike that for pharmaceutical generics. Even a minor alteration in the process of manufacturing may have a potential impact on the efficacy and safety of the product.…”