P-616 Systematic review and meta-analysis of efficacy and safety of r-FSH biosimilars EMA-approved compared to reference r-FSH (follitropin alfa)
Authors: Carrera M , Dominguez J.A , Pérez Milán F , Caballero M , Alonso L , Moratalla E , Alcazar J.L , Carugno T 
Published: June 2022

Study question

Are recombinant FSH biosimilars approved by the European Medicines Agency (EMA) comparable in efficacy and safety to the originator follitropin alfa?

Summary answer

Pooled analysis from studies comparing EMA-approved biosimilars with the reference product did not detect differences in efficacy or safety between these two gonadotropins.

What is known already

A biosimilar is, according to EMA, a biological medicine highly similar to another already approved (‘reference’), and are approved according to the same standards of quality, safety and efficacy. Their development and approval opens a window of opportunity to make IVF treatments more affordable for the general population. Two previous meta-analysis of phase III non-inferiority randomized controlled trials (RCT) including non EMA-approved rFSH biosimilars (Chua et al., 2021 and Budani et a., 2021) have suggested that pregnancy and live births are lower with biosimilars compared to follitropin alfa.

Study design, size, duration

Systematic review with meta-analysis following PRISMA guidelines.

Participants/materials, setting, methods

Databases searched from inception to november 2021 were: PubMed-MEDLINE, WOS, The Cochrane Library, ClinicalTrials.gov, EudraCT and Google Scholar using these keywords: ‘biosimilars’, ‘follitropin alfa’, `originator’ and ‘ovarian stimulation’. RCTs and non-randomized comparative studies were included. Risk of bias was assessed with ROB-2 tool and Newcastle-Ottawa Scale studies. Pooled Odds Ratios (OR) and mean differences (MD) when applicable, with a 95% confidence interval (CI), were calculated. PROSPERO protocol registration has been requested.

Main results and the role of chance

After the systematic search,five studies were included in the meta-analysis: two phase-III RCT (Strawitzki, 2016 and Rettenbacher, 2015) and three non-randomized comparative studies, one of them prospective (Kaplan 2021) and the other two retrospective (Sprem Goldstajn, 2021 and Van den Haute, 2021) involving 2173 IVF cycles. Risk of bias was low for the two RCT and moderate for the observational studies. The OR of clinical pregnancy was 0.89 (95% CI = 0.74,1.07; I2=0%) and the OR of live birth was 0.86 (95% CI = 0.71,1.04; I2=0%). No differences were observed in the cumulative birth rate either (OR = 0.86; 95% CI = 0.68, 1.09; I2 0%). The total number of oocytes retrieved was similar (MD = 0.25; 95%CI,-0.93, 1.43; I2 79%); as it was the total dose of gonadotropins employed (MD=-19.56; 95% CI, -57.88, 18.76; I2 0%) and the length of the stimulation (MD = 0.12; 95% CI,-0.23, 0.47; I2 80%). The risk of Ovarian Hyperstimulation Syndrome was similar in both cases (OR = 1.36; 95% CI, 0.63, 2.91; I2 21%).

Limitations, reasons for caution

Main limitations of this meta-analysis include the fact that three of the five included studies are not randomized studies and two of them are retrospective, which can bias the results.

Wider implications of the findings

This is the first meta-analysis including only results from studies with biosimilars EMA-approved. The results show that there are no differences between the biosimilars and the reference in terms of efficacy or safety. Larger RCTs including patients with different patterns of ovarian response are needed to confirm these findings.

Trial registration number

Not applicable