By studying four populations of women (poor responders, suboptimal responders, normal responders and oocyte donors) the BIRTH study shows a clear and related continuum of ovarian response and fertility among women. The majority of patients were not classified consistently across all centres with a clear sole cause of infertility illustrating the complexity of understanding the cause of infertility and agreeing to a common diagnostic terminology . Nevertheless, there were obvious differences seen between the populations of women in this study. The populations showed both quantitative and qualitative differences in terms of oocyte number achieved and embryo quality, respectively, associated with striking differences in implantation rates and pregnancy rates. This illustrates the value of assessing a new drug across a wide range of patients treated in diverse ways in real-world situations, as randomised control trials will include patients of often very limited prognoses, which may not be adequately balanced between study groups following randomisation, particularly if the sample size is relatively low, and which may not reflect the potential populations in real clinical practice. Furthermore, the study confirmed that Bemfola® was able to meet the treatment requirements for all patient types whether using monotherapy or combination protocols.
Although this study adopted the Bologna criteria  to define the poor responder population, the limitations of this definition are acknowledged, which is why a further population of suboptimal responders was included in this study. Although the concept of poor ovarian response has been recognised for a very long time, in 2011 an enormous variability of the definitions of poor ovarian response in the literature was reported . Thus in 2011 the European Society of Human Reproduction and Embryology (ESHRE) established strict criteria (Bologna consensus) to define poor ovarian response thereby establishing a more homogenous population to support research . Although the Bologna criteria was a crucial step towards defining poor ovarian response, it became clear that even when using the Bologna criteria, the poor ovarian response population remained heterogeneous primarily because the criteria did not adequately take the age-related impact on oocyte quality into consideration, which significantly impacts success rates . In 2016 a group of reproductive endocrinologists and scientists gathered to further refine the definition of poor ovarian response . As a result, the new POSEIDON (Patient-Oriented Strategies Encompassing Individualized Oocyte Number) classification was developed, providing a more detailed classification to reduce the heterogeneity of the Bologna criteria . When considering the definition of “poor ovarian response”, the introduction of the follicular output rate (FORT)  provides an alternative measure of ovarian response to exogenous stimulation by assessing the ratio between the number of pre-ovulatory follicles obtained in response to gonadotropin administration and the pre-existing pool of small antral follicles. The FORT concept might even be taken a step further, including also the ratio between the final number of oocytes retrieved correlated to the antral follicle count (AFC) to measure successful ovarian response. As an example, a patient with a poor ovarian reserve who finally ends up with 70% of the antral follicles, resulting in retrieved oocytes has a high FORT, and in reality, a good ovarian response to stimulation regardless of the total number of oocytes retrieved. Evidentially, although the concept is clear, the precise definition of poor ovarian response remains a challenge. This paper presents two populations of relatively less than normal ovarian response demonstrating relatively poorer outcomes supportive of a heterogenous, continuum of ovarian responsiveness with associated differing prognoses rather than a discrete group of poor ovarian response patients.
No lack of efficacy nor pharmacovigilance signals were revealed in this real-world study of the use of this new product and in fact the differences between patient groups was far more relevant to whether a patient was successful with ART or suffered an adverse event than the choice of gonadotrophin. Furthermore, the pregnancy rates in the BIRTH study were consistent to the overall pregnancy rates per embryo transfer reported in 2017 to the national Spanish ART registry of 42%, 36.5% and 25.6% for IVF (n = 6473) and 44.5%, 36.3% and 21.2% for ICSI (n = 43,790) according to ages < 35 years, 35–39 years and ≥ 40 years respectively . The national overall multiple embryo transfer rates for Spain were 49% in 2016 and 44% in 2017 .
One area of particular interest explored in this study was the use of FSH with a product providing LH activity in what is referred to as combination, combo or mixed protocols. The study showed combination protocols are commonly used in Spain, particularly in patients over 35 years of age or among patients anticipated to have a reduced response to ovarian stimulation. Although this study is not a randomised control study and there is considerable heterogeneity in terms of the details of the combination protocols used at different centres, the results are interesting to consider in the context of the literature and recent guidance on ovarian stimulation for IVF/ICSI from the European Society of Human Reproduction and Embryology .
In each BIRTH study population the implantation and pregnancy rates were numerically lower with combination protocols than with mono therapy. Although statistical comparisons of these results would be inappropriate as patients allocated to combination protocols might be of a poorer prognosis even within patient populations, at the very least the results do not suggest any benefit for combination protocols in any of the patient populations studied. The ESHRE ovarian stimulation for IVF/ICSI guidelines similarly could not identify any groups that would benefit from the addition of LH activity to FSH stimulation, other than the rare cases of WHO-I anovulatory patients. The ESHRE ovarian stimulation for IVF/ICSI guidelines specifically commented there was no evidence of a beneficial effect on live birth rates for the LH supplementation of rFSH in poor responders or women of advanced age. In addition and of note, the ESPART Study in “poor responders” suggested fewer oocytes with LH and no benefit in pregnancy rates  and a meta-analysis of 5840 patients in twenty-nine studies confirmed LH reduced number of oocytes when added to FSH . A further large randomised trial, MEGASET, showed that not only was the addition of LH activity associated with fewer oocytes, but there was no benefit in the quality of oocytes, embryos and blastocysts .
This evidence of clinical effectiveness from this study is particularly important as further to Bemfola® being approved by the European Medicines Agency in 2014 as a biosimilar of follitropin alpha, in 2017 the Bemfola® drug substance batch number T128/FSH/B1 was adopted as the European Follitropin Chemical Reference Substance (CRS) [24, 25]. The drug substance is essentially the active pharmaceutical ingredient (API) or the ‘naked’ drug without excipients. The API is what will have a therapeutic effect inside the body as opposed to the excipients that serve to package and deliver the API. The drug product is the formulated mixture of the drug substance and excipients which results in the final marketed product. The quality and consistency of any rFSH drug substance prior to release of the final rFSH drug product may be assessed against the Follitropin CRS according to the European Pharmacopoeia (Ph.Eur) of the European Directorate for the Quality of Medicines and Healthcare (EDQM).
Although a real world study has the advantage of reporting on the whole highly heterogeneous population receiving a very diverse range of clinical ART practices, inevitably this leads to study limitations of low internal validity, lack of quality control and susceptibility to multiple sources of bias. Further the BIRTH study did not present spontaneous abortion rates, live birth rates and rates of congenital anomalies. Hence, real world studies such as the BIRTH study should be viewed as part of a wider body of evidence to guide clinical practice.