4.1 Comparison with Previous Studies
The results from this study confirm the similarity in terms of safety between originator epoetin alpha and biosimilars when used in patients with CKD receiving dialysis. Specifically, no difference emerged between the two cohorts of users with regard to any kind of adverse events.
Phase III equivalence studies have been carried out in patients with CKD to obtain marketing authorization. These studies showed that biosimilars were therapeutically equivalent to the comparator epoetin alfa in changing mean absolute Hb; the two products also had a comparable safety profile in the intravenous treatment of anemia with regard to adverse events, serious adverse events, and death [
7,
8].
Completed and ongoing observational post-authorization studies provide important additional information in a real-world setting under conditions of greater heterogeneity of patients and clinical practices [
9]. PASCO I and EPO-PASS were single-arm studies designed to investigate the incidence of adverse events of epoetin alfa biosimilars; these studies ascertained that their safety profiles were in line with other ESAs and with the data from pre-marketing studies [
10,
11]. In particular, the PASCO I study was conducted for up to 1 year among patients with renal anemia treated with an intravenous epoetin biosimilar [
10]. The median age was similar to our findings, while other characteristics such as the proportion of patients with diabetes or cerebrovascular diseases differed significantly. We found a similar frequency of fistula and shunt malfunction (about 10% of patients); the differences observed in relation to other events may be due to different inclusion criteria. With regard to EPO-PASS, our study had a comparative design (enabling a direct comparison between epoetin alpha drugs), focused on more severe patients (CKD patients without dialysis were not included), and had a longer follow-up (12 vs 6 months) [
11].
A recent large observational study based on the record linkage of different regional databases (the Electronic Therapeutic Plan Register, the Health Care Assistance File, the Mortality Information System, and the Hospital Information System of the Lazio Region) did not find any difference between originator epoetin alfa and biosimilars on relevant effectiveness and safety outcomes measured during the follow-up period in patients with CKD [
12]. In this study, comparing the occurrence of a composite outcome (including all-cause mortality, blood transfusion, major cardiovascular events, and blood dyscrasia), the adjusted HR was 1.02 (95% CI 0.78–1.33). However, only a small number (154: 1.9%) of the 8161 CKD patients included had received an epoetin alfa biosimilar; moreover, even though many potential confounders were taken into account, limited clinical information was available at baseline (e.g., dry weight, comorbidities, iron supplementation) because of the retrospective study design. In our study, we observed the same estimates in a population of biosimilar users that was almost three times larger and for which individual clinical information was recorded at baseline and during the 1-year follow up by means of an ad hoc case report form. A recently published comparative study (involving 57 and 47 patients who received originator and biosimilar epoetins, respectively) found that both groups of products were equally effective and safe for the treatment of anemia in patients with CKD [
13]. However, in the cohort treated with one of the originator epoetins, only six patients were receiving epoetin alpha, thus limiting the transferability of the comparison between originator epoetin alpha and biosimilars.
We found that patients who received biosimilars were significantly older, with more comorbidities, and were more likely not to be included on the transplant waiting list than those treated with the originator. This partly reflects the results shown in other studies where patients receiving biosimilar ESAs were slightly older and with more comorbidities such as diabetes [
1,
13]. These observations may suggest that doctors who are concerned with the benefit–risk profile of biosimilars might preferentially select the originators to treat younger and healthier patients.
4.2 Implications for Clinical Practice and Health Systems
The European Medicines Agency (EMA) was the first regulatory authority in 2005 to clarify the general principles to be applied to a biological medicinal product claiming to be similar to another one already on the market [
14]. However, the evaluation of biosimilar medicines for authorization purposes by the EMA does not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. Consequently, any recommendations for switching are within the remit of the EU member states [
15].
The issue of biosimilar use is still a matter of debate, at least in Italy: the various scientific societies [
3], patient associations [
16], and political authorities [
4,
17] operating at the local level express different positions, therefore contributing to the caution of clinicians. For instance, while our study was ongoing in 2014, the Italian Society of Pharmacology (SIF) published a working paper suggesting the need to carry out additional studies gathering real-life data on the comparative safety and efficacy of originator and biosimilar ESAs [
3]. Moreover, Italian consumption data showed a modest use of biosimilar epoetins, which accounted for only 37% of the total defined daily dose per 1000 inhabitants per day in 2016, although an increase of 20% was observed from 2015 to 2016 [
18].
Our study involved only four Italian regions, accounting for about 15% of the Italian population. However, there is no reason to expect that any clinical characteristics associated with the geographical area would modify the estimated safety of the epoetin originator and biosimilars. Therefore, the findings of our study should contribute to reassuring physicians about the equivalence of the epoetin alfa originator and biosimilars. The analysis of the available evidence accumulated during almost 10 years of use, in addition to post-authorization studies and spontaneous reports, may help scientific societies in making clearer statements about the equivalence of the two products. More generally, studies aimed at comparing originator and biosimilar drugs, far from being redundant, will reinforce the credibility of the approval process of any biosimilar and thus boost confidence in their use.
The study had a limited power to detect a difference between the two formulations in terms of incidence of rare events such as hypersensitivity reactions (e.g., pure red cell aplasia [PRCA]). However, even though no event of PRCA was observed in our study, this information is of value in that it can contribute to a meta-analysis of studies that collected similar data at an individual-patient level.
Given the observational nature of the study, no indication was provided to the participating centers about the use of different epoetin alpha products; since almost all the biosimilar prescriptions referred to one biosimilar epoetin, the observed findings cannot be extended to the other marketed products. Moreover, our findings do not extend to the comparative safety of all marketed epoetins. Since the main objective of the study was to establish whether any clinically relevant difference could be highlighted between biosimilar and originator epoetin alfa products in current practice, we excluded from the analysis patients receiving other originator epoetins.