Switching

With respect to transitioning or switching between a reference product and a biosimilar, several considerations are relevant for clinical practice. The absence from many regulatory guidelines of requirements for multiple switching between reference and biosimilar products may be seen as a gap in our understanding. Of note, we often do not see studies in the public domain that address manufacturing changes of a reference product, even though post-translational differences occurred. It is left to the regulators to require such studies, which remain confidential between sponsors and FDA, although EMA does issue a notification. Drift may occur at any time, but there is no need for additional trials as long as batches remain within the predefined specifications for the product.

Most RCTs investigating transitioning to a biosimilar have incorporated only one randomised switch from the reference product to the biosimilar that occurs after assessment of the primary end point. Currently several efforts are underway to collect real-world data about transitioning.10 One example is the NOR-SWITCH study, supported financially by the Norwegian government. NOR-SWITCH was designed as a non-inferiority study over 12 months to evaluate maintenance of efficacy as well as adverse event monitoring following transitioning from reference to biosimilar infliximab, compared with maintaining treatment with the reference product in patients with RA, SpA, PsA, Ps and IBD. Eligible patients on stable treatment for at least 6 months were randomised to either continue treatment with reference infliximab or to transition to CT-P13. The primary end point of this study is disease worsening. Enrolment was completed in June 2015; 498 patients were randomised. Those who complete 12 months’ treatment are then asked to participate in an open-label follow-up study during which all patients will receive the biosimilar for 26 weeks. Results from this study are expected to be available at the end of 2016.39

Early transition data from the PLANETAS extension study showed comparable rates of serious treatment emergent adverse events (TEAEs) between maintenance and transition groups (4.4% vs 4.8%), but fewer patients experienced more than one TEAE during the 2nd year with continuation of CT-P13 compared with those transitioning to CT-P13 (48.9% vs 71.4%)—predominantly due to more mild/moderate events.40 These data were published in abstract form in sufficient detail to allow analysis of comparability for safety, as illustrated by statistical considerations (table 2). On the other hand, in the long-term extension of the Japanese study of CT-P13, 41 of 43 ADAb-negative patients remained negative and 10 ADAb-positive patients became negative after transitioning from reference product to CT-P13 or having the CT-P13 dose escalated (Y Tanaka, et al. Evaluation of safety and efficacy of CT-P13 in patients with rheumatoid arthritis when CT-P13 is continued throughout the extension study and switched from the reference drug innovator infliximab. manuscript submitted). ADAb positivity and hypersensitivity reactions during the 2nd year of both PLANETRA and PLANETAS did not differ significantly between patients exposed to both reference and biosimilar as compared with those who received only the biosimilar over 2 years. Recent studies have demonstrated that the binding specificity of ADAb to reference infliximab and CT-P13 is identical: the same epitopes are recognised on both mAbs.43 ,44

Table 2 Limitations of safety data derived from trials: statistical reminders when interpreting regulatory trials for reference and biosimilar products

Although close analytical similarity of the critical attributes of a biosimilar with its reference product suggests that clinical differences will be unlikely, RCTs for biosimilars, which typically enrol fewer than 600 participants, are underpowered to identify unexpected rare adverse events.45 Thus, careful postmarketing pharmacovigilance is important for both biosimilars and reference products.

With respect to the naming of biosimilars, many have debated the need for these agents to be named differently from their reference products to inform, document switches and facilitate pharmacovigilance.46 WHO has suggested that each international non-propriety drug name be followed by a four-letter suffix to identify each brand3 ,47 ,48 recently endorsed by FDA in their 2015 draft guidance.30 To date, EMA has required brand naming which in practice has worked well: a survey of 13 790 biologic entries in the EUdravigilance system showed >96% ability to track the biosimilar.49 In the future it is expected that biosimilars and reference products will be substituted back and forth repeatedly as will biosimilars of the same reference product.2 ,10 ,28 There will be a need to introduce new ways to track and document which products a patient receives—for example patient passports or similar traceability methods. Such strategies for drug monitoring and immunogenicity assessments before and after switching will facilitate mandated as well as voluntary pharmacovigilance. Accumulated experience with biosimilars of smaller therapeutic proteins than mAbs have not indicated a safety risk of switching between reference products or biosimilars.50