Due to the functional sensitivity of biologics to the specific processes by which they are manufactured, innovative biologics are developed and first manufactured at a single facility. Per ICH guidelines, regulators require that pivotal clinical studies of new biologics are conducted with investigational material that is fully representative of the to-be-commercialized drug. Product from the first facility is used in the clinical studies that are conducted for registration in the first market, and the same clinical studies are included in the marketing applications to most other jurisdictions, either concurrently or subsequently. Table 2 illustrates this practice by showing that the same major clinical data were used for the authorizations of the representative biologics in multiple jurisdictions. Moreover, the product’s nonclinical, quality, and manufacturing data are also necessarily largely the same across multiple jurisdictions. When the commercial strategy in a particular jurisdiction requires a variation from the original data, complementary studies are conducted and included in the marketing application, but the core data remain the same as were submitted in the first market(s). While there are exceptions to this rule, and while the burden remains on the sponsor to make the case, this commonality of data can effectively vitiate the need for new bridging studies between product versions.
A common representation by some regulators and the innovator biologic industryFootnote 7 is that reference product bridging studies are necessary because differences in critical quality attributes (CQAs) between an FAC and an RBP might be introduced or exacerbated by manufacturing changes to either or both of them after their approvals in their respective jurisdictions. A related argument is that data from bridging studies promote realistic acceptance ranges for the biosimilar. A third argument is that bridging studies are necessary because comparison of biosimilar candidates to the local version of the innovator biologic is required by regulatory text. In our view, these positions generally do not bear examination.
As preamble, it should be clear that, even if small differences in CQAs, within their acceptance limits, were to be introduced, there is no associated clinical safety or effectiveness issue arising from choosing either the FAC or the RBP as a biosimilar comparator, because both of these products must remain true to the clinical profiles described in their marketing applicationsFootnote 8 . In this sense, bridging studies are not necessary; while the careful comparison of CQAs is important in establishing the ‘high similarity’ of a biosimilar candidate to its comparator, there is no additional risk to patients from choosing the FAC or the RBP as comparator as both are approved with the expectation of the same clinical outcomes.
Manufacturing changes to biologics are always justified by data showing that the pre- and post-change products are comparable, as described in the ICH Q5E guideline . While most changes are supported only by analytical comparability data,Footnote 9 occasionally regulators require nonclinical or clinical (pharmacokinetic or even safety and efficacy) comparability data. The huge collective experience with this approach has allowed individual biologics to maintain adequate consistency to remain on the market despite multiple manufacturing changes [2, 7]. While data from bridging studies demonstrate the analytical differences between the FAC and the RBP, their clinical properties, which are the ultimate ‘litmus test’ for accepting a biosimilar candidate as similar to its reference, are explicitly the same. Logically, therefore, these data in common between the FAC and the RBP are sufficient for bridging; no biosimilar candidate has failed to be approved just because the analytical data of the FAC and the RBP were discrepant if there were not also evident differences in their clinical profiles. Consequently, it is possible to define circumstances in which a manufacturing change to a biologic that is approved in one jurisdiction, based upon comparability data, can equally be accepted by the other jurisdictions applying the same guidelines, without a requirement for additional data. Because regulators in the different jurisdictions have similar technical experience and are applying the same principles of comparability (via shared guidelines ), and because the changed products in each of their jurisdictions have a common origin and share the same core data describing their structure and functions, the material representivity of the FAC for the RBP is preserved—any quality differences between the two product versions can be considered inconsequential as regards their use as comparators for biosimilar development. Indeed, any such differences simply broaden the ‘goal posts’  (the design spaceFootnote 10) for the biosimilar.
Whether or not comparator bridging studies have been conducted, the inconsequentiality of any quality differences between the FAC and the RBP is confirmed unequivocally by the fact that biosimilars are routinely expected to be, and have been, approved as biosimilar to the local RBP in different jurisdictions (see Table 3). This closes the logical circle on the concept that, when a reference product satisfies the criteria that we propose (see below), the versions of it approved in different jurisdictions cannot be differentiated as reference comparators for biosimilar development. If this were not the case, sponsors would potentially have to develop and manufacture a product variant for each jurisdiction, which would completely deny the purpose of the biosimilars model. It can be concluded that, as a practical matter, it is generally redundant to conduct bridging studies of the FAC and the RBP—there is, effectively, only a single reference comparator approved globally.
As to the argument that bridging data are necessary to satisfy textual requirements to compare biosimilars to the local version of the originator’s product, we have justified above our position that the data in common between the FAC and the RBP are adequate for this purpose as a scientific matter. We note that regulators have very large discretion in such mattersFootnote 11; in the absence of a strong scientific basis for a requirement, there is ample precedent for regulators either waiving it or effecting a change in regulations or guidance.