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1000
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Abstract/Summary
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Background There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for
the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs).
Objective The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and
clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA).
Methods In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated
by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted
rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications. For
the two withdrawn applications, the comparative efficacy trials suggested biosimilarity, but the quality/CMC package was
not accepted by EMA. We therefore investigated whether a negative MAA outcome could have been predicted based on the
evidence generated in the quality/CMC packages, regardless of clinical trial data. For this purpose, we reviewed the respective
European Public Assessment Reports (EPARs) or withdrawal assessment reports, and the first regulatory assessments
for all these 36 MAAs (i.e. day 120 of the centralized procedure), which are not publicly available. During EMA review,
where significant issues are identified which would preclude a marketing authorisation, these issues are raised as questions
to the applicant and are classified as major objections (MO).
Results In 67% of cases, the outcome of the quality and clinical assessment was the same, i.e. both the quality and clinical
assessments either supported approval or did not support approval. In 11% of cases, MO were identified in the quality part
of the submission but not in the clinical data. In 22% of cases, MO were raised on the clinical data package but not on the
quality data. However, we found no instance where seemingly negative clinical data, including failed efficacy trials, led to a
negative overall decision. In each instance, the failure to confirm similar clinical performance in all investigated aspects was
eventually viewed as not being related to the biosimilar per se but as being due to imbalances in the trial arms, immaturity
of secondary endpoint results, change in the reference product, or even chance findings. Furthermore, when performing an
in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars, we found that in no case
were clinical trial data necessary to resolve residual uncertainties regarding the quality part.
Conclusion The results further support the argument that sufficient evidence for biosimilarity can be obtained from a combination
of analytical and functional testing and pharmacokinetic studies which may also generate immunogenicity data.
This calls into question the usefulness of comparative efficacy studies for the purposes of regulatory decision-making when
approving biosimilar mAbs and fusion proteins.
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