This month, Elena Wolff-Holz, MD, PhD, chair of the European Medicines Agency’s (EMA’s) Biosimilar Medicinal Products Working Party, together with coauthors from the EMA and the Federal Institute for Drugs and Medical Devices in Germany, published a new paper in which the team outlines the extent of clinical confirmation of biosimilarity, taken together with analytical and functional data, that is considered necessary for biosimilar drugs to be approved in Europe.
In recent months, the discussion about whether the biosimilar development paradigm can be made more efficient has gained new strength, with the publication of papers that argue that some studies generally undertaken to facilitate biosimilar approval are unnecessary or even unethical in nature.
This month, Elena Wolff-Holz, MD, PhD, chair of the European Medicines Agency’s (EMA’s) Biosimilar Medicinal Products Working Party, together with coauthors from the EMA and the Federal Institute for Drugs and Medical Devices in Germany, published a new paper in BioDrugs in which the team outlines the extent of clinical confirmation of biosimilarity, taken together with analytical and functional data, that is considered necessary for biosimilar drugs to be approved in Europe.
Up to July 2019, a total of 91 marketing authorization applications for biosimilars (including duplicate authorizations) have been submitted to the EMA, write the authors, and 61 products have been given positive opinions from the Committee for Medicinal Products for Human Use and have been approved by the European Commission. The foundation of demonstrating biosimilarity to the EMA, the authors note, is analytical and functional comparison of the biosimilar and its reference, followed by confirmation of biosimilarity using clinical data.
Generally, the authors write, 1 confirmatory randomized controlled trial will be conducted to assess efficacy, safety, and immunogenicity, though in orphan indications in which such a trial might not be feasible, exceptions may exist. They note, however, that analytical and functional in vitro assays are “generally more specific and sensitive than studies in humans” at detecting potential differences.
The extent of clinical work needed varies by molecule; for example, biosimilar teriparatide, a single-chain, nonglycosylated protein, does not require an efficacy or safety trial, while biosimilars of infliximab, adalimumab, trastuzumab, and bevacizumab, which are more complex, require safety and efficacy trials in sensitive populations.
Comparative pharmacokinetic (PK) studies, however, remain a bedrock of development, and in the presence of suitable pharmacodynamic (PD) endpoints, a PK/PD study “may be sufficient clinical work for marketing approval.” The authors point out that, in recent years, insulins, pegfilgrastim, and low—molecular-mass heparins have derived their pivotal evidence from PK and PD studies, and comparative efficacy trials were not deemed necessary. More complex products will still require comparative safety and efficacy trials, however, though “there should always be a sound scientific rationale for conducting clinical studies.”
With respect to efficacy end points, clinical end points should be sensitive to potential clinically relevant differences, and hard clinical end points—like overall survival—are “rather insensitive in this respect,” the authors say. Thus, PD endpoints are preferred to establish similar efficacy. For smaller proteins, PD parameters—like absolute neutrophil count for granulocyte-colony stimulating factor therapies or serum calcium levels for teriparatide—are preferred. For larger molecules, such as eculizumab, a potential PD marker could be serum lactate dehydrogenase level.
According to EU guidelines, comparability margins should reflect the largest difference in efficacy that would not matter in clinical practice; acceptable equivalence margins will depend on patient populations, end points, concomitant therapy, and estimated treatment effect; population differences should be considered when planning these margins.
The paper also provides case studies that show how the totality-of-the-evidence approach to biosimilar development is currently handled by regulators:
The authors write that guidance documents that put forth the requirements for the development and licensing of biosimilars must be considered living documents, and should be revised and updated as needed. They conclude that, as experience and analytical capabilities mature, and as understanding of structure—function relationships progresses, “a continuing reduction in clinical data requirements for biosimilar developments can be foreseen.”
Wolff-Holz E, Tiitso K, Vleminckx C, Weise M. Evolution of the EU biosimilar framework: past and future [published online September 20, 2019]. BioDrugs. doi: 10.1007/s40259-019-00377-y.