T-31: Regulatory and Clinical Perspectives on Non-Comparable Biologics
Hexal A.G Germany
To evaluate and compare the development, regulatory processes and minimum data requirements, pharmacovigilance and available evidence for non-comparable biologics (NCBs) and biosimilar medicines.
Published information on NCBs was retrieved. Alternative names include Intended Copy Biologics, Biogenerics and Biomimics. Products were evaluated against the standards required for approval of biosimilars by the European Medicines Agency (EMA) and United States Food & Drug Administration (USFDA).
Paul Cornes, Comparative Outcomes Group, Bristol, UK.
Andriy Krendyukov, Sandoz Biopharmaceuticals, Holzkirchen, Germany.
Sreedhar Sagi, Sandoz Asia-Pacific, Singapore.
Julie Maréchal-Jamil, Medicines for Europe, Brussels, Belgium.
A biosimilar medicine has been shown to match a reference biologic with regard to quality, primary and higher-order structure, biological activity, efficacy, safety and immunogenicity. Approval by EMA and USFDA is based on the totality of evidence produced by multiple regulatory steps; this includes data from comprehensive analytical characterization and comparability exercises, non-clinical studies, and phase I and confirmatory phase III clinical studies. Manufacturing/production processes must match consistently the high standards for reference biologics. Post-approval, biosimilar medicines undergo robust pharmacovigilance monitoring to ensure their safety in real-world use (a standard approach for any new medicine).
The term Non Comparable Biologic (NCB) is applied to intended copies of biologics that miss out one or more of the obligatory regulatory steps that would confirm comparability for a biosimilar. In some regions NCBs compose more than 90% of follow-on biologics in development. Examples include generic-type regulation, showing only similar structure and pharmacokinetics in small trials, whilst missing out pharmacodynamics, immunogenicity and phase III comparative trials. Without the totality of evidence, it is difficult to predict the safety and efficacy of these medicines in practice.
Meeting reports and published papers give examples from nephrology, rheumatology and oncology where NCBs show increased risk of adverse outcomes. For a limited number of NCBs there are published real-world case series with outcomes suggesting broadly comparable activity to the reference. Worryingly for many NCBs, no clinical data beyond small single-arm studies can be found in the public domain for appraising potential medicines for formularies. Furthermore, position papers from some medical societies have used data about NCBs to raise concerns about biosimilars, without clearly differentiating between them.
Biosimilars have generated confidence over more than a decade of use in Europe. Recent position statements by medical societies in highly regulated regions such as Europe and North America have supported biosimilar medicine use. This support has included concepts such as extrapolation of indications and reassurance around possible switching between reference biologics and biosimilars. These statements need to be interpreted with caution in regions with different regulatory standards. Equal caution is needed when concerns raised about World Health Organization (WHO)-standard biosimilars are based on data derived from NCBs.
The safety and efficacy of NCBs in practice cannot be predicted through the comparability with a reference biologic, since they lack the totality of evidence from a multi-step biosimilar regulatory pathway. Lacking phase III confirmatory data of sufficient scale, it is challenging for them to be seen as novel biologics matching the reference medicine. Instead they are approved by a pathway that lacks one or more of the key components of evidence required by either of the two conventional routes to biologic drug development.
Approval as a NCB does not necessarily imply the product is good or bad – their efficacy and safety in practice cannot be confidently predicted from the limited data available. For many health systems NCBs create a significant challenge in selecting medicines for hospital formularies, where affordability may have to be balanced against the consensus of global regulatory standards.
Reassuringly, some countries that have previously approved follow-on biologics as NCBs with minimum data packages are now adopting the WHO standards used by the EMA and USFDA. However with the large numbers of NCBs already available and with a likely increase, there may still be a legacy of medicines approved as NCBs from earlier eras that will need to be addressed.