Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges

Abstract

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio™, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory.We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.

Nonclinical Evaluation of PF-06438179: A Potential Biosimilar to Remicade® (Infliximab)

“…The strategy of conducting a single-dose TK and tolerability study in male rats was successful in allowing initiation of comparative clinical (phase I) trials in humans in the US, and is consistent with recent publications, suggesting that the requirement for nonclinical in vivo testing of biosimilars shifts from being a default requirement to being necessary only under selected situations where there is residual doubt regarding similarity that remains following in vitro testing [13, 18–20]. However, because pharmaceutical companies are seeking to develop biosimilar drug products globally, the overall program must meet the requirements of all countries where trials and registration are planned.…”

Looking to the Future of Organ-on-Chip and Toxicity Assessment: a Regulator’s Opinion

“…Scientists are constantly working on ways to reduce the use of animals in research and the MHRA's work in this area was outlined in a 2014 government publication “Working to reduce the use of animals in scientific research” [2]. A paper entitled ‘Waiving in vivo studies for monoclonal antibody biosimilar development: national and global challenges’ was also published in the journal mAbs recently and the authors include myself, other MHRA Toxicologists and scientists from the NC3Rs [3]. …”

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

“…The FDA also suggests that CGQs should be classified into three tiers and there is a statistical approach for assessing CQAs, namely an equivalence testing for Tier 1, a quality-range approach for Tier 2 and descriptive testing (raw data and graphical comparison) for Tier 3. The processes are relatively similar worldwide, although there are differences in how biosimilars are assessed in different countries or regions throughout the world with respect to the need for in vivo toxicity testing [101]. There is also a need to provide evidence that all batches of the biosimilar will fall within the established range.…”