Content Series:

Challenges in clinical development of biosimilars

Written by :

  • Dr Alex Kudrin, MD, MBA, PhD
  • Biopharmaceutical Consultant
  • United Kingdom

In last decade more than 40 similar biological products were approved in EU, US, Canada and Japan and these constitute biosimilars to somatotropin, erythropoietin, filgrastim, parathyroid hormone, heparin, infliximab, adalimumab, trastuzumab, bevacizumab and rituximab. Some of the clinical development programs for biosimilars included >600 patients and studies were required to include at least one year of safety and immunogenicity surveillance. In addition to pre-marketing clinical requirements, a number of sponsors were requested to run extensive registries and postmarketing pharmacovigilance activities. Whilst regulatory requirements are overall comparable between US and EU, there are some inherent differences that force sponsors to execute larger studies and often use different clinical endpoints and study designs. The typical expectation for biosimilar pivotal comparative efficacy study is to demonstrate therapeutic equivalence and for some types of products this means that studies around 600-800 patients are required. The costs of these studies can exceed 60-80 million USDs and require large operational efforts on a global scale in opening multiple sites, ensuring regulatory compliance and timely completion. There are cases when some sponsors spent in excess of 5 years to complete a large pivotal study and yet being unable to accomplish registration goals in all jurisdictions. Despite that both EMA and FDA and other stakeholders are discussing ways for abbreviating clinical development programs and increasing reliance on analytical similarity data, very little progress has been made and there are regulatory obstacles facing sponsors in enabling abbreviated / tailored clinical program to be accepted by all jurisdictions.

Therefore, sponsors who are planning to initiate development of complex biosimilar products should consider multiple factors which are not limited to the following:

  • Addressing residual differences and uncertainties in the analytical studies to enable abbreviated clinical program
  • Harmonisation and addressing different requirements from FDA and EMA in respect to biosimilar clinical studies
  • Multiple iterative discussions with regulatory agencies for agreement on acceptance of proposed clinical studies
  • Cost and time-related considerations in conducting clinical studies, including time to the market launch and competitive landscape
  • Operational feasibility of the proposed clinical studies
  • Leverage of the proposal program to prayers, physicians and patients

Considering regulatory, operational, cost and time-related challenges in executing biosimilar clinical studies, sponsors and clinical research organizations should be well equipped with relevant knowledge and expertise on how to overcome these obstacles and ensure successful approval and launch of the biosimilar. There are additional clinical considerations in respect to postmarketing pharmacovigilance and risk management plan activities and generating the data on switching. The interchangeability requirements for US cover a separate set of clinical studies that should include switches back and forth from reference product to biosimilar to demonstrate that pharmacological profile and safety remain stable and similar.

In conclusion, the clinical development of biosimilars is complex and requires comprehensive understanding of regulatory requirements and knowledge around operational execution of these studies on the global scale.


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