Totality of Evidence

Robust analytical, non-clinical, and clinical data will be reviewed to understand the level of similarity of a proposed biosimilar.1

Seeking marketing authorization, biosimilar manufacturers will submit robust analytical, non-clinical, and clinical data.1-3


Since biosimilars are intended to mimic the effect of a known product, the clinical data requirements are more targeted than for reference products and studies will be carefully designed to demonstrate any differences between the biosimilar and the reference product. Furthermore, biosimilars must undergo rigorous analytical studies before approval.

The “totality of evidence” needs to be reviewed holistically to properly evaluate the proposed biosimilar.

Analytical Similarity Assessment

The analytical data of a biosimilar is the foundational component to demonstrating a high level of similarity. The key to assessing analytical data is to understand the quality of the assessment:3

  • Was a comprehensive set of tests conducted so that all relevant biologic activities were tested?
  • Were current state of the art testing methods used to ensure a high level of sensitivity in the assessment?
  • Was the best process for the assay followed to ensure clear resolution of the comparison of the reference product to the biosimilar?

A comprehensive set of analytical testing is needed to evaluate:

  1. Every relevant biological activity that has been identified for the reference product, especially the mechanism or mechanisms of action
  2. Each structural component of the molecule, such as the amino acid sequence, the attached carbohydrates, and the proper molecular folding
Clinical Considerations

The goal of the clinical development program for a proposed biosimilar is to use the data from the pivotal trials to demonstrate that there is no clinically meaningful difference between the proposed biosimilar and the reference product in terms of efficacy, safety, and immunogenicity.1

Once approved for use, it is important to continue to monitor the safety of the new biosimilar product.

Totality of Evidence Approach for the Development of Biosimilars

Totality of Evidence Approach for the Development of Biosimilars

References:

  1. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed November 23, 2016.
  2. Kozlowski S. US FDA Perspectives on Biosimilar Biological Products. Presented at: 2014 Biotechnology Technology Summit; June 13, 2014; Rockville, MD.
  3. US Department of Health and Human Services. Quality considerations in demonstrating biosimilarity to a reference product. Guidance for industry. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291134.pdf. Accessed November 23, 2016.
  4. Chhina M. Biosimilar biological products. Presented at: FDA Basics Webinar; August 19, 2013. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM365448.pdf. Accessed November 23, 2016.
  5. Alten R, Cronstein BN. Clinical trial development for biosimilars. Semin Arthritis Rheum. 2015;44:S2-S8.