Totality of the Evidence

All of the data – including analytical, non-clinical, and clinical data, is reviewed to understand the level of similarity of a proposed biosimilar.

Evaluation of biosimilar data requires a mental shift for many stakeholders because the analytical data package is as critical as the clinical data package. For an innovative biologic, the fundamental understanding of each product is missing. Therefore, clinical trial design and the resulting data are highly scrutinized to understand the risk and benefit of a medicine.  For a biosimilar, there is a foundation of knowledge based on the reference product. Therefore, a step-wise approach is taken. First, analytical testing to demonstrate physical, chemical, and functional similarity provide the bridge to the reference product and along with non-clinical studies is fundamental to the design and understanding of the subsequent clinical trials. The clinical trials are conducted to understand whether a proposed biosimilar stays in the body for the same amount of time, and can be expected to have a highly similar efficacy and safety as the reference product. 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:

  • 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 needs to test 1. every relevant biological activity that has been identified for the reference product, especially the mechanism or mechanisms of action and 2. each structural component of the molecule such as the amino acid sequence, the attached carbohydrates and the proper molecular folding.

Sensitivity refers to the point at which you can detect something. An analogy for sensitivity of testing can be seen in baking when sugar is added. The amount of sugar added will impact the taste of sweetness. A little sugar sometimes does not result in the taste of sweetness. If an insensitive analytical test is run, lack of similarity may not be detected.

Resolution provides the ability to see the details of a molecule. The difference in the level of resolution in a test can be seen in human weight scales. Older weight scales can closely approximate weight within 2 to 3 pounds. Modern scales can give a precise weight to the first decimal. Both are weight scales, but the level of precision is different.  In some circumstances the difference in resolution of the two different tests may not matter, but in some cases the differences may matter to the efficacy of the biosimilar.  In general, a more precise test provides greater confidence in the level of similarity of two products.

When the right test is used and the right method applied, the analytical test can give meaningful clarity into the level of similarity of a biosimilar to its reference product. In contrast, tests can also be run, but not provide true insight. The right set of tests that are comprehensive, sensitive and resolving are the critical components to good analytical testing.

Clinical Considerations
The goal of the clinical development program for a proposed biosimilar is to demonstrate that there is no clinically meaningful difference between the proposed biosimilar and the reference product – in terms of efficacy, safety and immunogenicity. The understandings from clinical testing depend on the degree of similarity demonstrated in the analytical similarity assessment and non-clinical testing. Clinical studies include assessment of pharmacokinetics (how long the medicine stays in the body), pharmacodynamics (how the medicine impacts the body), safety, and efficacy. As many medicines can be used to treat more than one disease or condition, the choice of patient population can be important for biosimilars. In particular, biosimilar clinical trials should be performed in populations that are sensitive enough to detect clinically meaningful differences between the proposed biosimilar and the reference product. These studies should be designed to demonstrate that the proposed product has neither decreased nor increased efficacy compared to the reference product. In addition, these studies should demonstrate a similar safety profile for the biosimilar and the reference product. 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