Over the next few years, the patents for many therapeutic biologics will expire, allowing drug manufacturers to request US Food and Drug Administration (FDA) approval for biosimilars, medical products which are almost identical copies of an original biologic (referred to as “originator”).
Biologics, which were first developed in the 1980s using recombinant DNA technology, are versions of proteins or complex polypeptides naturally found in our bodies, either mimicking them or carrying out a modified function. Currently approved biologics include, among many others, vaccines, enzymes, antibodies, and insulins. Therapeutics in the biologic class are significantly more complex than traditional chemical drugs, given their much larger molecular structures. Because their manufacturing processes are difficult to replicate and involve some proprietary processes, it is virtually impossible to generate biosimilars that are exact copies of their originators. Because of this, they may be structurally different or carry alternative molecular modifications. Therefore, biosimilars must have demonstrated to have the same clinical benefit as their reference product.
To achieve this, biosimilars are developed to the highest scientific standards under rigorous regulatory requirements. According to the Biologics Price Competition and Innovation Act (BPCIA) passed by the US Congress in 2010, a “biosimilar” is “highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and “there are no clinically meaningful differences between the biological product and the [FDA-licensed biological] reference product in terms of safety, purity, and potency of the product.” The BPCIA also made more stringent requirements for “interchangeable” (as opposed to “biosimilar”) biologic products, and directed the FDA to establish guidelines for manufacturers to prove that their drugs meet the standards of “biosimilarity” and “interchangeability”. The final guidance for demonstrating biosimilarity was issued in 2015, at about the same time that the first biosimilar was approved in the US. The first draft guidance for demonstration of interchangeability was made available last January, while the final guidance is not expected until 2019. Due to lack of guidance from the FDA, none of the biosimilars approved until now have therefore obtained interchangeable status, which would allow for automatic substitution by pharmacists without the consent of a physician1.
Their development of biosimilars follows a systematic process, using the most modern technology. Although biosimilar manufacturers must demonstrate the safety, purity and potency of their products just like manufacturers of the originators, a key difference is that each biosimilar must be rigorously tested to prove that it is not significantly different from its originator before obtaining regulatory approval.
The Biologics Price Competition and Innovation Act (BPCIA) of 2009 authorized the FDA to establish a regulatory pathway for biosimilars. The criteria for such pathway not only determine its effectiveness in assessing a biosimilar relative to its originator, but also affect the difficulty and cost of developing and marketing a biosimilar, influencing the price at which it is marketed.
The FDA has issued guidelines for the generation of data supporting biosimilarity of a candidate product with respect to the reference originator 2,3,4. It recommends a stepwise approach, with evaluation of residual uncertainty about the biosimilarity of the two products at each step. It is expected that the design of the clinical development program for each biosimilar will be different depending on the intended strategy to demonstrate biosimilarity. The type and scope of each clinical study will depend on the degree of residual uncertainty identified after extensive “structural and functional characterization” of the candidate biosimilar. Through this process, researchers examine the structural makeup of each product and test product attributes for significant variation. If there are clinically relevant differences between the proposed biosimilar and the reference product, one or more comparative clinical studies will be needed to demonstrate biosimilarity — otherwise, the product may receive biosimilar classification.
As commercial biologics lose patent protection in the near future, there will be increased opportunities to develop and launch biosimilars. The choice of clinical development strategies that meet regulatory expectations will be critical for manufacturers to achieve a competitive edge in what will be a complex marketplace.
1 -ENABLING COMPETITION IN PHARMACEUTICAL MARKETS Fiona Scott Morton and Lysle T. Boller Yale School of Management; https://www.brookings.edu/wp-content/uploads/2017/05/wp30_scottmorton_competitioninpharma1.pdf