BioRationality: Bringing the FDA and the USP Together to Revolutionize Biosimilars

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Next to the clinical efficacy testing, comparative analytical assessment of biosimilars with the reference products is the highest cost, and time, item. It is also a difficulty when it comes to collecting reference product batches with different expiry dates.

It is at this stage where pharmacopeias play a pivotal role. For example, the European Pharmacopoeia (Ph. Eur.) sets public standards by providing harmonized quality requirements regardless of the regulatory process for which a given product was approved. If a monograph is available, compliance with such a written standard is required; however, a demonstration of biosimilarity to the reference medicinal product cannot be inferred. The European Medicines Agency’s Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues states that comparison of the biosimilar to a publicly available standard (e.g., a pharmacopeial monograph, is insufficient for comparability). Similarly, the reference standards described in Ph. Eur. monographs are not intended to be used as reference medicinal products (comparators) to demonstrate biosimilarity.

Following the publication of the general monograph Products of recombinant DNA technology (0784) in 1992, the Ph. Eur. actively developed monographs for many first-generation biotherapeutics using the multisource approach, which involved working closely with the various manufacturers of biotherapeutics (Procedure 1; Guide for the work of the Ph. Eur.). During the last decade, however, the majority of Ph. Eur. monographs for biotherapeutics have been developed via an alternative mechanism, which is applied to substances still under patent protection and is based on a close collaboration with the innovator company, offering the advantage of having a public standard in place by the time further products reach the market (Procedure 4; Guide for the work of the Ph. Eur.). The latter procedure was launched in 2008 in a pilot phase for biotherapeutics (P4-BIO pilot phase), which successfully concluded at the 156th plenary session of the Ph. Eur. Commission in November 2016. The work under the P4-BIO procedure elaborates 2 new monographs for monoclonal antibodies (i.e., Golimumab concentrated solution [3103] and Ustekinumab [3165]).

The US Pharmacopeia (USP) had decided to actively develop monographs of biologic drugs until the FDA wrote to the USP in May 2018, requesting that it refrain from producing monographs for biological medications. “Because USP’s proposed revisions would aggravate existing concerns that a monograph could impede or delay the licensure of biosimilars and other biological products, FDA strongly encourages USP to withdraw its proposal. FDA welcomes future interaction with USP on these issues to ensure that biological product monographs do not create an unnecessary barrier to the availability of biosimilars and other biological products to patients. For example, we see opportunities for optional methodological standards that could encourage innovation and product development.”

The FDA was concerned that biologic manufacturers would manipulate the monograph procedure to prevent competition from biosimilars “by incorporating patented characteristics of their product that are not relevant to safety, purity or potency, further impacting competition.” However, this was not a valid argument since the USP could develop the specifications of the reference product based on its multiple batches as required in the testing of biosimilars to enable confirmation of both product and process-based critical quality attributes. Side-by-side testing is needed if the test methods are not validated, a clear step the USP can take. In those cases where validation is not possible, the USP can provide reference standards (not the product) to establish comparability. I do not see any conflict of interest or scientific hurdles in accepting these data. The USP can ensure that the test methods do not infringe on any intellectual property and keep updating the release specifications of the reference product if its formulation or presentation changes.

A detailed study concluded that the time and cost to market can be reduced by more than 20% if product-specific guidelines are available. USP monographs for biosimilars are the most appropriate suggestion to reduce development costs.

I am requesting the FDA and the USP to reform a group, engage in a constructive debate, and create a system that will enable faster and lowest-cost development of biosimilars without compromising their safety or efficacy. A pharmacopeia-based analytical similarity demonstration will be more robust and remove many uncertainties created because of the variable testing approaches taken by biosimilar developers. There is also a need for harmonization between the Ph. Eur. and the USP, a wishful suggestion on my part, but worth trying.

This single change can completely turn the destiny of biosimilars and help bring hundreds of molecules waiting for entry as biosimilars with a dramatic drop in their price as the competition builds in.