Biosimilars: Are they generics?

Article contributed by Shaun Lee Chia Choon.

Shaun Lee is an aspiring clinical research professional with an interest in drug safety and development. He graduated with a Masters of Pharmacy qualification from The University of Bath UK and at the time of writing, is a study coordinator at Kuala Lumpur Hospital.


The short answer is no and here is why.

Generics are conventionally small-molecule drugs, commonly produced via synthetic methods. They are interchangeable with the reference innovator products as their approval depends on the fulfilment of regulatory requirements to be both bioequivalent (comparable pharmacokinetics) and pharmaceutically equivalent (identical active substance). In other words, generics are therapeutically equivalent carbon copies of the reference innovator products.

In contrast, biosimilars (or “follow-on protein products” in the United States) are biological products which are highly similar, but not identical, to the reference innovator products for the approved indications. These pharmaceutical products contain active drug substances derived from living systems which are innately highly variable with regards to their post-translational modifications of proteins. In addition, the active substance of biological products generally consists of high molecular weight protein isoforms folded in specific three-dimensional configurations which are highly sensitive to changes. Consequently, there is increased probability of heterogeneity even between biological products of the same active ingredient and hence, a more comprehensive regulatory pathway is required for the approval of biosimilars compared to generic products.

REGULATORY APPROVAL OF BIOSIMILARS

Following the approval of the first biosimilar product (Omnitrope®) by the European Medicines Agency (EMA) in 2006, there have been many updates on the regulatory processes with regards to the approval of future biosimilars.

The United States Food and Drug Administration (FDA) uses a “totality-of-evidence” approach to approve biosimilars whereas the EMA uses a stepwise approach, which is the method adopted by the Malaysian regulatory body. Nevertheless, biosimilars are approved in both approaches upon demonstration of an absence of clinically significant differences in safety, quality and efficacy profile to the reference product. As a result, the approval pathways for biosimilars are generally more simple than novel biological products, with only selected nonclinical and clinical studies which are primarily comparative studies against reference innovator products.

In addition, the Malaysian regulatory authority imposes requirements for robust post marketing safety studies, particularly on the immunogenicity of certain biosimilars. This is in response to reported safety concerns including the development of antibodies that may attenuate the action of the biological product or neutralise the biological activity of endogenous proteins such as in the rare case of antibody-mediated pure red cell aplasia.

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INTERCHANGEABILITY AND SUBSTITUTION POLICIES

Presently, the Malaysian regulatory authority does not permit the interchangeability and automatic substitution of biosimilars and reference products at the pharmacy level. In contrast, automatic substitution by pharmacists is permitted under Section 351(i) of the United States Public Health Service Act once a biosimilar is given an “interchangeable” status by the FDA. This is supported by a recently released draft guidance on the interchangeability of biological products by the FDA in January 2017, in line with the Biologics Price Competition and Innovation Act of 2009. While the EMA pioneered the approval of biosimilars, the agency does not have the authority to decide on the interchangeability status of biological products; this decision resides with the regulatory authorities in individual EU state members.

TAKE HOME MESSAGE

The development of biosimilars has increased treatment options at lower costs, thus, improving the access to medicines for a larger patient pool. However, healthcare professionals should be aware of the regulatory approval pathways and potential differences between biosimilars and the reference innovator products to make an informed treatment decision which is in the best interest of their patients.