Rules for Evaluating Biosimilars Put Applicants Through Hoops

The FDA will make a final determination on regulations intended to permit the sale of ‘follow-on’ biologics

Thomas Morrow, MD

As insurers face the extreme costs associated with biologic agents, they wait for the FDA to create standards to ensure equal safety and efficacy for biosimilars.

The discovery of the ability to modify the DNA of living organisms and use it to create novel proteins has revolutionized the pharmaceutical industry. It has brought new and highly effective therapies to patients for whom small molecules have failed to provide relief.

But from a payer perspective, this relief has come at a price. The cost of biologic drugs has, in many cases, dwarfed the cost of the small molecules. In addition, in the United States there is no legal pathway by which these complex proteins can be made and marketed in a generic manner, even though the patent for many of these drugs has expired or is nearing its expiration date.

Son of Hatch-Waxman

Since the passage of the Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act), payers have experienced tremendous price relief as many of the most widely used small molecules have gone generic. Payers have longed for the day when similar relief occurs for biologic drugs. But the biological system used in manufacturing a biologic drug can have a significant effect on the structure and function of the product, presenting challenges in evaluating protein products solely by the physiochemical and functional testing done on the small molecules

Recently, after a three year delay, the FDA released a series of three guidance documents based on the Biologics Price Competition and Innovation Act (BPCI Act), part of the Affordable Care Act of 2010.

The BPCI Act amends the Public Health Service Act and other statutes to create an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, a biological reference product licensed by the FDA.

The three documents are:

  • Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
  • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
  • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009


In the 1980s the FDA began to receive marketing applications for biotechnology-derived protein products.

In 1996 the FDA provided “Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Products” which explained to an applicant how, through a combination of analytical testing, functional assays, assessment of pharmacokinetics and/or pharmacodynamics, and study of toxicity in animals, as well as clinical testing, a manufacturing change proposed by the manufacturer of a reference product would not adversely affect the identity, purity or potency of its FDA- approved product.

This guidance has allowed the FDA to approve many manufacturing process changes for licensed biological products based on product comparability before and after the process change. In some cases, these studies have led the FDA to require additional nonclinical or clinical testing to prove comparability.

These documents have defined a biosimilar as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”

Replication errors

The FDA acknowledges that in organism-derived products there are low levels of replication errors in the DNA encoding of the protein sequence and amino acid mis-incorporation during translation and that most protein products undergo some post-translational modifications that can alter the functions of the protein. The FDA advises that an applicant determine the relative levels of these protein variants in the comparability studies.

The FDA also stated that multiple lot comparisons of both the reference and the biosimilar product, with a side-by-side analysis, must be performed. If differences are found, they need to be clearly described and discussed and the potential effect of the differences on safety, purity, and potency should be addressed and supported by data.

Since therapeutic protein products can be produced by microbials, animal cells, and human cells, the FDA suggests keeping the expression system as close as possible to that of the reference protein.

In addition, impurities can derive from cell substrates and cell culture components, such as media and antibiotics, process-related reagents, solvents, leachables, endotoxins, and others.

Clinical studies

The FDA finally states that the application “must include a clinical study or studies sufficient to demonstrate safety, purity and potency in one or more appropriate conditions for which the reference product is licensed and intended to be used, and for which licensure is sought for the biological product.”

The agency also says that “the scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products” after the other data are analyzed.

The FDA discusses specific study design and statistical analysis of these studies and specifically states that the studies should include immunogenicity studies that address binding antibodies, neutralizing antibodies, and other immune responses. Clinical studies “should be designed such that they can demonstrate that the proposed product has neither decreased nor increased activity compared to the reference product. Decreased activity ordinarily would preclude licensure of a proposed product.”

Public comment

These long awaited FDA guidance “drafts” provide the first glimpse of how the FDA will address the market desire for biosimilars. The requirements are considerable and are designed to balance the market desire with the concerns of the scientists and clinicians who are cautious about the safety and efficacy of biosimilars. The FDA is awaiting comments before finalizing these documents and processes. One thing is certain: Tomorrow’s Medicine will eventually include biosimilar products that will result in increased competition.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at [email protected]
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.