Biosimilars: What Providers Need to Know

At IAS 2020, Jonathan Kay, MD, outlined the development, legislation, and economic aspects of biosimilars. He is a professor of medicine and population and quantitative health sciences and Timothy S. and Elaine L. Peterson Chair in rheumatology at the University of Massachusetts Medical School in Worcester, Massachusetts.

Biosimilarity was defined by the United States Congress in the Affordable Care Act as:

• A product that is highly similar to the reference product not withstanding minor differences in clinically inactive components.
• There are no clinically meaningful differences in safety, purity, and potency between the product and the reference product.

Essentially, a biosimilar is a legitimate copy of a therapy that is no longer protected by patent, said Dr Kay. The biosimilar has to undergo rigorous clinical and analytical assessment and be approved by a regulatory agency.

Since 2006, the European Union has approved 58 commercially available biosimilars. While the United States has approved 26 biosimilars, only 15 are commercially available.

Dr Kay reviewed the manufacturing process for biosimilars, which are created by reverse engineering the product using the amino acid sequence disclosed on the reference product’s patent. He noted that the process to create a biosimilar and a bio-originator is essentially the same, but there may be some differences because information related to the reference product is proprietary. For example, the vector of the biosimilar, the way the cells are expanded and grown, and the purification process could differ from the reference product.

While there may be differences in the manufacturing process, the product must be proven to be similar to the reference product and found to have no clinically meaningful differences in safety and efficacy to be approved as a biosimilar.

All biologic therapies are subject to variability, drift, and evolution. “There is normal batch-to-batch variability,” said Dr Kay. During the initial approval of a therapy, manufacturers established proven acceptable ranges of variation during development. As long as a batch fits into that range, it is not considered to have any safety or efficacy risk to the patients, he explained. Dr Kay also defined drift—unintended alteration in the process—and evolution—deliberate changes in the manufacturing processes. For each of these, as long as the product fits into the proven acceptable ranges, it is considered to be the same and does not have to undergo any label changes. However, these changes can have functional and clinical consequences. Compared with bio-originators, biosimilars typically have tighter ranges of acceptable variation, said Dr Kay.

In a phase 3 study that compared a trastuzumab biosimilar SB3 with the reference drug among patients with HER2-positive early breast cancer, 51.7% in the biosimilar group achieved pathologic complete response compared with 42% in the reference product group. While SB3 was determined to be a biosimilar, “this raised questions are to whether it might be a bio-better to trastuzumab,” said Dr Kay. In an analysis to clarify this finding, downward drifts were found in 2018 lots and a second drift was found in 2019 lots of the reference product. The drifts were associated with decreased activity in antibodies, which could have an effect on clinical outcomes, said Dr Kay. When survival of patients treated with SB3 was compared to older lots of trastuzumab, there was no difference, but the decrease in the reference product resulted in loss of efficacy overtime. “This is the only way we might be able to determine if a reference product has lost efficacy over time,” he added.

The United States FDA designated interchangeability to mean a biologic product may be substituted with a biosimilar without intervention of the health care provider who prescribed it. The FDA published final guidance to demonstrate interchangeability, which said a product must be a biosimilar, provide the same clinical results, and the safety of switching from the reference to a biosimilar would not be impacted. Studies designed to demonstrate this use pharmacokinetic endpoints. In the United States, 48 states have passed legislation on biologic agents and substitution.

According to Dr Kay, the justification for biosimilars is that they would extend access and decrease costs for patients by introducing market competition and driving down costs. However, the United States has been slow to adopt biosimilars. This is due to a slow regulatory process, patent litigation by the bio-originators, preferred status given to bio-originators, lack of education among patients and physicians, and no economic incentive, said Dr Kay.

For more coverage of IAS 2020, visit the newsroom.

—Melissa Weiss

Reference

Kay J. Biosimilars for IMIDs: availability, affordability, and interchangeability. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 12, 2020.