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With five therapies already approved by the Food and Drug Administration, and with more than 60 in development, the term “biosimilars” will be seen and heard much more frequently in the U.S. health care system throughout the next decade.
So what exactly are biosimilars? Often incorrectly referred to as “generics” for biologic medicines, a biosimilar is a biologic that is “similar” to another biologic product already on the market. However, unlike small molecule generics, biosimilars cannot be exact copies of the reference product due to being comprised of very large complex molecules made from living cells, rather than by a straightforward chemical synthesis.
Biologic medicines first became available 25 years ago and have revolutionized the treatment of some of the most complicated and life-threatening illnesses, including multiple sclerosis, rheumatoid arthritis, and a variety of cancers. While biologics have transformed the medical landscape, they are significantly more expensive than traditional, small molecule medicines. For this reason, clinicians and patients have welcomed biosimilars as a new category of therapy, as they have the potential to increase competition and eventually lower the cost of these life-changing treatments. In the U.S. alone, the cost savings from using biosimilars in comparison to the original biologic are projected to be between $40 and $250 billion over the next 10 years, with the first biosimilar to hit the U.S. market expected to contribute about $5-7 billion in savings.
However, the foundation of successful biosimilars uptake is built on strong data. As a prescribing physician, I heavily rely on this data when developing a treatment plan for my patients. While generally welcomed by physicians, interchangeable biosimilars complicate treatment regimens as they “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” Therefore, the development of biosimilar interchangeability standards must ensure that patients receive drugs consistent with their physician’s treatment plan. Physicians know what’s at stake for our patients — and we want to be able to convey confidence about the safety and effectiveness of interchangeable biosimilars.
In January 2017, the FDA released the much-anticipated draft guidance addressing the standards for biosimilar interchangeability. By the May 19 deadline, more than 50 stakeholder groups — including the American College of Rheumatology and the Biologics Prescribers Collaborative — submitted comments. Comments showed stakeholders’ encouragement of the guidelines FDA set forth, which would require the biosimilar product to meet additional regulatory standards beyond being highly similar to the reference product in order to demonstrate interchangeability. According to the draft guidance, an interchangeable biosimilar must be “expected to produce the same clinical result as the reference product in any given patient,” and “for products that are administered more than once to an individual, the safety and efficacy risks from switching back and forth between a biologic and biosimilar product must not be greater than the risk of using the original biologic without switching.”
Data required to demonstrate biosimilarity should be robust and risk-based to build prescriber confidence in this new class of medicine. It is critical that we, as prescribers, have all of the information we need to make informed decisions with our patients.
Of utmost importance for interchangeable biosimilars is to demonstrate that alternating between drugs won’t cause patients to “become immune” to them. This is called immunogenicity. We strongly support the FDA’s proposal for clinical trials with multiple switches to study immunogenicity. Clinical trials that study what happens when patients switch back and forth twice from the reference brand drug (A) to the biosimilar (B) (ie, A, B, A, B), a protocol that requires three switches, are a reasonable attempt to simulate what patients are likely to experience with changing formularies in a multi-payer and ever-changing market. However, there are several methods for determining immunogenicity — such as measuring levels of drug during the low point or “trough” between doses, or measuring levels of antibodies patients make that neutralize the drug. FDA should consider standardizing this testing for manufacturers to use for all products submitted for interchangeability.
Additionally, FDA should remain cautious when granting approval based on extrapolation. In this process, a biosimilar can be proven to be highly similar to the reference biologic in a clinical trial in one disease, and then approved for use in additional diseases for which the reference biologic has been approved. Caution is necessary here for multiple reasons: a reference biologic may work through different pathways in different diseases; patients with different diseases have different immunogenicity profiles; and if a biosimilar is not deemed interchangeable in all diseases for which a reference product is approved, there would be a risk of inadvertent substitution or misprescribing. Therefore, care must be taken in the final FDA guidance, and throughout the approval process, to promote and ensure that a drug pursuing interchangeability has successfully demonstrated extrapolation for all indications for which the originator is approved.
Lastly, the product label is a critical tool for physicians to make the best prescribing decision. Therefore, every biosimilar label should include a statement of whether the biosimilar is interchangeable with its reference product and/or other biosimilars on the market and for which specific indications interchangeability was demonstrated. Notably, the guidance did not outline the naming conventions that will be applied to products found to be interchangeable. Distinguishable names for biosimilars deemed interchangeable will reduce any confusion among health care providers and ensure that manufacturers can better report any adverse events.
As with any new therapy coming to market, there will be a learning curve for health care providers and patients alike. In the end, biosimilars give us the opportunity to overcome the trade-off between cost and innovation, and physicians are encouraged by their promise.
Angus Worthing is a practicing rheumatologist in Washington, D.C.; chairman of the American College of Rheumatology’s Government Affairs Committee and a scientific adviser for the Biologics Prescribers Collaborative.
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