University of Cincinnati
Rowena N. Schwartz, PharmD, BCOP, has disclosed that she has received consulting fees from Heron Therapeutics.
It seems like the discussion of biosimilars among oncology clinicians started before the availability of a biosimilar in the United States. The concern about a drug that was “highly similar” to a biologic rather than identical seemed to center around the importance of these drugs in both supportive care and treatment. I have heard a number of oncology practitioners express concerns when biosimilars are used for the treatment of cancer. As additional biosimilars come on to the market, some will be available for curative intent treatments; it is, thus, important that practitioners, patients, and caregivers review the foundation of biosimilar development to optimize understanding and confidence with the use of these agents in practice. To that end, I discuss some key factors in the pathway to biosimilar approval and how biosimilar agents compare with reference biologics.
What Are Biologics?
Biologics are an essential component of modern medicine. Current and evolving clinical applications for biological products are as diverse as the drugs themselves. A biologic is defined as “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man” by the US Code of Federal Regulations. This definition encompasses many of the drugs used in the treatment and management of individuals with cancer. Monoclonal antibodies, vaccines, and growth factors are all classified as biologics.
Transitioning From Biologics to Biosimilars
Advances in recombinant DNA technology have provided the ability to manufacture biologics, resulting in their ever-expanding role in practice. Of importance, biologics—being protein-based and, therefore, complex structures—are very different from chemical-based, conventional small-molecule drugs. The complexity of each biologic is a key consideration on the path to regulatory approval. Biologics are licensed under the Biologics License Application (351a) of the Public Health Service Act. When the Patient Protection and Affordable Care Act was signed into law in 2010, an abbreviated licensure pathway to allow manufacturers to produce highly similar versions of licensed biologics (ie, biosimilars) was made available in the United States. This pathway was created to be different from the full pathway required for a biologic, addressing the unique aspects of biosimilars, their comparability with biologics, and their substantial differences from small-molecule drugs.
The approval of a biosimilar product includes a comprehensive comparability exercise with the reference, or originator, biologic product. This comparison must demonstrate that the biosimilar and the reference biologic are highly similar and that there are no clinically meaningful differences in safety, efficacy, purity, or potency between the drugs. A stepwise approach is used to compare the biosimilar with the reference biologic, which focuses on structure, function, animal toxicity studies, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical studies. The FDA considers a totality of evidence when evaluating biosimilars. Information obtained in analytical and preclinical testing is the foundation of this evaluation.
Analyzing Structure and Function
Biologics are often large, high-molecular-weight products with complex and heterogeneous structures. Unlike small-molecule drugs with well-defined chemical structures that can be reliably replicated, biosimilars are not exact copies of a biologic product. Although the primary amino acid sequence would match between a biosimilar and its reference biologic, each manufacturer uses a proprietary process and unique cell line for production. Even slight changes in the manufacturing process can result in a modified version of the end product. The current inability to produce an exact copy of a biologic means that a biosimilar must be highly similar but is never identical.
In vitro analyses of biosimilar structure and function are essential. The structure of a proposed biosimilar must be highly analogous to its reference biologic, demonstrating very few differences; any differences between product structures must not result in clinical differences from the reference biologic. This also means the biosimilar must not be considered “better.” The biological attributes of the biosimilar must also be highly similar to the reference biologic, including but not limited to binding to targets, pharmacokinetics and pharmacodynamics profiles, and relative potency. Where comparative clinical studies are essential for the initial approval of a biologic, these molecular and preclinical characterizations are critical for establishing the predictability and for licensure of biosimilars.
Biosimilars are being approved for the treatment of cancer and other diseases. To date, outside of biosimilars for supportive care (eg, filgrastim), only 2 biosimilars for biologics used to treat cancer have been approved by the FDA: bevacizumab-awwb and trastuzumab-dkst. Many additional biosimilars are currently under development, and as the tally of approved agents increases, clinicians must equip themselves with a sound understanding of these drugs to facilitate decision making for practice and the explanation of those decisions to patients and caregivers. How do you foresee incorporating biosimilars into your practice? Please share your thoughts and experiences in the comments box or by answering our polling question.