Per the Food and Drug Administration’s (FDA) draft industry guidance on biosimilars from February 2012, a biological product may be demonstrated to be “biosimilar” to an already-licensed FDA biological product (the “reference product” or innovator product) if data show that the product is highly similar to the reference product notwithstanding minor differences in clinically inactive components AND there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency. However, why are we stuck with “similar” in biosimilar and not “generic” such as “biogeneric”? Are biogenerics possible so that we can have an “identical” copy of both an innovator and follow-on biologic? I would argue that biogenerics are possible to the level of sameness seen between innovator and generic small molecules and that we will one day see biogenerics on the market.
Commonly accepted arguments for describing biosimilars as only the “same” but not “identical” to the reference product include:
- Biologics are large molecules that are much more complex than small molecules, and follow-on products can only hope to be similar.
- It’s the process not the product.
- Small variations in impurity profile can impact the safety and efficacy of the product.
Let’s evaluate what it means to be “identical” by analyzing small molecule generics from the perspective of drug substance (active pharmaceutical ingredient, or API) being structurally identical to the reference product. The FDA requires that the drug substance for generics of small molecules meet certain thresholds for impurities but differences can exist relative to the reference product that may produce toxic or unexpected pharmacological effects. Furthermore, impurities in generics must be evaluated and monitored to ensure that there are no differences in clinical safety and efficacy between manufacturers or even between batches of API. Therefore, generic small molecule therapeutics are “identical” to the reference product because of the relative ease of chemical synthesis and a manageable impurity profile that can be characterized relatively easily, but they are not 100% identical to the reference product in every respect (e.g., there may be variations in impurity profiles below threshold levels). Fundamentally, follow-on biologics are no different than generic small molecules in that impurity profiles can have negative and potentially dangerous consequences. Biologics are simply more complex and currently we lack the breadth of scientific tools for biologics to enable the level of sameness seen between innovator and generic small molecules on a molecular level.
Biological sciences continue to improve mostly through academic institutions focusing on basic science and research, and these advances eventually will trickle down into pharmaceutical know-how. While the hurdles are many and complex, science does not stand still, and the ever evolving knowledge of biologics will lead inevitably to novel tools and more sensitive methods for synthesis, purification, and analysis of biologics. A look at the evolution of biological sciences over just the past few decades makes it difficult to imagine that it will not continue to evolve and improve. Scientifically, a biogeneric (i.e., an “identical” copy of an innovator’s biologic comparable to small molecule generics) is absolutely a possibility, but the challenge will be to have a combination of biological science, industry practices, regulatory structure, and legal framework evolve as well to allow for biogenerics to be realized in the pharmaceutical marketplace.