When the Supreme Court upheld the constitutionality of the Patient Protection and Affordable Care Act on June 28, the impact was diverse and widespread. Relief was felt in one corner of the pharmaceutical industry, however, as the decision protected continued research and investment in a relative newcomer to the industry: the biosimilars.
Enacted as part of the PPACA on Mar. 23, 2010, the Biologics Price Competition and Innovation Act of 2009 amends the Public Health Service Act § 351(k) to create an “abbreviated licensure pathway” for biological products shown to be biosimilar to or interchangeable with a biological reference product already licensed by the Food and Drug Administration. Per the revised standards of § 351(k), a proposed biological product with demonstrated biosimilarity (i.e., a “biosimilar” product) can come to market by relying on certain existing scientific knowledge regarding the safety, purity, and potency of the reference product.
What does this mean?
In simpler terms, the “reference product” is a prototypical drug: a relatively small molecule with an equally uncomplicated chemical structure, synthesized in a laboratory. Drug development generally has two distinct prongs: at the big-picture level, preclinical and clinical trials evaluate the safety and efficacy of a drug in treating a particular medical condition, while a separate set of R&D experiments attempts to determine the drug’s molecular targets (receptors) and the downstream cellular signaling pathways it regulates. The advantage of small-molecule drugs is the reliability and reproducibility of both their physiological effects and the underlying molecular bases. This characterization’s utility is limited, however, because the drugs don’t naturally occur in the body, and subsequent unexpected and unwanted side effects are a familiar concern.
Biosimilars may solve this latter problem. Briefly, biosimilars are proteins: typically, either antibodies or recombinant versions of endogenous proteins. They interest the pharmaceutical companies because their gene sequences are usually known, making them amenable for therapeutic development, and because their biological effects are similar to or more powerful than typical drugs. The promise of biosimilars is apparent: as naturally occurring molecules, the body should tolerate them better.
They also have plenty of potential downsides. Notably, biosimilars (and their targets) are much larger and have a more complicated structure than typical drugs, so they have greater potential to interact with other molecules in the body. Endogenous proteins also usually have more than one target to begin with, and they may have post-translational modifications that alter their function. In the body, their expression is closely regulated, because cells express proteins only when and if they need them. Perhaps most importantly, while a biosimilar’s effect on one pathway may be similar to that of a branded drug, it is not necessarily biologically identical. A biosimilar may interact with a different portion of the target, or it may regulate its function via an entirely different mechanism. If the target is a member of a chain of communication within the cell, the biosimilar could achieve the same desired effect by interfering with a different member of the chain. Ultimately, the implications of these differences may in fact be quite profound, as individual proteins often serve numerous cellular functions.
What all this boils down to is that the regulators should scrutinize the equivalency of biosimilars and their reference drugs with great care. Biosimilar manufacturers must fulfill the testing requirements necessary to bring their products safely into the pharmaceutical market. Fortunately, the FDA’s draft guidance language, issued earlier this year, indicates awareness of these problems. Per § 351(i), the FDA must find that a biosimilar is “highly similar” to the reference product, with “no clinically meaningful differences” between the biosimilar and the reference drug in terms of safety, purity, and potency. To do so, a biosimilar must satisfy a fairly sophisticated totality-of-the-evidence standard, including comparisons of the biosimilar and the reference drug with respect to structure, function, animal toxicity, human pharmacokinetics and pharmacodynamics, clinical immunogenicity, and clinical safety and effectiveness. The guidance leaves some questions unanswered, however: to name a few, the extent of interchangeability required to satisfy the “highly similar” standard and specific requirements for the testing involved.
Thus, in developing biosimilars, the drug manufacturers’ challenge is not so unusual. Besides meeting regulatory standards, clinical safety and efficacy testing for pharmaceuticals is extremely time-consuming and expensive; meanwhile, sick people and their supporters clamor for new treatments. It seems reasonable for them to at least try to expedite the process by piggybacking on existing scientific results demonstrated for the reference products.
While the need for effective medications is great, however, we must ensure that these drugs meet the highest quality safety standards for the benefit of the patients they are designed to serve. We can look forward to plenty of litigation to clarify the meaning of terms in the FDA’s draft guidance as drugmakers’ new confidence propels biosimilars onto the market.