The US Biosimilar Approval Pathway: Policy Precedes Science - A Regulatory Perspective
By David Shoemaker, senior vice president, R&D, Rho
With the passage of the Biosimilar Price Competition and Innovation Act (BPCIA) in 2009, the US created new pathways for development and approval of biosimilar and interchangeable products (Section 351(k) of the Public Health Service (PHS) Act (42 U.S.C. 262)), in the hopes of creating a low-cost alternative to expensive, innovator-marketed biologics whose patent terms were expiring. The origin of the BPCIA had its roots in the Drug Price Competition and Patent Restoration Act of 1984, which has provided low-cost generic alternatives to prescription brand-name drugs for the three subsequent decades.
The analogy of “generic” does not transfer well from the realm of small-molecule drugs to that of biologics, due primarily to biologics’ considerably larger molecular size and complexity of manufacturing that may affect the final product in terms of tertiary structure or post-translational modifications. The FDA has issued four draft guidances to help clarify expectations regarding the concept of “biosimilarity” and thereby to assist manufacturers in the development and approval of biosimilars.
However, despite the availability of these guidances, no biosimilars have been approved by the FDA to date. The primary reason is that the additional work required to demonstrate similarity of the efficacy and safety to the original biologic is sufficiently burdensome to make approval via the original approval pathway for biologics (351(a)) equally attractive to manufacturers. Also, by choosing the 351(a) BLA innovator biologic pathway, the company is entitled to a 12-year marketing exclusivity period associated with this development pathway versus as little as 12 months of marketing exclusivity if it was approved as a biosimilar (351(a)(6)).
The FDA espouses that clinical and nonclinical work will be abbreviated for biosimilar approval and that approval will be granted on the basis of the “body of evidence” provided by the manufacturer, but that each application will have to be handled on a case-by-case basis. However, this is potentially much more labor intensive than the traditional biologic development process familiar to pharmaceutical and biotechnology companies. Development of a biosimilar currently requires significant comparability work be agreed upon a priori with FDA and this work must be “front-loaded” in the development program. Depending upon the results of this comparability nonclinical and manufacturing work, additional work most likely will be required. There are several companies who have been successful in gaining marketing approval for biosimilars in Europe who are effectively currently assisting FDA in determining the data package that will eventually be required for approval of a biosimilar in the US.
Also, achieving an FDA determination of true interchangeability of a biosimilar versus an original biologic product as exists for generic and innovator small-molecule drugs will not be accomplished until a great deal more is understood about the biochemical processes generating these molecules and the contributions of the various regions of the molecules to efficacy and safety concerns.
Consequently, while many large pharma companies have announced their intention to develop biosimilars, many manufacturers have chosen to develop alternative products designed to be more than just biosimilar -- biosuperiors or biobetters. These are products similar to the original approved biologics, but with some measurable superiority such as extended therapeutic effect time or a reduced adverse event profile. These products are being developed and approved via the traditional 301(a) BLA pathway for biologics and are required to demonstrate efficacy and safety without the necessity of comparability studies designed to demonstrate their similarity to the originator molecule.
This approach has several advantages. First, it relieves the product sponsor from conducting a large Phase 3 active-control clinical study versus the innovator biologic demonstrating equivalence. Of course, the efficacy of the biosuperior product has to generate data demonstrating a risk/benefit ratio of the same approximate magnitude as the innovator product, but not in a head-to-head comparison. Consequently, the work required for approval of a biosuperior would more closely resemble the 505(b)(2) New Drug Approval (NDA) regulatory pathway for “improved” approved drugs leveraging FDA’s knowledge of previously approved innovator products as opposed to the 505(j) NDA pathway for generic drugs with its expectations of interchangeability.
One might say that focusing on biosuperiors defeats the original purpose of legislation for development of biosimilar products. However, due to the complexity of development of biologics, the expected sales price of biosimilars was anticipated to originally be in the range of 70 to 80 percent of the originator molecule as opposed to the approximately 30 percent of the originator drug that has been documented for generic drugs. Consequently, the price competition that might result from the presence of viable biosimilars on the market was never expected to be game-changing for consumers the way that small-molecule generics have been. For biosuperiors, the degree of superiority represented by the biosuperior competitor may alter this dynamic significantly, perhaps leading to a premium price for the biosuperior relative to the innovator product.
Aside from questions around how to prove “biosimilarity” or the likely effects on product pricing, the current debate raging between the biosimilar and innovator companies revolves around the International Nonproprietary Names (INN) convention for biosimilars. The generic companies argue that all derivatives of an innovator molecule must possess the same INN name. However, the manufacturers of the innovator molecules argue that while similar, the subsequently approved biosimilar molecules will likely possess significant differences in glycosylation and tertiary structure and consequently should be examined separately for adverse events that may not be affiliated with the safety profile of their innovator molecules. However, until a bona fide biosimilar is approved in the US, this discussion is perhaps premature, and assumes that regulatory protein science will eventually evolve to the point where detailed molecular structural information can definitively be matched with the safety and efficacy events a biological product demonstrates.
Hence, the current state of protein science seems to augur approval decisions and court battles focused on the clinical relevance of the superiority rather than the similarity of biosimilar compounds to innovator molecules.
About the author:
David Shoemaker, Senior Vice President R&D at Rho has over 25 years of experience in research and pharmaceutical development. He has served as an advisor for multidisciplinary, matrix managed project teams and has been involved with products at all stages of the development process. He has extensive experience in the preparation and filing of all types of regulatory submissions including primary responsibility for four BLAs and three NDAs. He has managed or contributed to dozens of INDs/CTAs and over a dozen successful NDAs, BLAs, and MAAs. Dr. Shoemaker has moderated dozens of regulatory authority meetings for all stages of development and supported several companies at FDA Advisory Committee meetings. Dr. Shoemaker has authored or overseen dozens of Orphan Drug Designation applications, has developed several successful Accelerated Approval programs, and has secured several Priority Review applications.