The vast generic pharmaceutical product market is fertile ground for litigation as companies seek to defend hard-won patent protection for their compounds in the face of fierce biogeneric competition. In the past, standards of equivalency were fairly clear, but today, with the rise of biopharmaceuticals, regulatory agencies have a far more daunting task, as attendees learned at the “BIO 2008” supersession on biosimilars.
Richard Kingham, a partner at Covington & Burling, outlined the EU’s new system, which requires substantial clinical and nonclinical evaluation of biosimilars. The EU recognized that generic procedures were inappropriate for biosimilars because there was no guarantee that the active ingredients were identical.
To cope with these challenges, the framework of the new system assumes that bioequivalence is not sufficient for approval and that additional studies will be required for full confidence in the safety and efficacy of the biosimilar.
To date, the EU panel has issued verdicts on six biosimilars, approving Sompatropin (for which the reference products were Genotropin and Humatrope), Epoetin alfa and zeta (reference product—Eprex), and Filgrastim (reference product—Neupogen). Two products were rejected, including Alfa interferon (reference product—Roferon) and human insulin.
Other agencies are following the EU’s lead. Canada has a draft guidance document for approval under consideration, WHO has issued a preliminary draft guidance on stand-alone versus biosimilar applications, and in the U.S., the Waxman-Clinton-Schumer bill, which provides an abbreviated path for approval of biosimilars, is winding its way through the legislative pipeline.
Scale-Up of Biologics
Production of a biological molecule is invariably more complicated than a small molecule since it requires cloning of gene sequences, transfection of cell lines, upstream and downstream processing, and finish-and-fill procedures. Given so many possible variances, according to Inger Mollerup, Ph.D., vp for regulatory affairs at Novo Nordisk, clinical studies are always required to demonstrate the absence of clinically meaningful differences.
Dr. Mollerup cited her company’s studies on Avonex. After initial development of the drug, scale-up procedures using a different cell line required new clinical studies. Extensive chemical characterization included a human PK/PD study comparing old and new versions and immunogenicity data with extensive follow-up. Additional clinical trials for efficacy, safety, and immunogenicity were required post-approval. A major finding was that the final Avonex was at least fivefold less immunogenic, an observation that could not have been predicted.
There are no definitive technologies currently available to predict how the human immune system will respond to a product, although a number of investigators are exploring properties of T-cell epitopes for their predictive value, Dr. Mollerup said.
“Biosimilars offer high-quality, established treatments at affordable costs and free up R&D funds for innovative drug discovery,” according to Friedrich Nachtmann, Ph.D., head of biotech cooperations at Sandoz. Dr. Nachtmann believes that the EU regulations are working well.
Sandoz’ Omnitrope (somatotropin) was among the first European biosimilar approvals. The firm generated extensive analytical, functional, and clinical data comparing Omnitrope with the original Genotropin. The biosimilar is now approved for the treatment of growth disorders in both children and adults. Sandoz is continuing to introduce other biosimilars as patents gradually expire.
Dr. Nachtmann sees biosimilars as a way out of the cost spiral that pharma companies and consumers are caught in today. With an aging population demanding more and more sophisticated treatments, “supporting a viable biosimilars industry is a key strategy for any government that is serious about solving the problem of delivering affordable pharmaceuticals to an ever-expanding client population, while at the same time freeing up scarce healthcare dollars for R&D,” he concluded.
U.S. Regulatory Process
Craig Wheeler, CEO of Momenta Pharmaceuticals, discussed the regulatory needs of the U.S. with respect to the licensing of biosimilars. “We need creative legislation and constructive dialog with the government,” he argued. Such legislation should empower and fund the FDA to review biosimilar applications by forging a pathway that allows for the possibility of substitutability, he added.
The burden of proof should fall on the applicant to demonstrate equivalence, and there should be appropriate mechanisms to preserve innovation incentives, he said. There should be a fair mechanism for patent review that protects both the innovator and the follow-on biologic under consideration. There should also be an appropriate period of data exclusivity for the innovator.
Wheeler further elaborated that legislation needs to be forward-looking and pro-competitive to spur innovation, pro-quality to raise the standard for analytical technologies, and pro-industry, that is, framed in a manner to bolster the reputation of the biotech community in the public eye through promotion of quality-based, cost-effective medicines.
“Biosimilar regulation is not about inhibiting or preventing legitimate competition, but rather, preserving the incentives for innovation in the development of new therapies,” stated Stephen Juelsgaard, J.D., DVM and executive vp at Genentech. “The biotech sector supports a path for follow-on biologics based on the right balance between lower cost of therapies and the need to maintain adequate incentives.”
According to Dr. Juelsgaard, under the current Hatch-Waxman legislation that governs protection of small molecules in the U.S., the generic compound and the original molecule must have identical structures in order to fall under the same patent umbrella. The problem for biologics patent protection is that under present law, the two substances must be “comparable” or “similar” to qualify for protection. But the biosimilar compound may have a composition that is different from that of the innovator molecule, and therefore, may not be covered by the innovator’s composition patent.
Given the vast R&D costs for a new biological product, a significant data-exclusivity period must be part of the legislation in order to provide sufficient incentive to companies to pursue new biotherapeutics. The current Hatch-Waxman Act, designed for small molecule drugs, is simply not adequate, according to Dr. Juelsgaard.