Defining the U.S. Biosimilars Program: The FDA Regulators' Take

Janet Woodcock, the Director of the Center for Drug Evaluation and Research (CDER) at the FDA and her colleagues recently discussed the development of the U.S. BioSimilars Program in a perspective in the NEJM (N Engl J Med 2011; 365:385-388).

The program is part of a movement to provide access to biologic products and therapies to patients that may not be able to receive the treatments due to high costs. The program was initiated upon approval by Congress of the Biologics Price Competition and Innovation (BPCI) Act in 2009. The BPCI Act authorized the FDA to oversee a shortened path for the approval of biologics that are "biosimilar" to already approved products, and the Affordable Care Act established a path for approval of biosimilars. The legislation allows for approval of biosimilars after the maker of the original patented biologic has had twelve years of patent exclusivity.

Biological products (biologics) are defined broadly as vaccines, antibodies, blood and blood components, allergenics, somatic cells, gene therapy, tissues and recombinant therapeutic proteins. Basically, complex molecules  that are produced by cells or extracted from cells that cannot be synthesized in a test tube. These products are typically expensive to develop and manufacture and come with a large price tag for patients.

The term "biosimilar" or "follow-on biologic" are essentially "me too" products that can be marketed after the expiration of a patent: biologics claim to have similar properties to the existing biologic product. However, unlike small molecules which have an exact chemical formula that's easily replicated, biologics are complex molecules that cannot be identical, only similar, because they are made by cells and not in a lab.

Biologics cause immunological responses, and minute differences in amino acids between biologics can produce vastly different reactions in a patient. Therefore, safety evaluation for these needs to be much more rigorous; potentially as rigorous as that for new FDA drug applications (NDA). The FDA does not currently allow the approval of generic biologics through the same, 1984 U.S. laws that allow for the abbreviated approval of nonbiological generic compounds.

While generic versions of biosimilars have been sold in Europe since 2006 (Hospira's Retacrit, a biosimilar of Amgen's erythropoietin, for example), the U.S. has been slower to create a biosimilars approval process and there is no deadline for establishing this approval pathway.

In November of 2010, the FDA held a two-day hearing on the potential approval pathway for biosimilars from pharmaceutical companies, pharmacy groups, academics, and doctors who treat patients with biologics.

Generic companies favor extrapolating safety and efficacy data of a biologic from one indication to another as long as there is proper scientific justification. The Alliance for Affordable Medicine, a group of employers, drugmakers, consumer groups, and pharmacies also support expanded access via expedited evaluation as human trials, especially randomized ones, are not always necessary or ethical. Brand name companies favor a more rigorous review process, stressing that such data extrapolation could be dangerous. A middle ground of safety and scientific rigor, with careful and scientifically-based extrapolation will likely occur in order to keep prices of biologics down. Many patients find it necessary to cut their dosage or miss doses in order to afford their drug.

In their perspective, Dr. Kozwolski, Dr. Woodcock, and the other authors highlight that biosimilar development requires a new regulatory framework. The first and most important part of this framework is the establishment of scientific criteria that address 'how similar is similar enough for a substitution biological drug?' For example, which structural features, amino acid sequence, glycosylation, protein folding, are essential to replicate the intended effect of the product? Additionally, immunogenicity must be addressed, as chemical modifications can easily change the immunogenic reaction of a patient to a biological compound.

The FDA regulators highlight that the FDA has relevant knowledge about biologics as relevant assays have been used to characterize these agents since the 1990s. The FDA is also carefully analyzing the data available from their counterparts in Europe at the European Medicines Agency (EMA), which has published guidelines on biosimilars in 2005.

The clear message is that there will not be a "one size fits all" systematic assessment of biosimilarity, given the complexity of these molecules. Developers will need to integrate different types of both preclinical and patient evidence. The regulators communicate that "an extensive product review will be required to determine how much additional data are needed for a biosimilar." The FDA will consider the product's "complexity, formulation, stability, and usefulness of biochemical and functional characterizations" and incorporate these factors into a risk-based approach.

The creation of the new paradigm of biosimilar evaluation is ongoing but still in its early stages. The rules of interchanging a biologic for its biosimilar counterpart are also still in development.

"A biologic will be considered interchangeable with a reference product if the developer demonstrates that it can be expected to produce the same clinical result in any given patient and that the risk associated with alternating or switching between the two products is not greater than that involved in continuing to use the reference product."

The biosimilar development pathway will likely be complex and also customized to the specific product in question, with a high regulatory rigor for both safety and efficacy data.