On February 9, 2012, the Federal Drug Administration (FDA) released draft guidance regarding how the FDA will review biosimilars, which are generic versions of FDA-approved biological products. The February 9 guidance relates to quality and scientific considerations in demonstrating biosimilarity as well as questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act).

The BPCI Act was enacted as part of the Affordable Care Act on March 23, 2010. Similar to the Hatch-Waxman Act, which established abbreviated pathways for the approval of generic drug products, the BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product. The BPCI Act also addresses exclusivity periods, including an exclusivity period for the first biological product determined to be interchangeable with the reference product. There is also an exclusivity period for certain biological products for which pediatric studies are conducted. Similar to the Hatch-Waxman Act, the BPCI Act also provides procedures for identifying and resolving patent disputes involving applications for biosimilar products.

The Public Health Service (PHS) Act defines biosimilarity as occurring where “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” An application for a biosimilar product must contain data demonstrating biosimilarity from analytical studies, animal studies or possibly clinical studies. The FDA recommends that sponsors of proposed biosimilar products request an initial meeting with the FDA to provide a proposed plan for developing the biosimilar product and to present preliminary comparative data with a reference biological product.

To meet the higher standard of “interchangeability,” the applicant must provide information sufficient to demonstrate biosimilarity, and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient. As indicated previously, the applicant must demonstrate that there are no clinical meaningful differences between the proposed product and the reference product in terms of safety, purity and potency. Specific analytical factors to determine biosimilarity between a proposed product and a reference product include functional activities, expression systems, cell types, manufacturing processes, physicochemical and immunochemical properties, quality and quantity of impurities, stability, and drug-specific reference standards based on the scientific literature. These factors need not be identical in the biosimilar and reference products.

Unlike generic drug products, an abbreviated pathway for biological products presents challenges because of scientific and technical complexities. For example, biological products are larger and more complex than the smallest molecular drugs. Also, most biological products are produced in living organisms, such as a microorganisms or cells, whereas small molecule drugs are usually synthesized. Because of the variability that exists in biological systems, it is difficult to guarantee uniformity among similar biological products.

The FDA definition of biosimilars remains vague. While in theory, biosimilarity may refer to “no clinical meaningful differences” between a proposed product and a reference drug, it is difficult to elucidate the meaning in practice. While numerous comparative experiments and clinical trials may be performed to demonstrate biosimilarity and interchangeability, it seems that there are no set guidelines for the approval process. In other words, a biosimilar applicant may not know how many experiments and/or clinical trials are necessary for demonstrating biosimilarity. While the FDA recommends working with sponsors of proposed biosimilar products, it seems that the FDA is reluctant to fully develop guidelines and prefers to work with sponsors on a case-by-case basis.

An example of the complexity of the technology involved in biosimilars is how proteins and peptides are defined. The February 9 guidance defines “protein” as an amino acid polymer with a specific sequence that is greater than 40 amino acids long and excludes a chemically synthesized polypeptide. On the other hand, a “chemically synthesized polypeptide” is defined as an amino acid polymer that is made entirely by chemical synthesis and fewer than 100 amino acids long. A chemically synthesized polypeptide is not a “biological product” and will be regulated as a drug unless the polypeptide otherwise meets the statutory definition of a “biological product” (e.g., a vaccine). The FDA also defines an amino acid polymer that is fewer than 40 amino acids long as a peptide, not a protein, which will be regulated as a drug unless the polypeptide otherwise meets the statutory definition of a “biological product” (e.g., a vaccine).

The FDA’s definitions of proteins, peptides and polypeptides are indicative of the questions raised by the February 9 guidance. The FDA classifies proteins, peptides and polypeptides based upon size, use and the method in which they are produced. Small proteins that meet the FDA definition of “peptide” (neuropeptides, for example) are routinely produced by biological organisms. However, under the proposed classification system, neuropeptides would be classified as a drug or a biological product, depending on how they were made (e.g., chemically synthesized or isolated from a cell) or how they are to be used (e.g., on their own or as part of a vaccine). Such a classification raises more questions than answers.

While the February 9 guidance is welcomed by applicants seeking to develop biosimilars, many questions remain. Undoubtedly there will be many comments and suggestions submitted in response to the February 9 guidance.