As of March 23, 2020, around 90 biological products approved by Federal Food, Drug, and Cosmetic Act (FD&C Act) new drug applications shifted to deemed to be biological license applications under the Public Health Service Act. On February 20, FDA published its final rule changing the definition of the term “biological product,” effectively enabling the submission of applications for numerous biological products proposed as biosimilars.
FDA had been working toward this end for some time. In 2010, to help alleviate the high costs of biologics and enhance patient access to these important products, Congress passed the Biologics Price Competition and Innovation Act (BPCIA).
Similar to the pathway for generic drugs created by the Hatch-Waxman amendments, BPCIA aimed to balance innovation and consumer interests by creating a period of exclusivity for originator biologics and an abbreviated pathway for approval of biological products that are shown to be biosimilar to FDA-licensed reference products once exclusivity expires.
In 2018, FDA issued the Biosimilars Action Plan (BAP) aimed at helping to improve the biosimilar product development and approval process and to further clarify regulatory and scientific concepts for biologic and biosimilar developers. The BAP focused on four areas:
- Improving the efficiency of the biosimilar product development and approval process,
- Maximizing scientific and regulatory clarity for the biosimilar product development community,
- Improving communications and understanding of biosimilars for patients, clinicians, and payors, and
- Reducing gaming of FDA requirements or other attempts to unfairly delay market competition.
FDA Expands Term “Protein” to Include Chemically Synthesized Polypeptides
FDA’s final rule, “Definition of the Term ‘Biological Product,’” amends the original definition of “biological product” to include FDA’s interpretation of the term “protein” and to account for changes found in the Biologics Price Competition and Innovation Act (BPCIA) and the 2020 Further Consolidated Appropriations Act.
The initial BPCIA definition of “biological product,” included “protein (except any chemically synthesized polypeptide).” The new definition of “biological product” removes the parenthetical from the term “protein.” Now, “protein” refers to any alpha amino acid polymer with a specific, defined sequence greater than 40 amino acids (including chemically synthesized polypeptides).
“Given the lack of a clear scientific consensus that FDA could consider for adoption, the Agency is applying its scientific expertise to interpret the statutory term ‘protein’ in a manner that establishes a scientifically reasonable, bright-line rule that provides regulatory clarity and facilitates the implementation of the BPCI Act, as further amended by the FCA Act,” FDA states in the final rule.
In deciding where to draw the line, FDA explains that it considered “the number of amino acids understood to be generally necessary for an amino acid polymer to exhibit characteristics that are generally associated with ‘proteins,’ lending a higher level of complexity to these products.”
FDA determined that including structural or functional attributes like folding, macrostructure support, transport functions, or catalysis functions in its interpretation of “protein” would only lead to regulatory uncertainty and inefficiency. For example, relying on a factor such as “folding” would only raise questions about how much folding is sufficient to differentiate between “peptides” and “proteins.”
Some comments suggested that uncertainty may exist around insulin under the new definition as insulin is made of two polypeptide chain subunits – both under 40 amino acids long. FDA confirmed that insulin is indeed a protein under the final rule definition and that the Agency intends to count the total number of amino acids in all subunits that are "associated in a manner that occurs in nature.”
Insulin Now Included in Biological Product Definition
Previously, chemically synthesized insulin products were not included in the “biological product” definition. Expanding the definition of biological products means that, for the first time, insulin products transitioning from approved drug applications to biological product licenses might experience potential competition from biosimilars.
According to the American Diabetes Association (ADA), one in every seven U.S. health care dollars is spent treating diabetes and associated complications. Increased competition and improved accessibility within the insulin market could help pull down the $327 billion that diabetes diagnoses cost the U.S. each year.
“Biologic drugs are often complex therapies that can be used to treat some of the most serious illnesses, including autoimmune diseases, rare genetic disorders and diabetes,” said FDA Commissioner Stephen M. Hahn.
“Life-sustaining insulin products are biologics, but to date, there has been limited competition in the marketplace, resulting in fewer choices and higher prices for patients. This transition will open new pathways for manufacturers to bring biosimilar and interchangeable versions of insulin and other transitioning products to market, facilitating greater competition in the marketplace.”
Protein products that were deemed to have a BLA on March 23 are not eligible for 12 years of market exclusivity, but new protein products approved after March 23 will receive 12 years of market exclusivity (where previously they would have received just three to five years of market exclusivity).
Critics of the change tend to focus on the comparison between the 3-year / 5-year exclusivity under the drug pathway versus the 12-year exclusivity for biologics. Biological products manufacturers have 12 years of exclusive marketing rights versus 5 years of exclusivity for small molecule drugs.
However, under the drug pathway, no insulins were true generics. All of them were considered full NDAs or 505(b)(2) NDAs because they could not be demonstrated to be identical and interchangeable as required under the drug rules. (That is, effectively no abbreviated approval pathway existed under the drug/small molecule classification.) Under the biosimilar rules, they do not need to be identical; they can simply be similar.
Indeed, as a result of the definition change, FDA added products to its list of NDA-approved products that were deemed to have an approved BLA as of March 23, 2020. Moreover, under FDA’s interpretation of products switching from drug to biologic regulations (nearly all marketed insulin products), the products will not gain any new exclusivity due to the change in regulatory status. Therefore, the change in definition makes many more biological products subject to biosimilar competition than under the previous definition.