Buried in a 2020 spending bill passed in December 2019 is a provision that amends the definition of “Biological Product” in the Biologics Price Competition and Innovation Act of 2009 (BPCIA) and thereby expands the products that will be regulated as biologic medicines and litigated under the BPCIA. The BPCIA defined “Biological Product” as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 42 U.S.C. 262 (i)(1). The spending bill expands the scope of the term “protein,” one of the key categories of biologic medicines.
The FDA interprets protein as a specific defined sequence that is greater than 40 amino acids in size, and chemically synthesized polypeptide as a polypeptide that is made entirely by chemical synthesis and greater than 40 amino acids but less than 100 amino acids in size. As a result, peptides of 40 amino acids in size or less are regulated as small-molecule drugs, not biologics, regardless of how they were made, as long as they did not fall into any of the other enumerated categories of biological products. Polypeptides of greater than 40 amino acids in length but less than 100 also fell under the umbrella of small-molecule drugs, as long as they were chemically synthesized and did not fall under any of the other enumerated categories in the biological product definition. The FDA considers polypeptides of 100 amino acids or greater as proteins and therefore biologics regardless of how they are manufactured (in live cells or chemically) due to their greater complexity at that length.
In Section 605 the 2020 spending bill removes “except any chemically synthesized polypeptide” from the definition of biologic product. As a result, any polypeptide products greater than 40 amino acids in length will be regulated as proteins and therefore biologic medicines under the BPCIA, regardless of how they are manufactured (even if entirely by chemical synthesis). Why the change and why now? The change is driven by the transition of certain biologics that were historically regulated as small-molecule drugs (such as insulins) to biologic status. On March 23, 2020, a number of biologics, including insulins, that were previously regulated as small-molecule drugs and subject to the Hatch-Waxman Act will be deemed to be licensed as biologics and therefore will be subject to the BPCIA. Since innovator insulin products will have the status of biologics, biosimilars of insulins will necessarily also have to be biologic products. Without the change in the definition, follow-on chemically synthesized insulins would fall through the cracks and could not be approved under any abbreviated regulatory pathway. They could no longer be approved under the Hatch-Waxman Act since the reference product would be deemed a biologic and subject to the BPCIA (i.e., there is no reference product regulated as a small-molecule drug to copy). They could not be approved as biosimilars because they themselves, absent the change in definition, would not be biologics. It is for this reason that the definition of biological product in the BPCIA was changed in the 2020 spending bill. The change allows chemically synthesized insulins and other chemically synthesized products to be approved under the abbreviated regulatory pathway of the BPCIA. The change in definition also avoids manufacturers having to choose a particular method of making the polypeptide (i.e., a method other than chemical synthesis) in order to fall under an abbreviated pathway for regulatory approval. Polypeptides greater than 40 amino acids will now be regulated as biologics whether made in a cell or entirely through chemical synthesis, and any follow-on versions of the innovator biologic will be regulated and litigated under the BPCIA.