Are You Prepared For Impending Changes To U.S. Biologics & Biosimilars Law?

By Kate Cook, Greenleaf Health

Sponsors for insulins and other protein products originally submitted for premarket review under a New Drug Application (NDA) may be anticipating the arrival of March 23, 2020 with trepidation. On that date, the Biologics Price Competition and Innovation Act (BPCIA) requires that those NDA-approved products will be deemed to have a Biologics License application (BLA) approval instead of an NDA approval. This is required due to the BPCIA’s amendment to the definition of “biological product” to include the term “protein” and the statute’s related transition provision, which identifies March 23, 2020 — the 10th anniversary of BPCIA’s passage — as the date those NDA approvals will be “deemed” to be a biological product license.

The Further Consolidated Appropriations Act, 2020, signed into law on December 20, 2019, contains three provisions with implications for transition products. This law:

• Provides a bridge to ease some of the administrative problems that would otherwise occur for NDAs or ANDAs for transition products that are still under review or are only tentatively approved on March 23, 2020. An application may have a tentative approval if the FDA has reviewed the application, but there are unresolved patent or exclusivity issues that limit the FDA’s authority to approve the submission.
• Clarifies the exclusivity provisions for NDA-approved transition products that are deemed to have a license.
• Amends the "protein" component of the biological product definition.

The following sections will review each of these three provisions — and their potential impact on sponsors — in further detail.

The Bridge

During the past several years, the FDA has urged sponsors to submit BLAs for protein products previously regulated under NDA if there was any chance the application might not be fully approved by March 23, 2020. The agency had warned sponsors that NDAs for transition products that had a tentative approval (for example, because they referenced the FDA’s prior approval of a drug with unexpired NDA exclusivity) or were otherwise still under review after March 23, 2020 could not be approved, and that the FDA intended to issue a complete response letter for any such applications not approved before midnight on March 23, 2020.

The recent appropriations act changed what would happen on March 23, providing a bridge to permit the FDA to review and approve applications that are still pending. On the date the product is approved, it will be “deemed” to have a license, just as the already approved transition products will be “deemed” as of March 23, 2020. This provision sunsets on October 1, 2022, on which date any such applications that have not been fully approved will be deemed withdrawn.

Exclusivity For Transition Products

Soon after the BPCIA was passed, sponsors of transition products raised questions about what would happen to exclusivity on March 23, 2020. Once a drug was deemed to be a licensed biological product, would the transitioned BLA receive a 12-year period of reference product exclusivity, preventing another applicant from bringing to market a biosimilar product that referenced the transitioned product? What would happen to exclusivity granted under the original NDA but not yet expired on March 23, 2020? These could include the five-year exclusivity granted to the initial approval of a new chemical entity, as well as seven-year exclusivity that may be granted to an orphan drug.

The appropriations act added a new provision about orphan drug and pediatric exclusivity for transition products that is consistent with the policy the FDA expressed in the agency guidance Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009. The act states that seven-year orphan drug exclusivity and six-month pediatric exclusivity “shall continue to apply to a biological product after an approved application for the biological product is deemed to be a license for the biological product.”

The act did not address the the FDA’s conclusion, based on legal analysis, that new reference product exclusivity would not be granted on March 23, 2020, or that certain other types of exclusivity (for example, five-year new chemical entity exclusivity) would not have effect after that date. To the extent FDA decisions under this policy are challenged after March 23, 2020, proponents of the agency’s policy interpretations will doubtless argue that Congress’ support of continued orphan drug and pediatric exclusivity, accompanied by silence about other continued or new exclusivities, means that Congress rejected any other new or continued exclusivities for these products after March 23, 2020.

Change To The Definition Of A “Biological Product”

The appropriations act made changes to the statutory definition of the “protein” component of the biological product definition by deleting the parenthetical phrase, “(except any chemically synthesized polypeptide).” The revised statutory definition reads as follows:

The term "biological product" means 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.

With this change, although a chemically synthesized polypeptide may meet the definition of a biological product, it still must meet some component of the biologic definition, such as the protein component. In guidance, and in a proposed rule that has not yet been finalized, the FDA has stated that an amino acid product must have more than 40 amino acids to meet the protein definition. Accordingly, it is important to bear in mind that, under this change, chemically synthesized polypeptides with 40 or fewer amino acids will remain NDA (and potentially ANDA) products unless they meet some other component of the biological product definition, such as vaccine or allergenic product.

This statutory change appears to be intended to assure that chemically synthesized protein products will be subject to approval under a BLA. This would avoid having two categories of protein products — the NDA category for chemically synthesized proteins, and the BLA category for traditionally produced proteins — and would allow synthetic proteins to demonstrate biosimilarity/interchangeability with currently approved protein products such as insulins. The FDA made the following statement upon passage of this statutory change:

Removing this exclusion will help patients because it provides the potential for chemically synthesized follow-on insulins and other protein products to come to market through more efficient abbreviated pathways, regardless of how they are manufactured. In addition to expanding access to lower-cost biosimilar and interchangeable protein products, removing this exclusion will help to promote potential innovation in manufacturing methods, which could lead to future efficiencies in manufacturing processes.

The FDA’s statement does not address the question of whether this change in definition sweeps additional NDA-approved products — chemically synthesized polypeptides with more than 40 amino acids — into the “biological products” definition. Sponsors for such approved products may wonder whether their products will be “deemed” to have a license on March 23, 2020. The FDA has now posted a revised preliminary list of transition products, adding three new drug products.  This could be a rude surprise for sponsors, with the news coming only a few months before the mandated transition.

About The Author:

Kate Cook is executive VP of drug and biological products at Greenleaf Health, Inc. She joined Greenleaf after a long career at the FDA, including 15 years in the Office of Chief Counsel, five years in the Office of the Center Director at the FDA’s Center for Biologics Evaluation and Research, and one and a half as associate director for regulations and policy at the FDA’s Center for Devices and Radiological Health. You can contact her at kate.cook@greenleafhealth.com.