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What the Rollover from Drugs to Biologics Means

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On Monday, March 23, over 90 products that had historically been regulated as drugs were deemed to be licensed as a biologic. This includes insulin products. During the past several years, the Food & Drug Administration (FDA) has released guidance about their interpretation of the provision to guide sponsors and provide information about what to expect for the transition.

The Biologics Price Competition and Innovation Act (BPCIA)

BPCIA, which was part of the Affordable Care Act (ACA), mandates that protein products that were approved as drugs under section 505 of the federal Food, Drug, and Cosmetic Act (FD&C) be licensed as biologics under section 351 of the Public Health Services Act (PHS) starting at midnight on March 23, 2020. Since BPCIA’s implementation, Congress has updated the definition of “protein” to include products that are 40 to 100 amino acids in length, including chemically synthesized products. New Drug Applications (NDAs) approved under 505(b)(1) or 505(b)(2) will be “deemed” to be 351(a) Biologics License Applications (BLAs). After March 23, new applications of similar product types have to be submitted as either a 351(a) “stand-alone” BLA or a 351(k) biosimilar or interchangeable biosimilar BLA that references a previously approved 351(a) BLA–which may include those products that have switched from 505(b)(1) to 351(a).

Products Affected

The FDA has released a list of the specific products that are expected to be affected. Previous guidance suggested additional updates to the list would be released prior to the transition, but no updates have been announced since December 31.

Key products besides insulin that are transitioning include:

  • Hyaluronidase
  • Insulins
  • Pancrelipase
  • Somotropin

What to Expect as Products Transition

In a guidance document released on December 2018, the FDA explained its interpretation of the regulatory transition. Specifically, both 505(b)(1) “stand-alone” NDA products and 505(b)(2) NDA products that use data not produced by the sponsor for approval become 351(a) “stand-alone” BLAs. These products will not receive additional exclusivity or even remaining exclusivity other than that for orphan indications or pediatric populations, as these apply to competition regardless of pathway. Transitioning products will also not receive exclusivity as newly licensed biologics. At the time of the switch, all products that are transitioning were removed from the Orange Book and added to the Purple Book.

To follow up on this information, the FDA released another guidance document at the beginning of March 2020 with questions and answers about products deemed to be a license. The guidance states the following:

  • The FDA will send a letter to sponsors of products that transitioned on March 23, which will include the US license number (e.g., BLA ###).
  • The FDA does not plan to perform pre-license inspections prior to transitioning products.
  • Sponsors must ensure information in the electronic Drug Registration and Listing System is updated between March 23 and June 30.
  • Biological products will keep the same National Drug Codes.
  • Transition products will be listed in the Purple Book on or shortly after March 23; per the Purple Book protocols, it will not list therapeutic equivalences.
  • Biosimilar Use Fee Amendment fees will be required for a withdrawn NDA resubmitted as a 351(k) BLA; such products cannot reference themselves once they become a 351(a).
  • Transitioned BLAs will be overseen by the same office/division in the Office of New Drugs as the original NDA.
  • Transition products will not use non-proprietary naming conventions (4-letter suffix) but follow-on products to these will receive a suffix.

Implications of the Regulatory Transition

In the US, medicinal products are generally regulated either under the FD&C or PHS depending on the type of product: drug or biologic, respectively. The specific regulation of many products, however, reflects historical precedents and expertise at the FDA at the time of review rather than strict or stagnant product categories. Rolling over these 91 products from 1 statue to another demonstrates the continuum of complexity in products that exists scientifically and the FDA’s flexibility to regulate as our technological understanding advances and analytical capabilities evolve. Various definitions of “protein” were put forth throughout the last 2 years, and a clear and concise definition resulted in December 2019–namely, any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size. This simplifies the rollover list but does not change the continuum between drugs and biologics inherent in their molecular structures. And, as methods of manufacturing and analysis advance, the regulation of complex products will continue to evolve such that the quality of all medicines overseen by the FDA can be maintained. It is also likely that ongoing dialog between sponsors, the FDA, and the scientific community will continue, especially as ultracomplex products emerge, including those specific to individual patients, such as cell therapy. As more complex products approach development and approval, the potential for patients remains promising, even though the regulatory complexities appear daunting.

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