At the end of a calendar year in DC, we expect to see a few flurries. Maybe some light snow, but definitely flurries of regulatory activity. December is often rich with FDA publications, specifically warning letters and guidance documents. And things have not changed this December. Indeed, in one day, FDA announced and published four new guidance documents, one proposed rule (really a technical correction), and one list related to biologics and biosimilars under the Biologic Price Competition and Innovation Act (“BPCIA”).
These FDA’s actions arise as part of the Biosimilar Action Plan (“BAP”) announced by FDA earlier in 2018. With the success of the competition-based generic market, FDA is looking to advance new policies that will have the same effect in the biologics market. Calling biologic medicines “increasingly the backbone of modern therapy,” Commissioner Gottlieb predicted in the announcement that 2019 will see a significant focus on the biosimilar market. And FDA decided to ring in the new year a bit early.
Two of the BAP guidance documents recently released focus specifically on scientific and regulatory considerations for the development of biosimilar and interchangeable products. These guidance documents are Questions & Answers on Biosimilar Development and the BPCI Act and New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2). These guidances, both in question and answer format, are part of a series to “facilitate development of biosimilar and interchangeable products” and revisions to previously issued guidance documents. Indeed, much of the information from prior versions remains substantively the same.
The first of the two guidance documents, Questions & Answers on Biosimilar Development and the BPCI Act, finalizes the questions and answers from both the April 2015 version of this (final) guidance and the May 2015 draft guidance Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. There does not appear to be any new questions or significant substantive revisions to the answers.
The second guidance, New and Revised Draft Q&As on Biosimilar Development and the BPCI Act, is still in draft form and includes similar questions as the other guidance and the May 2015 draft guidance with a few new ones sprinkled in. New questions and answers include questions about post-approval manufacturing changes for licensed biosimilar products; permissible differences in route of administration, dosage form, strength, or condition of use between proposed 351(k) products and reference products (spoiler alert: none); and REMS. The Commissioner has noted previously that abuse of REMS restrictions has led to problems obtaining comparator samples for the development of small molecule generics; to prevent the same blockade on the biosimilar side, this guidance announces that FDA will review study protocols submitted by biosimilar applicants to assess safety protections and issue a letter from the agency to the reference product holder stating that FDA will not consider it a violation of a REMS for the reference product holder to provide the prospective 351(k) applicant with a sufficient quantity to perform necessary biosimilar application testing. This is similar to the approach FDA has taken on the small molecule side.
The proposed technical correction regulation, the other two guidance documents, and the list deal with the transition of certain biological products from NDAs to BLAs. Starting with the simplest, the proposed (so-called) technical correction would amend the definition of “biological product” in 21 C.F.R. § 600.3(h) to conform to the definition implemented in the BPCIA and provide an interpretation of the statutory terms “protein” and “chemically synthesized polypeptide.” FDA calls it a “technical correction” in the proposed rule, but this isn’t really technical, nor is it a correction. Indeed, it reflects a significant change to the definition of biological product because the rule would replace the phrase “means any” with the phrase “means a” and would add the phrase “protein (except any chemically synthesized polypeptide)” to the definition of “biological product.” Consistent with the April 2015 Questions & Answers guidance, the proposed rule would amend 21 C.F.R. § 600.3(h) to further define protein as any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size, and the term chemically synthesized polypeptide as any alpha amino acid polymer that: (1) is made entirely by chemical synthesis and (2) is greater than 40 amino acids but less than 100 amino acids in size. Given that that FDA has been using this definition since the publication of the April 2015 final version of this Question and Answer guidance, this proposed regulation is unlikely to catch industry by surprise. But this is just one of multiple steps FDA is taking to prepare industry for the March 2020 transition of certain biological products approved under NDAs to BLAs.
As noted, this proposed technical revision arises from the BPCIA’s “Deemed to be a License” provision, which transitions all biological products approved under NDAs to BLAs as of March 23, 2020. To help ensure a smooth transition, FDA has published a preliminary list of NDAs that will become BLAs on March 23, 2020. All your favorite insulins are on the list, as are human growth hormones and other hormones. Commissioner Gottlieb posits that these protein products may be easier to “copy” under biosimilar standards than ANDA standards and may now see more competition. This, combined with the loss of certain exclusivities (discussed below), FDA expects to see more robust competition for the products transitioning from NDAs to BLAs under the BPCIA.
Additionally, FDA published two additional guidance documents related to the “Deemed to be a License” Provision of the BPCIA. The first was a revision of the March 2016 guidance, Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009. Renamed the Interpretation of the “Deemed to be a License Provision” of the BPCIA, the Guidance is largely the same substantively as the earlier version, but provides more specifics. For example, the new Guidance explains that only applications approved under an NDA will be deemed to be a BLA, and this transition will occur only on the transition date (rather than before or after). After 11:59 PM March 23, 2020, the guidance explains, a pending original 505(b)(2) application for a biological product will receive a complete response because the NDA for the listed drug relied upon will no longer exist. Applications may be withdrawn and submitted under sections 351(a) or 351(k) of the PHS Act, but there is no pathway akin to the 505(b)(2) pathway on the BLA side (affected sponsors can have Type 3 meetings with FDA to discuss new development options). FDA will, however, administratively convert any pending NDA supplements to BLA supplements and will maintain the same goal date.
Importantly, this guidance stresses that transitioning NDAs will lose all exclusivity other than orphan and pediatric as of March 23, 2020. And not only will transitioning products lose exclusivity, those that are deemed to be licensed under the Public Health Service Act won’t be eligible for a 12-year period of reference product exclusivity. As a result, those of you with protein products looking for NCE exclusivity are probably better off filing for BLAs now, which FDA states in this guidance, it will accept prior to the transition date rather than trying to squeeze in NDA approval. Further, while FDA previously expressed in a footnote of the 2016 version of the guidance that FDA is considering a mechanism that, in limited circumstances, would allow holders of approved applications under section 505 of the FD&C Act that reference a type II DMF to continue to reference the DMF after the application is deemed to be a license, this statement is nowhere to be found in the revised version of the guidance. Instead, the footnote directs readers to the Question and Answers guidance (discussed below), which includes no discussion of the use of DMFs or cooperative licensing arrangements in BLAs.
Finally, FDA published a Questions and Answers guidance on the “Deemed to be a License Provision” of the BPCIA. While the guidance is brand new, it covers a lot of the basics that have been explained in previous iterations (i.e. the April and May 2015 guidances mentioned above), as well as logistics. Indeed, it provides much of the same information as the Interpretation guidance, just in a different format. This guidance includes a robust discussion of the products affected by the transition (with a plug for the new Preliminary Transition List), the process for the transition (in which there are no active steps required by NDA holders for transitioning products and no pre-approval inspections for deemed licenses), and the results of the transition (BLA numbers will be sent to NDA holders). The guidance also informs readers that all NDAs will transition – even if discontinued – as long as FDA has not withdrawn approval of the application, and all transitioned BLAs will be considered 351(a) BLAs rather than 351(k) BLAs. Review divisions will remain the same, but the guidance provides a reminder that the requirements for approval will not remain the same. All pending supplements transitioned as of March 23, 2020 will be subject to BLA review processes, and sponsors are expected to revise transitions to meet any differing requirements with a specific emphasis on CMC. Further, all transitioned products will need to conform to BLA requirements, including labeling, but FDA will exercise enforcement discretion with respect to labeling until March 23, 2025.
Importantly, the guidance notes that pending NDAs withdrawn and resubmitted as 351(a) applications will not be subject to additional user fees, but pending NDAs withdrawn and resubmitted as 351(k)s will be subject to the biosimilar user fee. Nothing indicates that such a withdrawn application will be entitled to a refund, so resubmitting as a biosimilar may cost two separate user fees. Pending NDAs resubmitted as 351(a)s will not require a fee if:
- The applicant previously submitted an NDA for the same product and paid the associated PDUFA fee;
- The NDA was accepted for filing; and
- The NDA was not approved or was withdrawn.
This makes sense since BLAs are covered by PDUFA, but biosimilars under 351(k) have a separate user fee scheme set forth in BSUFA. And nothing in the BPCIA appears to grant FDA authority to waive user fees for transitioning products.
FDA has given us a lot to think about with respect to transitioning biologics. Luckily, we still have about a year and a half left to plan for and execute the transition, but March 23, 2020 is rapidly approaching. Collectively, these publications suggest that it’s not really worth rushing to get NDA approval prior to the transition date. FDA will take BLA applications for transitioning products now (but probably not 351(k)s since there are no reference products until the transition date), and no exclusivity other than orphan and pediatric will transfer. Going for the BLA may result in 12 years of exclusivity while going for the NDA will result in almost none.