The Biologics Price Competition and Innovation Act of 2009 (BPCIA) was enacted on March 23, 2010 as part of the Patient Protection and Affordable Care Act (Public Law 111-148). The BPCIA changed the regulation of certain protein products by amending the definition of a “biological product” to include a “protein (except any chemically synthesized polypeptide)”, with “protein” interpreted by the Food and Drug Administration (FDA) to mean any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.

Typically, the FDA’s Center for Biologics Evaluation and Research (CBER) regulates the majority of biologics and biosimilar products. However, in the past, some animal or human-derived protein products such as insulin, chorionic gonadotropin, and hyaluronidase as well as others, were regulated as drugs and approved by the Center for Drug Evaluation and Research (CDER) under section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act. This includes protein products which are sufficiently similar to a product already approved under the FD&C Act and are therefore eligible for submission of a 505(b)(2) application.

The Proposed Transition: NDA to BLA

However, the regulatory process for approval of a protein product is about to undergo significant changes. Under the “deemed to be a license” provision of BPCIA (section 7002(e) of the Act), an application for a biological protein product must now be submitted under section 351 of the PHS Act and can no longer be submitted as a New Drug Application (NDA). The BPCIA allows for exceptions to this provision during a 10 year transition period which will end on March 23, 2020. During this transition period, if the biological product is in a product class which has been previously approved under Section 505 of the FD&C Act then an application may be submitted as an NDA no later than March 23, 2020. However, if a biological product has been approved under section 351 of the Public Health Services (PHS) Act and could be considered a reference product for the new application under the 351(k) pathway, the biological product may not be submitted as an NDA under section 505 of the FD&C Act.

Regardless, if an NDA for a biological product has been or will be approved under section 505 of the FD&C Act (21 U.S.C. 355), on or before March 23, 2020, it will be deemed to be a license for the biological product under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) on the transition deadline (March 23, 2020).

In March of this year, FDA release a draft Guidance for Industry (Guidance for Industry: Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009, March 2016) which lays out FDA’s interpretation of the “deemed to be a license” provision of BPCIA and the proposed plan to implement the transition of approved biological products NDAs or those that will be approved as NDAs to a license for a biological product (Biological License Application [BLA]).

The Effects of the Transition

After the transition occurs on March 23, 2020, approved NDAs or ANDAs for biological products will be viewed as BLAs only, not as both NDAs and BLAs. Therefore, after this transition, the FDA will remove approved NDAs for biological products from the FDA Orange Book, as these products will no longer be considered “listed drugs” and will be deemed to be licensed as BLAs only. After the transition deadline, these former “drugs” (now considered BLA products) may not be relied upon by a 505(b)(2) applicant or ANDA applicant for approval. Based on this interpretation, after March 23, 2020, FDA will not approve any pending or tentatively approved 505(b)(2) applications for a biological product that relied upon a listed drug that has transitioned to a BLA. After March 23, 2020, any pending or tentatively approved applications which intend to rely upon these former listed drugs would have to be withdrawn and resubmitted as BLAs, disrupting ongoing reviews.

In addition, the FDA clarifies that any unexpired non-orphan NDA exclusivity (5-year new chemical entity, 3-year Hatch-Waxman or pediatric exclusivity) for a product that is transitioning to a BLA will cease to exist once the transition is made on March 23, 2020. Orphan exclusivity, which is available to both drugs and biologics, will remain in effect for the products that make the transition. However, according to the FDA’s interpretation in the draft guidance, products that transition to BLAs will not be granted the 12-year exclusivity given to new biologics under the BPCIA, because they were not “first licensed” under Section 351(a).

The subsequent transition of these protein product listed drugs to BLAs will have a dramatic effect on pending or future 505 applications for protein products. Given the deadline for approvals of March 23, 2020, when considering when and if to submit 505(b)(2) applications for proposed protein products, Sponsors will need to carefully assess timelines for submissions and approvals, taking into account issues which they have little control over, including the need for multiple review cycles, requests for major amendments, applicable unexpired exclusivity or listed patents, or a stay of approval due to patent infringement litigation.

Many companies, keeping in mind the transition deadline of March 23, 2020, will decide to delay the submission of their applications long before the deadline approaches. This will create a regulatory “dead zone” or “black-out” period in application timelines, when no protein product applications will be submitted and subsequently approved due to the FDA’s strict interpretation of the transition deadline for pending or tentatively approved applications.

Transition Options for 505(b)(2) Protein Products

The FDA acknowledges in the March 2016 draft Guidance that its interpretation of the “deemed to be a license” provision in the BPCIA (Section 7002(e) of the Act) could have a “significant impact” on development programs for any proposed protein products intended for submission under section 505 of the FD&C Act.  If the Sponsor believes that their planned 505(b)(2) application may not receive approval prior to the March 23, 2020 transition deadline, FDA suggests two options:

1. Modifying the development program to support submission of an application under section 351(a) of the PHS Act (ie a “stand-alone” BLA) before or after March 23, 2020; or
2. Modifying the development program to support submission of a 351(k) BLA for a proposed biosimilar product or a proposed interchangeable product once the reference listed drug product makes the switch to a biological product under section 351(a) of the PHS Act (ie after March 23, 2020).

The BPCIA created the 351(k) abbreviated licensure pathway (section 351(k) of the PHS Act) for biological products termed biosimilars, products highly similar to or interchangeable with an FDA-licensed biological reference product. Section 351(k) defines “biosimilarity” to mean “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product” (section 351(i)(2) of the PHS Act). The BPCIA also provides for a 4-year exclusivity period from the date of the first licensure of the reference product (data exclusivity: a 351(k) application referencing this product may not be submitted during this time) and a 12-year exclusivity period from the date of the first licensure of the reference product (market exclusivity: a 351(k) application referencing this product may not be made effective during this period of exclusivity). In addition, the BPCIA provides an exclusivity period for the first biosimilar product determined to be interchangeable with the reference product for any condition of use and also provided procedures for identifying and resolving patent disputes involving 351(k) applications.

However, even a switch from a planned 505(b)(2) application to a 351(k) application would still lead to delays. Any application which intends to rely upon a listed drug that will transition to a BLA could not file until after the March 23, 2020 transition deadline; there would be no reference BLA product until the transition takes place. Therefore, even with a switch from a 505(b)(2) application to a 351(k) biosimilar application, Sponsors who are ready to submit an application will be forced to delay their submissions until after the transition deadline, contributing to the so called application “dead zone” or “black-out” period. Given that the FDA’s minimum PDUFA timeline for review of 505(b)(2) applications is 10 months, it is likely that this regulatory dead zone would last for at least a year and could extend to several years prior to the March 23, 2020 deadline.

More Transition Issues: Reliance Upon a LD that will Transition to a BLA

There is another concerning issue for Sponsors of 505(b)(2) applications which intend to rely upon a listed drug that will transition to a BLA. 505(b)(2) applications that would seek approval for a new route of administration, dosage form, or strength or for a different indication for an already approved protein product will not have a viable path toward development through the 351(k) biosimilar application pathway, as they would be unable to meet the statutory requirements for a proposed biosimilar product. In order to submit a 351(k) application for a proposed biosimilar product, the Sponsor must be able to demonstrate that the proposed product:

• is “highly similar” to a single reference product licensed under section 351(a) of the PHS Act, and that there are “no clinically meaningful differences” between the proposed product and the reference product in terms of safety, purity, and potency
• has the same route of administration, dosage form, and strength as the reference product
• utilizes the same mechanism(s) of action as the reference product for the proposed condition(s) of use (but only to the extent that the mechanism(s) of action are known)
• seeks licensure for a condition(s) of use (e.g., indication, dosing regimen) previously approved for the reference product

This would mean that submitting a stand-alone BLA (351(a) application) would potentially be the only option for approval for some 505(b)(2) applications for biological products with a new route of administration, dosage form, dosage regimen, strength, or indication which intend to rely upon a listed drug which will transition to a BLA. In order to support the submission of a “stand-alone” BLA, the Sponsor would either have to obtain a right of reference from the application holder of the listed drug or conduct studies with the proposed product to provide the additional analytical and clinical data that would have been relied upon for approval, a costly endeavor which will significantly extend the development timeline. Both of these options, with extended development cost and timelines, are likely to deter Sponsors from developing and submitting applications for these biological products.

Submission Prior to the Deadline: Confounding Choices

This leaves Sponsors of biologic 505(b)(2) applications who wish to submit prior to May 23, 2020 with a conundrum. If their application is not likely to be approved by the deadline, then based on the recent FDA Guidance, they will be forced to resubmit as a BLA upon the transition date. If, per FDA’s proposed suggestion in the draft Guidance, they attempt to submit prior to the transition deadline as a 351(k) biosimilar application, they will be unable to do so as there will be no reference product until the transition occurs. Finally, many 505(b)(2) applications may not meet the requirements for a 351(k) biosimilar application. Modifying their development plan to target a 351(a) application instead of a 505(b)(2) or 351(k) application will require significant additional scientific data, leading to extended development timelines at a significant cost, which may not be financially feasible for some companies. Given these choices, upon assessing their options many Sponsors may choose not to pursue approval of such protein products long before the transition date, leading to delays in approval of lower-cost biological products.

Potential Routes Forward

The biopharma industry has weighed in on the FDA’s interpretation of the BPCIA in the initial Guidance and is clamoring for the Agency to take a more balanced approach. Many groups, including the Generic Pharmaceutical Association (GPhA) and the Biosimilar Council, cite the impending regulatory “dead-zone” or “black-out” period, which will delay approval and availability of affordable competitive biological products.

Comments on the FDA’s draft Guidance show that innovator, generic, and biosimilar industries feel that the Agency should allow pending NDAs and ANDAs applications to be reviewed and approved after the transition deadline (March 23, 2020) and oppose the FDA’s proposed plan to require withdrawal of applications and a subsequent new submission. Commenters also note the conundrum of the proposed biosimilar application route as an alternative, noting that a Sponsor could not submit a biosimilar application prior to March 23, 2020, as there would be no BLA reference product to rely upon until after the transition deadline.

Comments demonstrate that the industry believes that the FDA’s interpretation and proposed handling of pending NDAs and ANDAs is in direct contrast to what is clearly stated in the BPCIA, which allows submission of an application for a protein product under Section 505 “not later than” March 23, 2020 (section 7002(e)(2) of the Act). Alternative suggestions to FDA’s more hardline interpretation include allowing pending NDAs and supplements which will not be approved by the transition deadline to retain their NDA status until approval, at which time the products could transition to BLAs or to allow the determination of BLAs status during the review process.

In regards to the transition of listed drugs, because the biologic NDAs will not be withdrawn due to reasons of safety or efficacy (instead transitioned to BLAs), it has been suggested that pending 5050(b)(2) and ANDA applications submitted by the transition deadline and still under review during the transition could continue to rely upon these withdrawn listed drugs. This would allow applications which are pending or tentative approvals at the March 23, 2020 transition deadline to continue to be reviewed and approved without any disruptions or delays. In addition, commenters requested additional clarity on how the determination of a 351(a) standalone BLA or 351(k) biosimilar BLA would be decided for transition products initially approved under Section 505.

The Ongoing Debate

Clearly the implementation of the BPCIA is an ongoing debate and the current draft guidance leaves many questions unanswered. Given the effect the FDA’s current interpretation of the “deemed to be a license” portion of the BPCIA will have on pending and future 505(b)(2) protein product applications, it will be important to stay up to date on the Agency’s evolving viewpoint on the implementation of the BPCIA throughout the development of any proposed biologic products.

In order to clarify the path forward to approval for proposed 505(b)(2) biologics, the discussion of proposed development plans for these products with the Agency at Pre-Investigational New Drug (Pre-IND) and Pre-NDA meetings will be critically important. This is especially true for Sponsors which intend to submit a 505(b)(2) biologics application prior to the transition deadline.

Premier Consulting has extensive experience in Type-B meetings with the Agency. Contact us to see how we can help you navigate your 505(b)(2) development program options leading up to the impending BLA transition period.