On March 23, 2010, the U.S. FDA enacted the Biologics Price Competition and Innovation Act of 2009 (BPCIA) as part of the Patient Protection and Affordable Care Act (Public Law 111-148). The passing of BPCIA amended the definition of a “biological product” to include a “protein (except any chemically synthesized polypeptide)”, altering the way that certain animal or human-derived protein products, now deemed to be biological products, are approved and regulated.

Under BPCIA, applications for biological protein products, which were previously approved as New Drug Applications (NDA) under section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act, must now be submitted under section 351 of the PHS Act and will be approved as Biologics License Applications (BLAs) [section 7002(e) of the Act].

The BPCIA specifies a 10 year transition period, ending on March 23, 2020, during which an application for a biological product in a product class, which has been previously approved under Section 505 of the FD&C Act, may be submitted as an NDA. After the transition on March 23, 2020, previously approved NDAs or Abbreviated New Drug Applications (ANDAs) for biological products will be “deemed to be a license” (BLA) for the biological product under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262).

Any pending or tentatively approved 505(b)(2) applications for a biological product that rely upon a listed drug that has transitioned to a BLA will not be approved; these applications will have to be withdrawn and resubmitted as BLAs.

Previously, we discussed one aspect of the BPCIA 10-year transition in “Protein Product 505(b)(2)s Face a Looming Application “Dead Zone”, our first post in this series. Here, we will discuss a second angle to the Biologics Price Competition and Innovation Act of 2009 with Effects on Exclusivity, especially in regards to those products within 505(b)(2).

NDA to BLA Transition: Effects on Exclusivity

What impact will the impending transition from an NDA to a BLA have on exclusivity for already approved products? The FDA outlined their interpretation of the “deemed to be a license” provision of BPCIA and the proposed plan to implement the transition of approved or pending biological products NDAs to BLAs in a recent draft Guidance for Industry (Guidance for Industry: Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009,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).

In the Guidance, the FDA clarifies that upon the March 23, 2020, transition deadline, any unexpired NDA exclusivity (5-year new chemical entity, 3-year Hatch-Waxman or pediatric exclusivity) for a product that transitions to a BLA will cease to have any effect. However, orphan drug exclusivity (7 years), which can be granted to both drugs approved under section 505 of the FD&C Act or a biological product licensed under section 351 of the PHS Act (see section 527 of the FD&C Act (21 U.S.C. 360cc)), will remain in effect for the products that make the transition. In addition, any patents listed in the FDA’s Orange Book would no longer have any effect on determining the timing of approval of a 505(b)(2) or ANDA application referencing these products.

Will these NDA-to-BLA transitional protein products be eligible for the exclusivity granted to new eligible biologic products? The FDA’s interpretation of exclusivity eligibility for the biologic products transitioned under the BPCIA case is dependent upon the elucidation of the “date of first licensure” for these newly transitioned BLA products.

The BPCIA defines reference product exclusivity as the period of time (starting from the date of first licensure) during which a 351(k) Sponsor is not permitted to submit and the FDA is not permitted to license a 351(k) application for a biosimilar or interchangeable product that references a biological product licensed under section 351(a) of the PHS Act (Section 351(k)(7) of the PHS Act).

BPCIA Exclusivity Logistics

The “date of first licensure” is the initial date that a biological product was licensed under 351(a) in the United States and determines eligibility for reference product exclusivity as well as the date on which exclusivity for the product expires (FDA draft Guidance for Industry: Reference Product Exclusivity for Biological Products Filed under Section 351(a) of the PHS Act, August, 2014). Not all licensures of a biological product under 351(a) are considered a “first licensure” and therefore not all licensures are eligible for exclusivity.

Exclusivity is not granted for a supplement, a subsequent application by the same Sponsor for a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or a modification to the structure that does not result in a change in safety, purity, or potency filed by the original Sponsor.

Exclusivity for biologics as defined in the BPCIA (section 351(k)(7) of the PHS Act) includes:

• A 4-year exclusivity period from the date of the first licensure of the reference product under section 351(a) of the PHS Act, during which a 351(k) application referencing this product may not be submitted for review.
• A 12-year exclusivity period from the date of the first licensure of the reference product, during which a 351(k) application referencing this product may not be approved.

Therefore, Sponsors must wait 4 years after the date on which the original reference product was first licensed under section 351(a) of the PHS Act to submit a 351(k) biosimilar or interchangeable application for review (data exclusivity). Although a 351(k) application can be accepted for review by the FDA 4 years after the reference product’s date of first licensure, the application cannot be approved until 12 years after the date of first licensure of the reference product (market exclusivity).

If the product is granted pediatric exclusivity (pursuant to section 505A of the FD&C Act), an additional 6-month period of exclusivity will be added to the 12- and 4- year exclusivity periods. Similarly, if a biological product is designated and approved for an orphan indication, it will be granted 7-years of orphan drug exclusivity (under section 527(a) of the FD&C Act); a 351(k) product may not be licensed by FDA for the protected orphan indication until after the expiration of the 7-year orphan drug exclusivity period or the 12-year reference product exclusivity, whichever is later.

Transitional Products: No Biologics Exclusivity

In regards to granting biologics exclusivity to transitional products, the FDA states within the draft guidance that “Nothing in the BPCI Act suggests that Congress intended to grant biological products approved under section 505 of the FD&C Act — some of which were approved decades ago — a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032.”

According to the FDA’s interpretation, products that transition to BLAs will not be granted the 4- or 12-year exclusivity given to new biologics under the BPCIA, because they were not “first licensed” under subsection 351(a) of the PHS Act and instead will be “deemed” to be licensed as a BLA with the transition on March 23, 2020.  The FDA’s conclusion is that these products would not have a date of first licensure under section 351(a) and therefore would not qualify for the exclusivity typically granted to new biologic products.

Transition of these products from NDAs to BLAs within the FDA’s interpretation of the BPCIA will clearly lead to a loss of exclusivity protection for some of these products. While older products with exclusivity set to expire prior to the transition will not be affected, some of the younger transition products could potentially receive less exclusivity than either NDAs or BLAs.

This will be especially true for products approved after March 23, 2015, which have been on the market for a shorter period of time and will therefore stand to lose a longer period of exclusivity. However, even the loss of less than 6 months of exclusivity would be equivalent to substantial financial losses.

Given the March 23, 2020 transition deadline, Sponsors will need to carefully assess whether pending biologic applications should be initially submitted as an NDA or BLA, considering timelines for submissions and approvals, as well as the potential loss of exclusivity if their NDA is transitioned to a BLA under BPCIA.

Future Considerations

The implementation of the BPCIA is an ongoing debate, with many questions that remain unanswered by the current draft guidance. Sponsors considering a 505(b)(2) NDA application for a proposed protein product prior to the March 23, 2020, transition deadline should consider the potential for the loss of any unexpired exclusivity upon NDA to BLA transition. Interactions with the Agency at Pre-Investigational New Drug (Pre-IND) and Pre-NDA meetings to clarify effects of the impending NDA-to-BLA transition on a proposed program will be critically important.

Premier Consulting has extensive experience in Type-B meetings with the Agency and can help Sponsors navigate through the development of 505(b)(2) transitional products leading up to the impending BPCIA transition period. Contact us for expert help in navigating the changing regulatory landscape, expediting a drug’s time to market, and managing the risk in a drug development program.