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). 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 allows for a 10 year transition period, ending on March 23, 2020, during which certain biological protein products may continue to be submitted as NDAs. After the transition, NDA or ANDA biological products will be “deemed to be a license” (BLA) 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that relies upon a listed drug that has transitioned to a BLA will not be approved; these applications will have to be withdrawn and resubmitted as BLAs.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 several aspects of the BPCIA 10-year transition in the “Protein Product 505(b)(2)s Face a Looming Application “Dead Zone” and “Effects on Exclusivity”  posts in this series. Here, we will discuss another angle to the Biologics Price Competition and Innovation Act of 2009: Effects on Combination Products.

Transition Effects on Approved Combination Products

What impact will the impending transition from an NDA to a BLA have on already approved combination products?

Currently, the Agency has not provided clarity on how it intends to address the transition of approved combination products. Specifically, how will the Agency deal with combination products in which a biological protein component would transition to a BLA while the other drug product component remains approved under Section 505 of the FD&C Act? The FDA’s recent draft Guidance for Industry (Guidance for Industry: Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009,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) does not address how the “deemed to be a license” provision would be applied in these cases.

It is possible that the transition of these drug/biologic combination products may depend upon the Agency’s determination of which component (drug or biological) has the ‘single primary mode of action’. However, given that the draft Guidance does not address combination products, it is unclear how the Agency intends to address the transition and make this type of determination with the Sponsor. If the Agency determines that the primary mode of action for the combination product is attributed to the biological protein component, the combination product as a whole could be transitioned and “deemed to be a license” upon the transition deadline. Given the lack of recommendations in the draft Guidance, the biopharma industry will need to look to the Agency to provide clarity on how the transition of drug/biologic combination products will occur.

Pending Combination Product Applications: A Looming Deadline

The draft Guidance is clear on the effect that the transition will have on pending 505(b)(2) applications which intend to rely upon approved products which will undergo transition to BLAs- this would likely be applicable to pending combination products as well. Upon the transition deadline, 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 (discussed in detail in “Protein Product 505(b)(2)s Face a Looming Application “Dead Zone”).

This means that Sponsors will need to carefully consider the timing for pending combination 505(b)(2) applications which intend to rely upon approved protein products which will undergo transition upon the March 23, 2020 deadline. As with single active pharmaceutical ingredient products, combination applications which face any unexpected delays in approval (such as multiple review cycles, requests for major amendments or a stay of approval due to patent infringement litigation) could be unapproved at the transition deadline and face a requirement for subsequent resubmission as a BLA.

Transitional Combination Products: Exclusivity Upon Transition?

Drug/biologic combination products initially approved as NDAs may stand to lose any remaining exclusivity if the product as a whole is transitioned to a BLA. In the draft Guidance, the FDA clearly states 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, with the exception of orphan drug exclusivity.

FDA states that 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 [ie do not have a date of first licensure under section 351(a)] and instead will be “deemed” to be licensed as a BLA with the transition on March 23, 2020 (discussed in detail in “Effects on Exclusivity”) .

It likely that the Agency would apply this interpretation to combination products as well. However, the Guidance does not specifically review how exclusivity would be addressed for a combination product in which the biological protein component would transition to a BLA while the drug product component(s) remained approved under Section 505 of the FD&C Act. One alternative suggested by the biopharma industry is that the Agency consider administratively separating the NDA for the drug/biologic components, maintaining an NDA for the drug component, allowing the drug API to maintain its exclusivity and patent listings, while the biologic component a transitions to a BLA. However, it remains unclear how the Agency intends to address exclusivity for combination products upon the transition.

Future Considerations

The Agency’s current draft Guidance fails to address how the implementation of BPICA will affect transitional combination products. Given the uncertainty on how the FDA intends to handle the transition of drug/biologic combination products, it will be important for Sponsors to gain Agency insight to their proposed program for drug/biologic combination products early in development. Sponsors considering a 505(b)(2) NDA application for a proposed combination drug/protein product prior to the March 23, 2020, transition deadline should also consider the potential for the loss of any unexpired drug 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 combinations products 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) combination products leading up to the impending BPCIA transition deadline. Contact Premier Consulting for expert help in navigating the changing regulatory landscape and managing the risk in a drug development program.