The US Food and Drug Administration (FDA) today released a new draft guidance document intended to explain how biological products approved under Section 351(a) of the Public Health Service Act (PHS Act) are given periods of market exclusivity.
Under the Patient Protection and Affordable Care Act's (PPACA) Biologics Price Competition and Innovation Act (BPCI), new biological products are eligible for 12 years of market exclusivity during which time the US Food and Drug Administration (FDA) cannot approve any so-called "biosimilar" products for the same indication as the reference product (sometimes referred to as the reference listed drug, or RLD).
The provision is mirrored off the five years of market-based exclusivity now given to new chemical entities (NCEs), which is meant to promote the development of new drugs. Because a drug molecule and its potential uses are often patented at the time of discovery, that period of patent protection can often expire before (or soon after) a drug has a chance to be brought to market. Market-based exclusivity is meant to ensure that a company that has worked to bring a new drug to market will have a predictable period during which time it will face no competition from FDA-approved generics.
Legislators ultimately gave biologics 12 years of exclusivity due to the perceived complexities of bringing them to market (though exclusivity periods of 7 years were debated at the time, and continue to be advocated by some Democrats).
Under Section 351(k)(7)(C) of the PHS Act, a biological product's exclusivity period begins at a date of "first licensure," which in turns triggers a 12-year period during which FDA cannot approve a biosimilar application, and a four-year period during which it cannot even accept a 351(k) filing for approval.
But as FDA explains in its new guidance document, Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the Public Health Service Act, determining the "date of first licensure" isn't as easy as just determining which date a product obtained FDA approval—though "in most instances" it will be.
For example, FDA notes that "not every licensure of a biological product under 351(a) is considered a 'first licensure' that gives rise to its own exclusivity period."
FDA will not grant a 12-year period of exclusivity for:
- a supplement for the biological product that is the reference product; or
- a subsequent application filed by the same sponsor or manufacturer of the biological product that is the reference product (or a licensor, predecessor in interest, or other related entity) for—
- a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or
- a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
The statutory provisions are similar to those for chemical drugs, for which FDA gives only three years of market exclusivity for new indications based on clinical data used to approve other drugs.
In other words, a sponsor of a biologic looking to prove to FDA that its product is worthy of 12 years of exclusivity is going to have to work hard to describe the differences between its product and any predecessors, most notably including structural differences that result in changes in safety, purity or potency.
FDA's guidance goes on to recommend that sponsors of 351(a) applications include four pieces of information in their applications to the agency:
- A list of all licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application being considered. This list should include products that share some of the same principal molecular structural features of the product being considered, but generally can be limited to products that affect the same molecular target. Products that target different epitopes of the same molecular target should be included. Where specific molecular targets have not been defined, this list should include products that share the narrowest target that can be characterized. This may be a pathway, cell type, tissue, or organ system. If this assessment results in the conclusion that no product that has the same molecular target or shares some of the same principal molecular structural features has been licensed, a sponsor should provide an adequate justification to support the assertion that there are no previously licensed products that are relevant for purposes of determining the date of first licensure.
- Of those licensed biological products identified in item 1 above, a list of those for which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.
- Description of the structural differences between the proposed product and any products identified in item 2 above. For protein products, this should include, but is not limited to, changes in amino acid sequence, differences due to post-translational events, infidelity of translation or transcription, differences in glycosylation patterns or tertiary structure, and differences in biological activities.
- Evidence of the change in safety, purity, and/or potency between the proposed product and any products identified in item 2 above. This should include, but is not limited to, a description of how the structural differences identified in item 3 above relate to changes in safety, purity, and/or potency.
Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the Public Health Service Act (FR)