FDA's Draft Guidance on Biologic Exclusivity Needs Revisions, Industry Groups Say

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By Bronwyn Mixter

Oct. 14 — In recent comments to the Food and Drug Administration, industry groups said the agency's draft guidance on determining exclusivity periods for biologic products needs revisions.

Branded drug and biotechnology industry groups said the draft guidance is too complicated and burdensome, lacks clarify and goes beyond the FDA's statutory mandate. Meanwhile, the generic drug industry said the draft guidance places too much emphasis on the role of reference product sponsors and the types of information that they should submit to support exclusivity determinations. The generic industry said the draft guidance should be revised to recognize the contributions and interests of other stakeholders.

The FDA released the draft guidance in August to assist sponsors and other interested parties in providing information that will help the agency determine the exclusivity period for biologics approved under Section 351(a) of the Public Health Service Act (PHS Act). A notice announcing the draft guidance was published in the Aug. 5 Federal Register (79 Fed. Reg. 45,448).

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act), part of the Affordable Care Act in 2010, amended the PHS Act and other statutes to create an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biologic reference product. Section 351(k)(7) of the PHS Act describes reference product exclusivity, during which a 351(k) sponsor (that is, a sponsor of a biosimilar drug) isn't permitted to submit and the FDA isn't permitted to license a 351(k) application that references a reference product, the agency said.

Under this section, approval of a 351(k) application may not take effect until 12 years after the date of first licensure of the reference product, the FDA said. A 351(k) application for a biosimilar or interchangeable biological product can't be submitted for review until four years after the date on which the reference product was first licensed.

Comments were due Oct. 6. The agency will take the comments into consideration as it works on the final version of the guidance document.

BIO Cites Burden

The Biotechnology Industry Organization (BIO) said that the proposed process and many of the recommendations in the draft guidance are “needlessly complicated, unnecessarily burdensome on both sponsors and FDA, and lack sufficient clarity on important issues.”

BIO also said that in some aspects, it appears that the draft guidance goes beyond the agency's statutory mandate. BIO said it “strongly” urges the FDA to make clear in the final guidance that it interprets the BPCIA as containing a presumption of reference product exclusivity that operates by statute.

“Moreover, any 351(a) application that is not a supplement or a ‘subsequent application' to a previously approved 351(a) application should be granted exclusivity without FDA requiring or recommending that the sponsor provide data regarding the date of first licensure,” BIO said. Section 351(a) refers to the application for the branded, or reference, product.

BIO also said the FDA should revise its recommendations regarding the information that 351(a) sponsors should provide to assist the agency in determining the date of first licensure. The group said the FDA should “request that 351(a) sponsors provide to FDA only information that is not already in the agency's possession, and only information regarding products previously submitted by that applicant or a related party.”

The FDA also should clarify the timeline and process for “first licensure” determinations, including explaining whether the agency will make a first licensure determination for all 351(a) products or if first licensure for any given product will be decided only on request, BIO said. The agency also should clarify that:

• not requesting a first licensure determination doesn't result in a waiver of exclusivity or a later determination of first licensure; and

• if the date of approval of a supplement or subsequent application is deemed not to be the date of first licensure, the product approved by the supplement or subsequent application nevertheless is protected by any remaining time of the 12-year exclusivity afforded the reference product.

BIO also requested that the FDA narrowly interpret the terms “licensor, predecessor-in-interest, or other related entity” in order “to avoid undermining the clear intent of Congress to craft a limited exception to the presumptive 12-year grant of exclusivity.”

“In particular, the term ‘other related entity' should be interpreted consistent with the intent of the statute to be limited to those situations in which, solely by virtue of a particular type of corporate relationship, a subsequent applicant will be able to shorten its path to approval by relying on data contained in the relevant prior application as essential to approval of the subsequent application,” BIO said. “Further, we urge FDA to interpret ‘other related entities' with a focus on ownership and control, and to not include ‘commercial collaborations' in its interpretation of ‘related entities.'”

PhRMA's Views

The Pharmaceutical Research and Manufacturers of America (PhRMA) said it agrees with passages in the draft guidance that suggest that reference product exclusivity presumptively applies to innovative biologics. However, the group recommended that the agency revise other passages that suggest that reference product sponsors must prove that innovative biologics are entitled to exclusivity.

PhRMA said it doesn't believe that justification for exclusivity requests is required. “Based on the statutory language, exclusivity should be presumptively available, and FDA should not place the onus on the reference product sponsor to prove in every case that its biological product does not fall within the narrow first licensure exception,” PhRMA said.

Also, PhRMA suggested that the FDA adopt “a much more streamlined process for exclusivity requests than that described in the draft guidance.” Specifically, the group said the agency should adopt a checklist process for reference product sponsors to request exclusivity.

PhRMA also said that the FDA should rule on a product's eligibility for exclusivity as early as possible during the product development process because it is “essential for sponsors to have early certainty with respect to the exclusivity of their products.”

“Developing biological products is time consuming, expensive, and risky,” PhRMA said. “Sponsors need to know about the availability of exclusivity to justify continued investments in products.”

PhRMA said FDA should accept exclusivity requests before a biologics license application (BLA) is submitted, provide advice on a proposed product's eligibility for exclusivity as early as possible and commit to making prompt decisions on all exclusivity requests.

Generic Industry's Concerns

The Generic Pharmaceutical Association (GPhA) said the draft guidance “places undue emphasis on the role of reference product sponsors and the types of information that they should submit to support exclusivity determination.”

The GPhA said biosimilar applicants also may have relevant information about the structure and safety/effectiveness of a reference product and an interest in timely exclusivity determinations. The group said decisions about whether to develop a biosimilar product may be determined based on whether the reference product has exclusivity and, if so, when that exclusivity expires.

The draft guidance “should be amended to recognize the contributions and interests of other stakeholders, particularly on complex scientific issues like those required for an exclusivity determination,” GPhA said.

The GPhA also said that while it supports the FDA's decision to communicate biologic exclusivity decisions in the so-called Purple Book, the current version of the Purple Book contains very little information about exclusivity for most currently marketed biologic products. In September, the FDA published the Purple Book, a list of licensed biologic products and biosimilars that is meant to be equivalent to the Orange Book for small-molecule drugs.

The generics group said the FDA should update the Purple Book to clarify which products have been determined not to have exclusivity and those which still are subject to pending decisions. “This will provide greater clarify to sponsors who may be considering developing biosimilar and interchangeable biologics and allow them to request exclusivity determinations for specific reference products, if necessary,” the GPhA said. “In addition, we suggest that a mechanism be created whereby FDA makes an exclusivity determination upon the request of a biosimilar applicant, not just the BLA holder or on the agency's own initiative.”

The GPhA also said that the FDA should clarify whether the draft guidance just lists examples of the types of modifications to previously approved reference products that aren't eligible for exclusivity. According to the draft guidance, data exclusivity doesn't apply to a subsequent BLA filed by the same applicant or manufacturer for a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength. “The draft guidance, however, does not indicate whether FDA intends to interpret this list as exclusive or merely illustrative,” the GPhA said.

Also, the GPhA said the draft guidance “focuses on a relative narrow area of exclusivity and ignores several other exclusivity issues.” For example, the draft guidance doesn't explain whether the FDA will apply an “umbrella policy” similar to the one applied in the Hatch-Waxman Act with respect to new chemical entity (NCE) exclusivity. Under an umbrella policy, changes that wouldn't give rise to a new exclusivity period (such as new indications or dosage forms) would be protected by whatever remains of the original exclusivity period. The GPhA asked the FDA to clarify its policies on this issue.

To contact the reporter on this story: Bronwyn Mixter in Washington at bmixter@bna.com

To contact the editor responsible for this story: Brian Broderick at mailto:bbroderic@bna.com

The comments are available at http://www.regulations.gov under Docket No. FDA-2013-D-1165.

The draft guidance is at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM407844.pdf.


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