FDA Biosimilar Guidances Stir Innovator Worries About BLA Exclusivity, Trade Secrets

Brand pharma/biotech stakeholders say that BLA sponsors should not have to request and justify the award of 12 years of innovator exclusivity, as FDA’s draft guidance suggests. They also raise concerns about disclosure of BLA trade secrets, with Abbott asserting that approval of biosimilars that reference products licensed before March 2010 would constitute a “taking.”

FDA’s proposed approach to awarding 12 years of exclusivity for novel biologics and its protection of reference product trade secrets in the course of evaluating biosimilars have emerged as key concerns among brand pharmaceutical and biotechnology companies.

In comments on FDA’s three biosimilar draft guidances, innovators and their trade associations challenge the agency’s proposal that BLA sponsors should “request” 12 years of innovator marketing protection. They also question whether FDA review staff will protect innovators’ trade secret information during the agency’s interactions with biosimilar sponsors.

Abbott’s argument about the need to protect innovator trade secrets invokes the Takings Clause of the Constitution’s Fifth Amendment.

One innovator, Abbott Laboratories Inc., goes so far as to argue that approval of a biosimilar referencing an innovator product licensed before March 2010 would represent a “taking” of the BLA sponsor’s trade secrets under the Constitution’s Fifth Amendment.

Innovators May “Request” Exclusivity

In February FDA released draft guidances on scientific considerations, quality considerations and general questions related to use of the new 351(k) approval pathway for biosimilars. Guidance provisions that have drawn extensive stakeholder comment include use of comparator data involving foreign products, the threshold amount of clinical data needed to support a biosimilar’s approval, and extrapolation across indications (Also see "Biosimilar Guidance Comments Reveal Small Window Of Agreement On Foreign Data" - Pink Sheet, 23 Apr, 2012.).

The draft guidances’ provisions, or lack thereof, on interchangeability also have left a variety of stakeholders wanting more (see related story, (Also see "Biosimilar Interchangeability: Stakeholders Want More FDA Guidance, Fewer Hurdles" - Pink Sheet, 30 Apr, 2012.)).

In the Q&A guidance, FDA said it is continuing to review the reference product exclusivity provisions of the Biologics Price Competition and Innovation Act, which created the 351(k) pathway and provides 12 years of protection for innovator products.

The duration of innovator exclusivity was one of the most contentious provisions in the development of, and debate over, the biosimilars legislation. The 12-year term was viewed as a major triumph for the branded industry; the generic sector had been pushing for less than 10 years of protection.

However, the statute also contains a “first licensure” provision aimed at preventing new exclusivity from attaching to minor changes made to biologic product, a practice known as “evergreening.” A separate 12-year term is not available to a BLA supplement or a subsequent application filed by the same sponsor of the reference product (or a licensor, predecessor or related entity) for a change that results in a new indication, route of administration or dosage form, or a modification to the biologic’s structure that does not result in a change in safety, purity and potency.

The draft guidance says an applicant “may include in its BLA submission a request for reference product exclusivity under section 361(k)(7) of the [Public Health Service] Act, and FDA will consider the applicant’s assertions regarding the eligibility of its proposed product for exclusivity. At this time, FDA suggests that an applicant’s request for reference product exclusivity specifically describe how the proposed product meets the statutory requirements in section 351(k)(7) of the PHS Act, and include adequate data and information to support the request.”

This statement struck a nerve with the innovator industry, which asserts that 12 years of protection automatically attaches to a qualifying product and that sponsors should not have to request it or justify why they are entitled to the benefit.

“The statute provides 12-year exclusivity presumptively, with a narrow exception that arguably should be invoked by the agency and only in certain narrow situations,” PhRMA said.

“The statute provides 12-year exclusivity presumptively, with a narrow exception that arguably should be invoked by the agency and only in certain narrow situations. It does not seem consistent with the statute to require applicants to prove in every case that the exception does not apply,” the Pharmaceutical Research & Manufacturers of America’s comments state.

“Moreover, the draft guidance does not describe the data and information that FDA expects a sponsor to include. A reasonable understanding of the exclusivity that may result is critical to investment decisions with respect to new medicines, and we are extremely concerned about the lack of transparency with regard to the rules FDA intends to apply. We strongly request the agency to provide additional clarity on exclusivity requests and supporting ‘data and information’ as soon as possible.”

Innovators said FDA should make reference product exclusivity determinations earlier in the development process, well in advance of BLA submission or approval.

“FDA’s Q&A Draft Guidance does not address when FDA would respond to a request for exclusivity, perhaps implying that such determination would be made upon BLA approval,” the Biotechnology Industry Organization’s comments state. “It is critical that this evaluation and response – which could be pivotal in drug development decisions – be available earlier in time and provided to a sponsor promptly.”

Abbott asks FDA to explain its view of the “first licensure” exception to exclusivity, particularly as it relates to structural modifications.

“A plain reading of the subclause indicates that any structural modification coupled with any clinical differences are sufficient to garner 12 years of exclusivity,” Abbott’s comments state. Furthermore, a sponsor should not have to prove a direct causal relationship between the structural modifications and clinical differences to secure exclusivity, the company asserts.

Wariness Over Trade Secret Disclosures

Biosimilar sponsors may include in their 351(k) applications publicly available information regarding FDA’s previous determinations that a reference biologic is safe, pure and potent.

The guidance defines “publicly available information” as generally including the types of information found in a BLA “action package,” such as documents generated by FDA related to the application review, a summary review that describes conclusions for all reviewing disciplines, and the division director and office director’s decision memoranda.

“FDA intends to post on the agency’s Web site publicly available information regarding FDA’s previous determination that certain biological products are safe, pure, and potent in order to facilitate biosimilar development programs and submission of 351(k) applications,” the Q&A guidance states. “We note, however, that the publicly available information posted by FDA in this context does not necessarily include all of the information that would otherwise be disclosable in response to a Freedom of Information Act request.”

Innovator companies, PhRMA and BIO raise concerns that additional information beyond the action package would be releasable under FOIA, and they call for FDA to update its regulations on disclosure of BLA information to make them consistent with the BPCIA.

FDA is urged to establish internal firewalls to ensure that confidential information contained in a reference BLA is not inadvertently disclosed by agency staff during the biosimilar development and review process.

The commenters ask FDA to adopt formal internal safeguards to ensure that agency staff do not improperly disclose or rely upon confidential or trade secret information in the reference BLA during biosimilar product development meetings, in communications with biosimilar sponsors, or when reviewing 351(k) applications.

“Employees who were significantly involved in reviewing a particular reference product BLA and who have meaningful knowledge of the trade secrets in the BLA should not be permitted to participate in any biosimilar application review activities or any communications with a potential biosimilar applicant seeking to rely on that reference product,” Abbott’s comments state. The company also calls for FDA to implement electronic safeguards to ensure that biosimilar application reviewers are not able to access the reference product BLA or other agency documents related to the BLA review.

Trade Secrets Should Block Some Biosimilar Approvals

Abbott takes the trade secret argument even further, however. The company asserts that approval of a biosimilar referencing any BLA approved before the BPCIA’s enactment would necessarily constitute the improper use of trade secrets.

In an April 2 citizen petition that is cited in the company’s comments, Abbott seeks to block approval of biosimilars referencing innovator BLAs approved before March 23, 2010.

At the time these BLAs were submitted, their sponsors had “reasonable, investment-backed expectations that the trade secrets in their applications would not be used to approve competing products,” the petition states. FDA’s use of trade secrets in these BLAs to support biosimilar approvals “would constitute a taking under the Fifth Amendment to the U.S. Constitution that requires just compensation. FDA should not implement the BPCIA in any manner that would raise this constitutional issue.”

The petition specifically seeks to block approval of biosimilars referencing Abbott’s blockbuster TNF-inhibitor Humira (adalimumab), first approved in 2002. “Abbott believes that at least three companies have begun preclinical and/or clinical testing of biosimilar adalimumab, but does not know whether FDA is advising any companies about the contents of a biosimilar application citing approval of Humira,” the company notes.