On March 23, 2010, President Obama signed into law the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), as part of the Patient Protection and Affordable Care Act. The BPCI Act modified the Public Health Services Act (PHS Act) and other relevant statutes to establish an abbreviated approval pathway for biological products demonstrated to be highly similar — that is “biosimilar” — to a reference biological product licensed by the U.S. Food and Drug Administration (FDA) and create a mechanism by which to make attendant determinations of whether the biosimilar product is indeed interchangeable with the reference product. While the BPCI Act creates a pathway, FDA has significant work ahead of it in defining the path’s course, which will be accomplished through development and implementation of related rules and guidance documents. All which must be completed amidst a veritable cacophony of stakeholders’ divergent interests.

Before implementation of the BPCI Act, there was only one way to obtain a biologics license. Under the PHS Act, FDA could approve a biologics license application (BLA) if the subject product demonstrated it was safe, pure and potent and its inspected facility for manufacturing, processing, or packing met standards designed to assure the product’s continued safety, purity and potency. Obviously, under this traditional route, preclinical and clinical information is typically essential to the Agency’s determination that a product is safe, pure and potent, the development of which can take significant time and resources. Consequently, U.S. approval of follow-on biologics has been virtually non-existent, limited to only a handful of products that the Agency has approved on a case-by-case basis primarily under the abbreviated 505(b)(2) pathway. (A 505(b)(2) application contains full reports of investigations of safety and effectiveness, but at least some of the information required for approval is derived from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.) For example, the recombinant human growth hormone Omnitrope was approved in May 2006 under 505(b)(2) as a follow-on protein version of Genotropin. However, the follow-on Omnitrope was not classified as “therapeutically equivalent,” and therefore substitutable, to any approved human growth hormone product. 

Under the BPCI Act pathway, an applicant must demonstrate that the subject product is biosimilar to a reference product, that it uses the same mechanism of action as the reference product for the approved use (but only to the extent it is known for the reference product), that the conditions for use in the proposed labeling have been previously approved for the reference product, that its route of administration, dosage form, and strength are the same as the reference product, and that the facility in which it is to be manufactured, processed, packed or held is designed in a way that will assure the product remains safe, pure and potent. 

Under the law, being “biosimilar” means the biological product “is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.” Demonstrating biosimilarity — the first element of the application described above — requires: 

1) submission and support of data derived from analytical studies showing the subject product is highly similar to the reference product,

2) animal studies, including toxicity assessments, and 

3) a clinical study or studies, including immunogenicity and pharmacokinetic/pharmacodynamic assessments, sufficient to show safety, purity and potency in one or more approved condition of use for the reference product. 

The BPCI Act pathway contemplates interchangeability of the biosimilar product with its reference product, specifically authorizing the inclusion of information in an application that the product meets certain standards. The enumerated standards are outlined in the Act, but will undoubtedly be augmented by rulemaking and guidance documents. FDA “shall” determine the subject and reference products to be interchangeable if the submitted information is sufficient to show the product is biosimilar to the reference product, can be expected to produce the same clinical result in any given patient as the reference product, and, for products administered more than once, that the risk of alternating or switching between the two products is not greater than the risk of solely using the reference product for the course of treatment, either in terms of safety or decreased efficacy. For the first-approved follow-on product, the mantle of interchangeability carries with it an exclusivity period of at least one year, during which no other biosimilar can be approved as interchangeable; this period can last as long as three and a half years after approval of the first interchangeable biosimilar product under certain circumstances. 

Original biologics license applicants, i.e. “innovators,” also received consideration under the statute. The BPCI Act provides reference biologics with 12 years of data exclusivity regardless of patent protection. While this does not forestall the approval of a second, similar biologic product through the full BLA process, it makes the potential for a follow-on product less likely during the 12-year period considering the level of information necessary to support a full BLA. In addition, the Act also prevents a biosimilar application from even being filed for at least four years following the licensure of the reference product. While the exclusivity is expansive, the BPCI Act reins in the possibility of multiple exclusivity periods by preventing exclusivity for (1) a supplement to the reference product or (2) subsequent applications by the reference product’s sponsor, including related entities, for a change (not including a modification to the biologic’s structure) resulting in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength, or a modification to the biologic’s structure that does not change its safety, purity or potency as a result. The BPCI Act also includes a preapproval patent litigation framework implicated upon the filing of a biosimilar product, the details of which, while of tremendous import, are outside the intended scope of this article. 

As foreshadowed, discourse on the topics of biosimilarity and interchangeability has been lively, with positions and opinions not surprisingly falling into branded and generic camps. A two-day November 2010 public hearing yielded nearly 800 pages of transcript, with presentations being made by roughly 50 individuals or companies, and close to 200 items have been submitted to the public docket. Topics identified by FDA that need to be addressed range from biosimilarity, interchangeability, patient safety and pharmacovigilance, the use of supportive data and information, guidance documents, exclusivity, transition provisions, and user fees. The Agency requested input from healthcare professionals, healthcare institutions, manufacturers of biomedical products, interested industry and professional associations, patients and patient associations, third party payers, current and prospective BLA and new drug application (NDA) holders, and the public, regarding implementation of the BPCI Act. FDA also specifically called upon companies and trade associations that would be affected by a user fee program in order to “prepare to begin” negotiations regarding a user fee program. 

The comments and feedback will ultimately be internalized as part of the rulemaking or guidance document development process. While proposed rules have not yet been announced, Dr. Janet Woodcock, co-chair of the Biosimilar Implementation Committee and director of the Center for Drug Evaluation and Research, signaled in an interview in early May the Agency’s plan to provide general guidance for companies seeking to market biosimilar products, expected to be released before year’s end, although she noted that FDA had not yet received any actual biosimilar applications. In the interim, she indicated the Agency was meeting with individual companies and providing advice to them on their programs. 

The Agency has been using this input to initiate development of rules and guidance documents to implement the biosimilar pathway under the BPCI Act, and has recently advanced its development of an appropriate user fee program for biosimilar and interchangeable product applications for fiscal years 2013-2017. Under the BPCI Act, FDA is required to develop and present recommendations to Congress on a user fee program by January 15, 2012. In a May 10 Federal Register notice, FDA stated that the development of a user fee program presents unique challenges as compared to other similar programs in that the regulated industry is mostly undefined. That is to say, a biosimilar and interchangeable product approval pathway historically did not exist, and no products have been approved under the new pathway, so the Agency does not have data or insight to inform development of the user fee program. To that end, FDA indicated that while it will model the user fee program after the Prescription Drug User Fee Act (PDUFA) program, it will undoubtedly include different elements to ensure an equitable program producing adequate revenue.

As a starting point, FDA proposed four key principles for development of the program:

1. biosimilar and interchangeable biologics represent a critical public health benefit such that FDA needs sufficient review capacity to prevent unnecessary delays in the development and approval of these products,

2. the program’s user fees should remain comparable to PDUFA’s for at least the first five years,

3. the program should provide funding for early-stage biosimilar and interchangeable product development activities, and 

4. the program should ensure adequate resources for the review of innovator biologic applications.

These key principles translate to the following proposed user fee program for an application in the premarket phase: a biosimilar product development fee paid upon submission of an investigational new drug application and annually thereafter for a product under active development, a marketing application fee paid for each application, an establishment fee paid annually, and a product fee paid annually. In its current thinking, the Agency has suggested the amounts would for the most part be in line with PDUFA fees. In addition to soliciting written comments to the docket, the Agency will hold a series of industry and public stakeholder meetings over two to three months in 2011 to review and discuss the key principles and criteria for design of a fair and adequate user fee program, the user fee program structure proposed in the notice, and any alternative structures submitted to the public docket that meet the key design principles and criteria, and the proposed performance goals. 

All of the preparations described above are being undertaken to better define a pathway that has yet to see an actual submission and consequently, has no test cases. While FDA suggests the lack of submissions under the new law is meaningful, industry would likely point to lack of tangible rules and guidance documents to serve as guideposts along the path, assuring more efficient use of company time and resources, as just as significant. At this time, it remains to be seen how quickly industry will seek to take advantage of the new provisions, although interest is high and many companies have signaled they are in active development.  

Colleen Heisey is a partner in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com) in the Firm’s Food and Drug Practice. She can be reached at [email protected].