COZEN O’CONNOR LEADS THE WAY IN BIOSIMILARS
Cozen O’Connor, among the 100 largest US law firms, is a global leader in representing and advising its clients regarding The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which was enacted in March 2010 as part of the Affordable Care Act. The BPCIA provides a pathway for biosimilar products in the United States that is an alternative to the traditional Biologic License Application. With a dedicated biosimilars team of nearly twenty professionals, Cozen O'Connor has a deep bench of experienced counsel actively engaged in securing positive results for its clients, including strategies for market entry.
The global biosimilars market is expected to be worth $19.4 billion by 2014, with an astonishing compound annual growth rate of over 85% in that time frame. That value provides a glimpse into the $100 billion in branded biologic sales expected to lose patent protection by 2020. The increasing demand from patients, insurers, and government agencies to reduce the costs of blockbuster biopharmaceuticals has created numerous opportunities in the global biosimilar market. Regulatory developments favoring the biosimilar market in many countries, including the United States through the BPCIA, are expected to increase the market shares and profit margins of the players in this lucrative arena. Given the high stakes, and the rare witness to the birth of a market valued at tens of billions of dollars over the next decade, having counsel like Cozen O’Connor versed in the law, from both patent and regulatory perspectives, as well as in the relevant science, is critical to the success of any biosimilar product and its sponsoring organization.
DRUGS VERSUS BIOLOGICS
A typical drug, often-referred to as a “small molecule” due to its simple structure relative to a biologic, is generally manufactured through a standard chemical synthesis by combining specific ingredients in an ordered process with defined reaction conditions. In contrast, a biologic is manufactured in a living system such as a microorganism, plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules, with many being produced using recombinant DNA technology.
Small molecule drugs generally have well-defined chemical structures, which can be positively confirmed through various analytical techniques such as high-performance liquid chromatography, powder x-ray diffraction, Raman spectroscopy, nuclear magnetic resonance spectroscopy and others. By contrast, it is difficult—with some opining impossible—to fully characterize a biologic using current testing methods, and consequently the structure of any corresponding biosimilar product will also be unknown. Comparative analytical data will be a cornerstone in this evolving market (and related patent landscapes).
Branded biologic product purveyors profess that the product is the process, and that small changes may significantly affect the product and its effects in and on the body. Consequently, manufacturing controls are likely not publicly disclosed (e.g., through patent applications or other publications) and remain confidential to the innovator. Without such patent protection, as biosimilar product applications are filed with the U.S. Food & Drug Administration, one would expect a corresponding uptick in non-patent efforts, such as citizen petitions, to block the approvals of competing biosimilar products.
GENERIC DRUGS VERSUS BIOSIMILARS – THERAPEUTIC EQUIVALENCE VERSUS INTERCHANGEABILITY
Under current FDA regulations, generic small molecule products are submitted as a 505(j) application, commonly referred to as an Abbreviated New Drug Application (“ANDA”), and must have the same active ingredient, strength, dosage form, and route of administration as the reference (branded) drug. When these criteria are met, the generic product is deemed to be pharmaceutically equivalent to the brand. A successful generic product will also need to show bioequivalence, meaning there is no significant difference in the rate and extent that the generic product is available at the site of action as compared to the reference drug. Bioequivalence is generally determined through relatively simple in-vivo and/or in vitro studies and without the need for full-scale clinical trials. Once pharmaceutical equivalence and bioequivalence are established, FDA may classify the generic drug product as therapeutically equivalent to the brand product, meaning that the generic product can be fully substituted for the brand.
In contrast, the BPCIA establishes requirements for a biosimilar product application, which is commonly referred to as a 351(k) application, referencing the section the BPCIA added to the Public Health Service Act, 42 U.S.C. § 1 et seq. A 351(k) application must contain, among other things, information demonstrating that the biologic product is biosimilar to a reference product based upon data derived from analytical studies, animal studies, and one or more clinical studies, unless FDA determines in its discretion that certain studies are unnecessary. What studies FDA may require is one of the largest risks in developing any biosimilar product, and one where Cozen O’Connor can add value with its guidance. Any clinical studies, if required, must include an assessment of immunogenicity and pharmacokinetics or pharmacodynamics, which must sufficiently demonstrate safety, purity, and potency for at least one use sought in the 351(k) application (and for which the reference product must also be approved).
Regarding the degree of sameness to the reference product, the BPCIA uses the concepts of “biosimilarity” and “interchangeability.” Under the statute, “biosimilarity" means the product is “highly similar to the reference product notwithstanding minor differences in clinically inactive components; and [that] there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” 42 U.S.C. § 262(i)(2). Going a step further, “interchangeability" means the product can satisfy the biosimilarity standard and also that the product: (1) “can be expected to produce the same clinical result as the reference product in any given patient,” and (2) “if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” 262 U.S.C. § 262(k)(4); see also Guidance for Industry, Biosimilars: Questions and Answers Regarding Implementation of the BPCIA of 2009 at p. 3 (Draft, issued February 2012). Importantly, like therapeutically equivalent generic drugs, interchangeable biologic products “may be substituted for the reference product without the intervention of the prescribing healthcare provider.” 42 U.S.C. § 351(i)(3).
BPCIA EXCLUSIVITY AND OTHER PROVISIONS
The various market and data exclusivities under Hatch-Waxman are key to balancing the incentives for brand and generic companies alike. While the BPCIA, unlike Hatch-Waxman, has no Orange Book-type patent listing requirements for the innovator or related 180-day market exclusivity for the first applicant to challenge a listed patent, the BPCIA attempts similar balancing through various exclusivities and other provisions, including the following:
a 12-year exclusivity period from the date of first licensure of the reference product, during which a 351(k) application may not receive final approval;
a 4-year exclusivity period from the date of first licensure of the reference product, during which a 351(k) application referencing that product may not be submitted;
an exclusivity period for the first biological product determined to be interchangeable with the reference product for any condition of use, during which a second or subsequent biological product may not be determined to be interchangeable with that reference product;
an exclusivity period for certain biological products for which pediatric studies are conducted in accordance with a written request;
a transition provision for biological products that have been or will be approved under Hatch-Waxman before March 23, 2020 (see § 7002(e) of the Affordable Care Act); and
a provision stating that a 351(k) application for a biosimilar product contains a “new active ingredient” for purposes of the Pediatric Research Equity Act.
The BPCIA also establishes a unique procedure for identifying and potentially resolving patent disputes between a 351(k) applicant and the corresponding innovator. The filing of a 351(k) application triggers the procedure, beginning with delivering the application to the innovator within twenty days of FDA’s acceptance. The next steps in the sequence provide for a back-and-forth exchange between the parties regarding which patents may be litigated, requiring a strategy mapped well in advance with the advice of counsel.
The above information is only a brief introduction into the complex world of the BPCIA. There is no doubt that qualified counsel is required, and Cozen O’Connor is ably positioned to partner with you through the entire process. Our attorneys hold advanced degrees in the natural sciences and nearly all members have experience as research scientists in industry or academia, meaning we understand the intersection of law and science. Discuss your biosimilar needs with our team, and you will undoubtedly learn that partnering with Cozen O’Connor means you are partnering with an industry leader.