§§7001-7003, Title VII, Subtitle A, codified at 42 U.S.C. §262 .
was signed into law by President Obama on March 23, 2010, as part of the Patient Protection and Affordable Care Act. 2
Public Law 111-148 , March 23, 2010.
Designed to establish a framework for expedited Food and Drug Administration approval of biosimilars, it represents the culmination of a long-standing debate on the safety of such biosimilars versus the need for lower-cost biologic drugs. Accordingly, it contains incentives and tradeoffs for both innovator and generic companies, while leaving the details of the approval process to the FDA.
Indeed, whether the BPCIA approval pathway ultimately takes hold will depend in significant part on FDA rulemaking and guidance documents, although it also will be informed by the litigation and exclusivity provisions contained in the act. On Nov. 2-3, 2010, the FDA held a public hearing to solicit information and comments regarding the FDA’s implementation of the BPCIA. 3
See Federal Register Vol. 75, No. 192, Oct. 5, 2010 at 61497-500. Transcripts of statements made and presentations given at the hearing, as well as public comments, are available online at www.regulations.gov, FDA docket number FDA 2010-N-0477.
While it likely will take months before FDA makes any decisions, one thing is clear—there is a vigorous debate as to how the act should be implemented.
Prior to the BPCIA, the only way to obtain a biologics license was pursuant to 42 U.S.C. §262(a) , which provides that the FDA will approve a biologics license if it is demonstrated that (I) the biological product is “safe, pure, and potent,” (II) the manufacturing, processing, or packing facility “meets standards designed to assure that the biological product continues to be safe, pure, and potent”; and (III) the applicant consents to inspection of that facility. See 42 U.S.C. §262(a)(2)(B) . The FDA typically requires an applicant to complete successful preclinical and clinical trials before submitting a BLA, 4
BLAs are evaluated by the FDA’s Center for Biologics Evaluation and Research (CBER) according to the requirements set forth in 21 C.F.R. §§600-680 , which provide for clinical trials. Such trials are not required by the statute.
a time-consuming and expensive process. These requirements applied to both brand and generic applicants and, as a result, the BLA process has not encouraged low-cost alternatives to preexisting biologic products.
The BPCIA sets forth an expedited approval pathway for generic biologics designed to determine whether a generic product can in fact substitute for the reference product. It contains incentives for generic companies, including exclusivity for the first “interchangeable” biosimilar and a pre-approval litigation process, as well as incentives for the brand companies including a 12-year exclusivity period. These provisions are discussed below.
The BPCIA provides high-level requirements for the contents and approval of a biosimilar application under 42 U.S.C. §262(k) . In particular, the application must demonstrate:
The act states that, to demonstrate the above requirements, the application should include analytical studies showing that the biosimilar and reference products are “highly similar,” animal toxicity studies, and “a clinical study or studies” that assess immunogenicity, pharmacokinetics or pharmacodynamics, and safety, purity, and potency in at least one approved condition of use. 42 U.S.C. §262(k)(2)(A)(i)(I) . Any of these requirements can be waived if the FDA determines it is “unnecessary.” Id.
The BPCIA also includes a determination of “interchageability” between the reference product and biosimilar, which means that “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” 42 U.S.C. §262(b)(3) . To achieve interchangeability status, the information contained in the biosimilar application must demonstrate that (1) the two products are biosimilar, (2) the biological product can be expected to produce the same clinical result in any given patient, and (3) for products administered more than once to a person, switching between the two products does not create any risk to the patient in terms of safety or diminished efficacy. 42 U.S.C. §262(k)(4) .
Despite this elevated standard, there are two upsides to obtaining approval for an “interchangeable” biosimilar. The first-approved interchangeable biosimilar enjoys an exclusivity period of at least one year during which no other biosimilar can be approved as interchangeable. 42 U.S.C. §262(k)(6) . In addition, interchangeability theoretically allows automatic substitution of the generic biologic for the brand at the pharmacy, and automatic substitution is key to the generic company business model: it results in a high volume of sales with minimal to no advertising. That means, of course, that interchangeable biosimilars could substantially reduce innovator product sales.
The BPCIA provides reference biologics with 12 years of data exclusivity regardless of patent protection; no biosimilar can be approved through the BPCIA until 12 years after the reference biologic was approved. See 42 U.S.C. §262(k)(7) . This is not marketing exclusivity; a similar biologic still could be approved through the traditional BLA process, as was reiterated by Sens. Kay Hagan (D-N.C.), Orrin Hatch (R-Utah), Michael Enzi (R-Wyo.), and John Kerry (D-Mass.) in a Jan. 7 letter to FDA Commissioner Hamburg. In addition to 12 years of exclusivity, no biosimilar application even can be submitted until four years after approval of the reference biologic. Id. On Jan. 20, AARP, along with a generics industry group and other stakeholders, sent a letter to FDA’s Hamburg stating that after the initial four years, “the data exclusivity expires (meaning that a biosimilar application that benefits from a reference brand biologic showing of safety and efficacy can be filed), and the market exclusivity continues for the remaining eight years.”
The act seeks to limit the possibility of multiple exclusivity periods through section 262(k)(7)(C) by providing that additional exclusivity shall not apply for a “supplement for the [reference] product”; nonstructural modifications to the product that result in “a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength”; or structural modifications that do not resulting in a change in “safety, purity, or potency.” 42. U.S.C. §262(k)(7)(C) .
The BPCIA contains a preapproval patent litigation framework that also could factor into a generic company’s decision to pursue expedited approval under the act. The patent litigation provisions of the BPCIA are triggered by the filing of the subsection (k) application. 42 U.S.C. 262(l) . Broadly speaking, there are four phases to the litigation framework. In phase one, the biosimilar applicant provides information concerning its product to the reference product owner, and the reference product owner in turn discloses infringed patents. In phase two, the parties disclose infringement, noninfringement, validity, invalidity, and unenforceability contentions. In phase three, the parties negotiate which patents ultimately should be part of the suit. Finally, in phase four, the suit is filed. Each of these phases is discussed in more detail, below.
The first phase of the litigation framework requires the biosimilar applicant to disclose its application and “such other information that describes the process or processes used to manufacture the biological product,” on a confidential basis, to representatives of the reference biologic company. 42 U.S.C. 262(l)(2)(A) . The statute provides that outside counsel and one in-house counsel can review the information. See 42 U.S.C. 262(l)(1)(B) -(H). If the patent has been exclusively licensed, one representative of the patent owner also can have access to the information. Id. Recognizing that significant confidential information must be disclosed by the generic company to its competitor, the statute imposes a protective order on the parties to protect that information. The protective order provisions, which last indefinitely or until the court enters a protective order, are typical of those imposed in virtually all patent litigations and include a prosecution bar.
The second phase of the litigation framework involves identifying patents and litigation positions. Because there is no Orange Book for biologics, the reference product owner is required to identify any patents it believes would be infringed by the manufacture or sale of the biosimilar drug. It has 60 days after receiving the subsection (k) application and manufacturing process documents to identify the patents. See 42 U.S.C. 262(l)(3)(A) . Once the generic applicant receives the list of patents, it must provide, on a claim by claim basis, the factual and legal basis for any assertion that the patents are invalid, unenforceable, or not infringed. See 42 U.S.C. 262(l)(3)(B) . Within 60 days after receiving the invalidity, unenforceability, and noninfringement disclosure from the generic applicant, the reference product owner must respond with claim-by-claim infringement contentions as well as a response to the statement of invalidity and unenforceability. See 42 U.S.C. 262(l)(3)(C) .
After exchanging contentions, the parties must negotiate in good faith to agree to a final list of patents to be asserted in the litigation. See 42 U.S.C. 262(l)(4) . There is no timeframe for the negotiations to begin, but if agreement is not reached within 15 days after commencement of the negotiations, the parties compile a joint list of patents according to the procedure of subpart (l)(5).
Finally, if the reference product sponsor wishes to bring suit, it must do so within 30 days of the parties agreeing to a list of patents or compiling a joint list if no agreement could be reached. See 42 U.S.C. 262(l)(6) . Unlike the Hatch-Waxman Act and its 30-month stay provision, nothing in the BPCIA limits the length of the litigation. Such a limit may not be necessary, however, in view of the 12 years of exclusivity and the pace at which many district courts conduct patent litigations.
The FDA has requested information, opinions, and comments on a number of topics relating to biosimilar applications, including the amount and types of data required to show biosimilarity. The Nov. 2-3, 2010, hearing elicited numerous views and suggestions regarding the biosimilarity determination, many of which also are reflected in the comments submitted to the FDA. Both companies and patient advocacy groups argued for requiring clinical trials to determine biosimilarity because minor changes in structure, formulation, or impurities could have significant and unanticipated effects for patients. See, e.g., FDA 2010-N00477-0006.3 (Testimony of Dr. Joe Miletich on behalf of Amgen); FDA 2010-N-0477-0006.16 (Testimony of Dr. Greg Schimizzi on behalf of the Coalition of State Rheumatology Organizations); FDA 2010-N-0477-0007.13 (Statement of Marie A. Vodicka, Ph.D., on behalf of Pharmaceutical Research and Manufacturers of America); FDA 2010-N-0477-0045.1 (Comment submitted by RetireSafe, a nonprofit senior advocacy organization); FDA 2010-N-0477-0046 (Comment submitted by Hemophilia Federation of America).
Under the act, a clinical study will be necessary to prove biosimilarity. But, if substantial clinical trials are required to show biosimilarity, the BPCIA hardly will differ from the current BLA procedure and thus would not produce moderately priced biologics. Thus, it is likely that Congress intended something less onerous than full clinical trials. Representatives for both Momenta Pharmaceuticals and Mylan Inc. advocated for less in the way of clinical trials. See, e.g., FDA 2010-N-0477-0007.4 (Testimony of James M. Roach, M.D., on behalf of Momenta Pharmaceuticals); FDA 2010-N-0477-0006.17 (Testimony of Rasmus Rojkjaer, M.D., Ph.D., on behalf of Mylan Inc.). Indeed, Dr. Rojkjaer argued that concerns over the safety of an expedited biosimilarity determination are overblown because the FDA addresses the same issue each time a branded manufacturer makes changes to its processes, opens a new facility, substitutes ingredients, or uses a new cell line. In these circumstances, Dr. Rojkjaer testified, the FDA evaluates the products on a “comparability” standard to assess whether the products have “highly similar quality attributes”—a standard he believes also should be applied to generic biosimilars.
Whatever decisions the FDA makes regarding biosimilarity requirements, it is evident that onerous clinical trial requirements could discourage use of the BPCIA expedited pathway and cause generics to continue with the traditional BLA process, thus maintaining the status quo of expensive biologic products.
The interchangeability rules have produced even more of a debate than the biosimilarity rules. Industry representatives and patient advocacy groups argued that not enough is known about biologics to make an interchangeability determination, and so at this point no biologic should be approved as interchangeable with the reference product. See, e.g., FDA 2010-N-0477-0006.16 (Testimony of Dr. Greg Schimizzi on behalf of the Coalition of State Rheumatology Organizations); FDA 2010-N-0477-0007.13 (Statement of Marie A. Vodicka, Ph.D., on behalf of Pharmaceutical Research and Manufacturers of America). More moderate views were also expressed, including that any interchangeability determination require clinical testing (FDA 2010-N00477-0006.21(Presentation by Jay P. Siegel, M.D., on behalf of Johnson & Johnson)); interchangeability determinations should not be made until after a product has been approved as a biosimilar and marketed for a period of time during which post-marketing studies are conducted (FDA 2010-N00477-0006.3 (Testimony of Dr. Joe Miletich on behalf of Amgen); FDA 2010-N-0477-0006.20 (Testimony of Marcia Boyle on behalf of the Immune Deficiency Foundation)), and any substitution of an interchangeable biosimilar cannot be automatic—it must be done with consent of the prescribing physician (FDA 2010-N-0477-0006.2 (Testimony of David Bromberg, M.D., FAAP on behalf of the American Academy of Pediatrics); FDA 2010-N-0477-0045.1 (Comment submitted by RetireSafe)).
Generic companies and their supporters contended that the FDA already is equipped to make interchangeability determinations and should use the same standards currently used to approve changes to the formulation or manufacturing of reference products. FDA 2010-N-0477-0006.17 (Testimony of Rasmus Rojkjaer, M.D., Ph.D, on behalf of Mylan Inc.).
Because the BPCIA describes the approval of “interchangeable” biosimilars, and because only interchangeability provides exclusivity to biosimilars, the FDA most likely will reject the notion that interchangeability should not yet be granted. Instead, it is expected that the FDA will institute rules for interchangeability determinations. And, even after such rules are implemented, the industry can expect that the FDA will subsequently issue clarifications and guidance documents. As a result, the interchangeability debate may continue for months or years.
The 12-year exclusivity provision has been criticized as overly generous to the reference product sponsors and contrary to the goal of an expedited pathway. However, at least one patient advocacy group supports the provision “to preserve and protect future innovation” and “to ensure an unhurried and very careful FDA process” for approval of biosimilars. FDA 2010-N-0477-0045.1 (Comment submitted by RetireSafe). In addition to such the criticism of the exclusivity provision is the view of Sen. Bernard Sanders (D-Vt.) denouncing it as a violation of Article 20 of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, which he expressed in a letter to the FDA. See FDA 2010-N-0477-0002. According to Sanders, if a generic company wishes to circumvent the 12-year exclusivity period, it must file a traditional BLA. The Declaration of Helsinki, Sanders argues, provides that physicians should halt clinical studies when there is “conclusive proof of positive and beneficial results.” Filing a BLA on a biosimilar, the argument goes, would require additional clinical studies when such conclusive proof already exists. Sanders has thus introduced a bill, S. 3921, entitled “The Ethical Pathway Act of 2010,” to eliminate the 12-year data exclusivity. FDA 2010-N-0477-0006.22. Enactment of such a statute would be a significant victory for generics and would serve to expedite the BPCIA approval process. In the meantime, it remains to be seen whether Sanders’s letter will influence the FDA’s rulemaking as to the degree of clinical testing required to demonstrate biosimilarity.
The litigation provisions of the BPCIA require disclosure of the subsection (k) application, manufacturing processes, and invalidity, unenforceability, and noninfringement contentions. In the press, some concern has been expressed that these disclosure requirements, in particular the disclosure of manufacturing processes, are too broad and favorable to the reference product sponsor. However, there may not actually be cause for much concern. The BPCIA disclosure requirements are very similar to those currently imposed by the local rules of a number of district courts and are not very different from the requirements of the Hatch-Waxman Act. The Hatch-Waxman Act requires the applicant to provide the factual and legal basis for any assertion that the patents are invalid or not infringed. See 21 U.S.C. 355(j)(2)(B)(ii) . The District of New Jersey Local Rules for Hatch-Waxman cases, for example, require the defendant to produce its entire abbreviated new drug application (ANDA) or new drug application (NDA) to the plaintiff prior to the scheduling conference. See District of New Jersey Local Rule 3.6(a). The Eastern District of Texas and the Northern District of California require the plaintiff to disclose infringement contentions, after which the defendant discloses invalidity and unenforceability contentions. See Eastern District of Texas Patent Rules 3-1 & 3-3; Northern District of California Patent Rules 3-1 & 3-3. In addition, any concerns over the disclosure of trade secrets should be mitigated by the protective order provisions of the BPCIA.
In deciding whether to pursue approval under the BPCIA , companies will need to weigh a number of factors. The FDA rules and guidance documents will be first and foremost, if for no other reason than because the degree of testing and data required to show biosimilarity or interchangeability could outweigh any benefits conferred by the act. It may take a significant amount of time for the industry to truly have clarity on the requirements for biosimilarity and interchangeability, and that could discourage the use of the BPCIA.
Timing also will be important to generic companies. A BLA may make sense if approval will be obtained before the 12-year exclusivity period expires for the reference product, especially if it is estimated that any additional cost from conducting clinical trials would be made up by the longer period of sales.
The litigation provisions also may factor into the decision. For example, if there is a significant concern over the innovator company’s patent portfolio, the generic may want to forgo the BLA process and the accompanying at-risk launch in favor of the pre-approval process offered by the BPCIA. Some companies may also want to wait and see how ambiguities in the process are resolved before pursuing approval under the BPCIA.
Ultimately, the decision of whether to take advantage of the expedited approval process of the BPCIA likely will be made on a case-by-case, company-by-company basis, with the FDA’s final rules playing a significant part in the decision.