3.9 Regulatory exclusivities

The FDA regulatory guidance

is used, it is preferable that the selected dose be on the steep portion of the dose–response curve of the reference product. Sponsors should provide data to support the claim that the selected dose is on the steep part of the dose–response curve and not on the plateau of the dose–response curve where it is not likely to result in observed differences between two products. Publicly available data for the dose (or exposure)–response relationship of the reference product can be analyzed using model-based simulations to justify the dose selected for the PK and/or the PD study. If the exposure–response data for the reference product are not available, the sponsor may decide to generate this information using a small study to determine an optimally informative dose (e.g., representing the median effective dose of the reference product). Such a study may involve evaluating PK/PD at multiple dose levels (e.g., low, intermediate, and highest approved doses) to obtain dose–response and/or exposure–response data. Alternatively, when possible, sponsors can conduct a similarity study between the reference product and the proposed biosimilar product with low, intermediate, and highest approved doses where a clear dose–response is observed. If multiple doses are studied, PK/PD parameters such as half maximum activity response, Emax, and slope of the concentration effect relationship should be evaluated for similarity. Such studies would be useful for the demonstration of PK, PK/PD, and PD similarities when the clinical pharmacology evaluation is likely to be the major source of information to assess clinically meaningful differences. Publicly available information on biomarker–clinical end point relationships accompanied with modeling and simulation can also be used to define the acceptable limits for PD similarity.

Regulatory exclusivities are automatically granted upon new drug approval by the regulatory agency that licenses the product for commercial distribution. (In its draft guidance document entitled Reference Product Exclusivity for Biological Products Filed under Section 351(a) of the PHSA [http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM407844.pdf], the FDA has proposed that the applicant include in its 351(a) application a request for reference product exclusivity. More specifically, the FDA recommends that the applicant provide an explanation how the biological product meets the statutory requirements for exclusivity, and submits adequate data and information to support the request.) These exclusivities provide pharmaceutical companies with an incentive to undertake the risk and the capital investment required to develop and obtain regulatory approval for drug and biologic products. Innovator companies requested this type of exclusivity during the negotiations that accompanied the enactment of the 1984 Drug Price Competition and Patent Term Restoration Act (more commonly known as the Hatch–Waxman Act), which defined the 101

Biosimilarity: The FDA Perspective

102 approval pathway that created the generic pharmaceutical market in the United States (§ 505(j) of the FDCA). Innovator companies grounded their request on the premise that the award of an exclusivity period would provide greater certainty that the financial investments required to develop a new drug would be repaid. Congress has characterized the regulatory exclusivities as a quid pro quo for the practice of allowing generic companies to file an abbreviated approval package focused on establishing that the proposed generic is a “bioequivalent” to the originator’s product and making reference to, and relying on, the clinical package of the originator’s product to establish safety and efficacy. Note that generic manufacturers obtain regulatory approval by filing an abbreviated NDA and by submitting data establishing the bioequivalence of the generic drug, without additional safety or efficacy data. The type of regulatory exclusivity that is granted, and the length of time that it provides exclusivity depends on the nature of the therapeutic agent and varies from country to country. Pharmaceutical companies that obtain approval for new chemical entities, pursuant to the provisions of Section 505 of the FDCA by filing an NDA, are granted five years of data exclusivity. Data exclusivity has the effect of creating a limited monopoly for the originator who sponsored the clinical studies, by defining a period during which generic manufacturers cannot make reference to the originator’s data package, and, therefore, cannot seek approval for launching a generic product. The BPCI Act grants originator biologic products a period of 12 years of reference product exclusivity, beginning on the date the FDA first licenses the product. An additional six months of exclusivity is available for biologic products approved for pediatric use. (If the FDA believes that studies relating to the use of a biologic in a pediatric population could benefit public health, it makes a written request for pediatric studies. If the applicant completes the pediatric studies then, regardless of the outcome of the studies, the term of the regulatory exclusivities can be extended by six months.) The 12 years of exclusivity comprises four years of data exclusivity followed by eight years of market exclusivity. During the data exclusivity period, biosimilar applicants (for both proposed biosimilar and interchangeable products) are barred from making reference to the reference drug’s clinical package as a basis for licensing their product. In fact, the exclusivity provisions of 42 U.S.C. § 262(k)(7) (B) prohibit the FDA from even accepting a biosimilar application during the reference product’s four-year exclusivity period. An application under this subsection may not be submitted to the secretary until the date that is four years after the date on which the reference product was first licensed under Subsection (a). The subsequent eight years of market exclusivity prohibits the FDA from approving a biosimilar product until the date that is 12 years after the reference product was first licensed under the provision of a full biologics license application (Effective Date of Biosimilar Application

The FDA regulatory guidance

Table 3.4 Market Exclusivity of Major Biosimilar Possibilities Based on Composition or Method of Use Patent

Biologic Brand Name Approval Date

Data Exclusivity

Market Exclusivity U.S. Patent Expiry

Adalimumab Infliximab

Humira Remicade

Rituximab Rituxan

Etanercept

Enbrel Bevacizumab Avastin Dec 2002 Aug 1998 Nov 1997 Nov 1998 Feb 2004

Trastuzumab Herceptin Filgrastim Neupogen PEG-Filgrastim Neulasta

Sep 1998 Feb 1991 Jan 2002 Procrit/Epogen Epoetin-α June 1989 Dec 2006 Aug 2002 Nov 2001 Nov 2002 Feb 2008 Sep 2002 Feb 1995 Jan 2006 Jun 1993 Dec 2014 Aug 2010 Nov 2009 Nov 2010 Feb 2016 Sep 2010 Feb 2003 Jan 2014 Jun 2011 Dec 2016 Sep 2018 Jul 2018 Apr 2029 Mar 2019 Jun 2019 Dec 2013 Oct 2015 Aug 2013

Approval: Approval of an application under this subsection may not be made effective by the Secretary until the date that is 12 years after the date on which the reference product was first licensed under Subsection (a) [42 U.S.C. § 262(k)(7)(A)]). No additional exclusivity is available to reference product sponsors that file supplemental BLA applications, for example, to secure approval for the use of a biologic to treat a second or a subsequent indication. Furthermore, the BPCI Act expressly prohibits reference product sponsors (or their related entities) from using subsequent BLA filings to “evergreen” their period of regulatory exclusivity by filing a new application for a change that results in new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or modification to the structure of the product that does not result in a change in the potency, the safety, or the purity of the reference product (42 U.S.C. § 262(k)(7) (C)). Table 3.4 provides the data exclusivity and the market exclusivity expiry dates for the top nine biologics in the United States This list is based on available expiry dates of composition or method of use; this may change over time as new patents appear, so the reader is advised to consult for its accuracy. The regulatory exclusivities function to protect originator products from biosimilar entrants attempting to use the 351(k) pathway, but not from competitors who secure allowance pursuant to a 351(a) biologics license application. This explains why biopharmaceutical companies protect their products with a combination of regulatory, patent, and trade secret exclusivities. It also explains why biopharmaceutical companies are unlikely to rely solely on regulatory exclusivities to protect their products. It should be noted that the statutory provisions do not prevent a biopharmaceutical company from filing a full BLA for the approval of a competitive product that has the same active ingredient as a branded biologic marketed in the United States. For example, the FDA approved 103

Biosimilarity: The FDA Perspective

104 tbo-filgrastim (short-acting recombinant GCSF) in August 2013, which has the same active ingredient as Amgen’s Neupogen (filgrastim), based on Teva Pharmaceutical’s biologics license application. Teva’s tbo-filgrastim is available in the United States under the brand name Granix® (Granix is approved to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia [tbo-filgrastim prescribing information, issued 2013, Teva Pharmaceuticals, Inc.]). While Granix is a filgrastim, it is not “biosimilar” to Neupogen. Teva’s application was filed under 351(a) and made no reference to, and did not rely on, Amgen’s filgrastim data. Its approval was based on an independent demonstration of the safety and the efficacy of tbo-filgrastim. It should be noted that filgrastim has several indications for which tbo-filgrastim is not approved including severe chronic neutropenia, stem cell mobilization, acute myeloid leukemia, and bone marrow transplant (Filgrastim [Neupogen] Prescribing Information, revised September 2013, Amgen Inc.). While a 351(k) applicant can rely on the originator’s safety and efficacy data to extrapolate all indications for the biosimilar based on the extensive comparative analytical similarity, a 351(a) applicant can rely only on actual clinical data from its own trials.

Teva Pharmaceutical filed for tbo-filgrastim approval before the enactment of the BPCI Act. Therefore, it did not have the option of using the abbreviated 351(k) pathway (tbo-filgrastim is licensed as a biosimilar in Europe). However, in the future, biopharmaceutical companies seeking approval for biologic therapies comprising the same active ingredient as a branded product will have the option of choosing between the two pathways. Filing a BLA allows an applicant to avoid the exclusivity time bars as well as other provisions and uncertainties that accompany the use of the 351(k) pathway. However, submitting a 351(a) application for a biosimilar requires submission of a complete analytical and clinical package as required for any new biologic. Unlike a generic applicant who receives 180 days of market exclusivity for being the first approved generic, the only biosimilar exclusivity available to a drug licensed under the provisions of 351(k) is a period of market exclusivity for the first applicant to obtain approval for a biosimilar product deemed to be interchangeable with the reference product; the length of the market exclusivity is not defined in the statute and will depend on whether the first interchangeable applicant has been sued for patent infringement by the reference product sponsor, and whether the suit remains pending when the first interchangeable product application is approved. The interchangeable exclusivity originates from a statutory provision that prevents the FDA from approving an application for a second or a subsequent interchangeable biosimilar during the exclusivity period. However, the market exclusivity does not prevent the FDA from approving a second or a subsequent biosimilar application.