Fixed Combinations Of ‘Old Antibiotic’ Plus New Moiety Eligible For NCE Exclusivity, US FDA Says
Executive Summary
A 2008 law that limited exclusivity for certain antibiotics to three years does not apply to Allergan’s Avycaz, which combines an approved old antibiotic active moiety and a new active moiety, CDER exclusivity board concludes.
A fixed-combination product that contains a new active moiety and an antibiotic approved prior to 1997 is eligible for five-year new chemical entity exclusivity, the US Food and Drug Administration said recently in a decision that examines the impact of a 2008 law on antibiotic product eligibility for Hatch-Waxman benefits.
The Center for Drug Evaluation and Research’s exclusivity board determined that Allergan, Inc.’s Avycaz, a fixed-combination antibiotic product, is eligible for five years of exclusivity under the agency’s post-2014 interpretation of NCE exclusivity for combination products.
The CDER exclusivity board issued its Avycaz decision on 21 December 2020, 10 months after NCE exclusivity would have expired. However, Avycaz remains protected until February 2025 thanks to a five-year GAIN Act exclusivity extension.
This conclusion is based on a legal and regulatory analysis of Section 125 of the FDA Modernization Act and Section 505(v) of the Food, Drug and Cosmetic Act, and “in accordance with the agency’s policy objectives of incentivizing the development of antimicrobial therapies that include at least one novel active moiety,” the decision states.
The CDER exclusivity board issued its Avycaz decision on 21 December 2020, which was 10 months after the five-year exclusivity would have expired in February 2020. However, Avycaz is a Qualified Infectious Disease Product with five-year exclusivity under the Generating Antibiotic Incentives Now Act. GAIN exclusivity runs consecutively with NCE exclusivity, not concurrently, meaning that Avycaz remains protected until February 2025.
Novel Moiety + ‘Approved Old Antibiotic’
Avycaz is a fixed combination of ceftazidime, a third-generation cephalosporin, and avibactam, a beta-lactamase inhibitor (BLI). The product was approved in February 2015 for treatment of complicated intra-abdominal infections and complicated urinary tract infections, but has since expanded its labeling to include a pneumonia indication as well as use in pediatric populations.
Ceftazidime is an “old antibiotic,” meaning it previously was approved in a drug product under Section 507 of the FD&C Act prior to the enactment of FDAMA in 1997. Avibactim, a new chemical entity, protects ceftazidime from degradation by beta-lactamase enzymes and maintains the cephalosporin’s activity against certain types of bacteria that express beta-lactamases.
Following Avycaz’s approval, a question arose within the agency as to whether the combination product was eligible for five-year NCE exclusivity because it contained, in part, an old antibiotic. The agency determined that it could not list any Avycaz exclusivity information in the Orange Book until it conducted a legal and regulatory analysis on the impacts of FDAMA Section 125 and FD&C Act Section 505(v). The latter was added to the statute as part of the QI Program Supplemental Funding Act of 2008.
FDAMA brought antibiotic approvals under Section 505. However, FDAMA Section 125(d) exempted certain applications for antibiotic drugs from Hatch-Waxman benefits. Specifically, antibiotic drugs for which the first application was received before FDAMA’s November 1997 effective data were not eligible for Hatch-Waxman benefits. The CDER board refers to these drugs as “old antibiotics.”
Section 125(d) was superseded by the QI Act of 2008, which added 505(v) to the FD&C Act. This created certain Hatch-Waxman benefits for drugs that contain old antibiotics, including three-year exclusivity.
The provision distinguishes between antibiotics approved prior to 21 November 1997 (approved old antibiotics), and those that were the subject of an application submitted before that date but never approved (unapproved old antibiotics).
Under 505(v)(1), an application submitted after enactment of the QI Act for drug that contains an approved old antibiotic may be eligible for three-year exclusivity under Hatch-Waxman. Under 505(v)(2), the sponsor of an application submitted after enactment of the QI Act for a drug that contains an unapproved old antibiotic may elect to be eligible for either three-year Hatch-Waxman exclusivity, five-year NCE exclusivity, or a patent term extension.
“Section 505(v)(4) provides that notwithstanding FDAMA’s exclusion of old antibiotic drugs from Hatch-Waxman provisions and subject to the limitations on exclusivity in section 505(v)(1)-(3), the Hatch-Waxman provisions apply to any ‘drug’ that contains an old antibiotic drug,” the agency said.
Zerbaxa Exclusivity Decision
At issue in the Avycaz analysis is the impact of 505(v)(1) on the Allergan product’s eligibility for five-year exclusivity.
The agency said it previously has opined on the applicability of 505(v)(1) in the single-moiety context, and separately made a determination of eligibility for exclusivity for a fixed combination that includes a new active moiety and an old antibiotic active moiety without consideration for how 505(v) affected that analysis.
In the latter case, the agency recognized five-year NCE exclusivity plus a five-year GAIN extension for Cubist Pharmaceuticals, Inc.’s Zerbaxa (ceftolozane/tazobactam), which was approved in December 2014, two months before Avycaz. The exclusivity determination for Zerbaxa was made by considering the agency's 2014 guidance on NCE determinations for fixed-combination products but did not take into account the potential impact of 505(v) on eligibility for five-year exclusivity, the agency explained.
In that 2014 guidance, the agency adopted a new, more expansive approach to applying NCE exclusivity to certain fixed-combination drug products. (Also see "All Over But The Lawsuits? NCE Exclusivity For Fixed-Dose Combos Remains Prospective" - Pink Sheet, 13 Oct, 2014.) It reinterpreted the word “drug” in the NCE exclusivity provision’s eligibility clause to mean “drug substance” rather than “drug product,” meaning that the agency analyzes each drug substance in a combination product separately to determine if the combination meets the NCE definition and is eligible for five-year exclusivity. (Also see "FDA Changes Its Policy On Exclusivity For Fixed-Combination Products" - Pink Sheet, 24 Feb, 2014.)
‘Contains’ = ‘Contains Wholly’
The FDA said it has not previously opined on whether a fixed-combination containing, in part, an approved old antibiotic active moiety and a new active moiety is subject to 505(v)(1), meaning that it is limited to three-year Hatch-Waxman exclusivity.
“The board finds that although there are other potential readings of the relevant statutory provisions, we’ve decided that five-year NCE exclusivity attaches and 505(v)(1) limitations on available exclusivity do not apply to a fixed combination of a new active moiety and an old antibiotic active moiety,” the agency said.
The board concluded the word “contains” in the 505(v) phrase “drug that is the subject of the application contains an antibiotic drug” means “contains wholly.”
“Under this interpretation, 505(v) would not apply to such a combination (because it does not consist wholly of an old antibiotic drug or drugs) and, if section 505(v) does not apply, such a combination would be eligible for five-year NCE exclusivity under our post-October 2014 interpretation of that provision.” – CDER Exclusivity Board
“Under this interpretation, 505(v) would not apply to such a combination (because it does not consist wholly of an old antibiotic drug or drugs) and, if section 505(v) does not apply, such a combination would be eligible for five-year NCE exclusivity under our post-October 2014 interpretation of that provision.”
Congressional Intent, Public Policy Considerations
The FDA said that denying NCE exclusivity to a fixed-combination product containing a new active moiety and an old antibiotic active moiety would not be fully consistent with congressional intent of the QI Act, through which lawmakers sought to encourage development of novel antibiotics and novel uses of old antibiotics.
Furthermore, there are important and compelling public policy reasons for allowing fixed-combination products comprising an old antibiotic and a new active moiety to qualify for five-year NCE exclusivity, the board said.
“The agency recognizes that there are important clinical and scientific reasons for certain old antibiotic active moieties to be in fixed-combination with certain new active moieties,” the decision states. “In particular, some such fixed-combinations may provide invaluable therapies against the growing threat of antimicrobial resistance.”
In addition, it is preferable to have certain BLIs available as part of fixed-combination products for effective patient care.
“Administering beta-lactam/BLIs as fixed combinations ensures that the components are given at the same time and in the appropriate ratios to provide effective therapy to patients,” the agency said, also noting that fixed combinations can avoid the types of medication errors that may occur if the drugs were administered separately.
A policy that “penalizes sponsors for developing these drugs in combination by denying five-year NCE exclusivity to the fixed combinations, when seeking approval for a new BLI or beta-lactam alone would guarantee such exclusivity, runs counter to important clinical and public health considerations,” the agency said. “Given the benefits provided by such fixed-combinations, it would be in the interest of public health to encourage the development of such fixed-combinations through eligibility for five-year NCE exclusivity.”