Time to GAIN: Are Your FDA Marketing Exclusivities Eligible for Extension?

Some innovative drugs are receiving an additional five years of marketing exclusivity on top of their other exclusivities because they qualify under the Generating Antibiotic Incentives Now (GAIN) title of the Food and Drug Administration Safety and Innovation Act as a qualified infectious disease product (QIDP).  GAIN came into play in 2012, and companies are already taking advantage of the benefits it provides.  QIDPs may receive priority review and fast-track status at FDA.  They also may receive five additional years of regulatory exclusivity.  This means, for example, that if the QIDP also qualifies as a new chemical entity (NCE), it may enjoy 10 years of regulatory exclusivity instead of five, and generic-drug companies may need to wait nine years to initiate Hatch-Waxman litigation instead of four.  By considering the requirements for QIDP designation and how other companies are using it for their products, pharmaceutical companies can gain insight into whether their own innovative products qualify for GAIN’s benefits.

Requirements for QIDP designation

Antimicrobial drug resistance has received increasing attention in recent years as a serious public health concern, with an estimated two million people in the United States infected by antibiotic-resistant bacteria each year (1).  GAIN was enacted in 2012 to encourage the development of next-generation antibacterial and antifungal drugs by providing various incentives (2).  To qualify for the incentives, a drug must be designated by FDA as a QIDP, defined as “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by-an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens; or qualifying pathogens listed by the [FDA]” (3).

FDA, in consultation with scientific and medical experts, provided its first list of qualifying pathogens in 2014 (4).  The list includes the 21 pathogens identified in Table I, and FDA will review and update the list at least every five years (3, 5).

FDA places pathogens on the list based on considerations of “the impact on the public health due to drug-resistant organisms in humans,” “the rate of growth of drug-resistant organisms in humans,” “the increase in resistance rates in humans,” and “the morbidity and mortality in humans” (3).  For the first consideration, FDA will assess evidence such as the transmissibility of the pathogen and the availability of effective therapies for treatment of infections caused by the pathogen.  For the second and third considerations, FDA will assess evidence such as the proportion of patients whose illness is caused by a drug-resistant isolate of a pathogen, the number of resistant clinical isolates of a particular pathogen, and the ease and frequency with which a proposed pathogen can transfer and receive resistance-conferring elements.  And for the fourth consideration, FDA will assess evidence such as a meaningful increase in morbidity and mortality rates when infection with a drug-resistant strain of a pathogen is compared to infection with a more drug-susceptible strain of that pathogen.  If the totality of the evidence demonstrates that the pathogen has the potential to pose a serious threat to public health, FDA will identify it as a qualifying pathogen (4).

Treatment of an infection caused by a qualifying pathogen is neither sufficient nor required for QIDP designation.  First, a drug does not necessarily receive QIDP designation just because it is intended to treat an infection caused by a qualifying pathogen.  This stems from differences in standards, with qualifying pathogens having “the potential to pose a serious threat to public health,” and QIDPs being “intended to treat serious or life-threatening infections.”  Second, a drug may receive QIDP designation even if it does not treat an infection caused by a pathogen on the list (4).  For example, a drug may receive QIDP designation if it is an antibacterial drug for human use intended to treat a serious infection caused by an antibacterial resistant pathogen that is not on the list.

QIDPs must be human drugs whose applications are submitted pursuant to § 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. § 355(b).  Combination products whose applications are submitted under that same section may also qualify for QIDP designation.  Biologic products, however, that are approved for marketing pursuant to § 351 of the Public Health Service Act, 42 U.S.C. § 262, cannot be designated as QIDPs.  Similarly, devices that are cleared pursuant to § 510 of the FDCA, 21 U.S.C. § 360, or approved pursuant to § 515 of the FDCA, 21 U.S.C. § 360e, cannot be designated as QIDPs (6).

QIDPs can be novel drugs or those that contain approved active moieties.  Many investigational QIDPs are approved drugs being developed with modifications, such as a new dosage form or indication (7).

Procedure for obtaining QIDP designation

A sponsor may request QIDP designation at any time before submitting a marketing application to FDA for that drug product and indication.  The request should be submitted either to an investigational new drug (IND) application or as pre-IND correspondence.  A QIDP-designation request for a new indication of an approved drug product should be submitted to the IND application for that drug product; the marketing application for the new indication would then be submitted as an efficacy supplement (6).

The cover letter for the request should provide the following text in bold font at the top of the page:  Request for Qualified Infectious Disease Product Designation.  The request should discuss information that supports the activity of the drug as an antibacterial or antifungal drug, and it should identify the specific serious or life-threatening indication(s) for which the sponsor intends (or has begun) to develop the drug and the rationale or suitability for developing the drug for the proposed serious or life-threatening infection(s).  The request may also include information to demonstrate that the product is an antibacterial or antifungal drug that has the capacity to treat a serious or life-threatening infection caused by one or more resistant pathogens, including novel or emerging infectious pathogens, or qualifying pathogens.  FDA will review the request and respond within 60 days of submission (6).

A QIDP designation applies only to a specific drug product, indication, and sponsor.  It does not apply to the drug substance generally, or to other products, indications, or sponsors (6).  Therefore, more than one designation may be granted for the same active ingredient.  For example, a sponsor may receive QIDP designation for multiple dosage forms of the same active ingredient or for multiple indications (7).

Benefits of QIDP designation

QIDPs may qualify for several benefits.  First, FDA gives priority review to the first application submitted for the QIDP (8).  A subsequent application from the same sponsor for the same product and indication will receive priority review only if it otherwise meets the criteria for priority review (6).  Priority review means that FDA will review and act on the application within six months, rather than 10 months under standard review (9, 10).

Second, at the request of the sponsor, FDA will designate the QIDP as a fast-track product, which means FDA will facilitate the product’s development and expedite its review (11).  For example, fast-track products may be eligible for more frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval, more frequent written communication from FDA about the design of the proposed clinical trials and use of biomarkers, accelerated approval, and rolling review of completed sections of its drug application (12).  Although QIDP designation may be requested before submission of an IND application, a request for fast-track designation may be made only with or after submission of the IND application.  FDA will respond to the request for fast-track designation within 60 days (11).

Third, QIDPs receive five additional years of regulatory exclusivity (3).  This means that for QIDPs, any NCE exclusivity is extended from five years to 10 years, any new clinical investigation exclusivity is extended from three years to eight, and any orphan drug exclusivity (ODE) is extended from seven years to 12 (3, 13, 14).  QIDPs may also qualify for pediatric exclusivity, which would extend each exclusivity period by six additional months (3, 15).  Accordingly, a QIDP that also qualifies for ODE and pediatric exclusivity will have a regulatory exclusivity period of 12.5 years, during which FDA cannot approve another application for the same drug for the same orphan disease or condition (3, 14, 15).

Most innovative drug companies rely on combinations of regulatory and patent exclusivities to protect their drug products from competition.  The patents covering their products and methods of using them are generally listed in FDA’s Orange Book.  If a competitor seeks to introduce a generic version of a drug product covered by one or more listed patents before patent expiration, the competitor must file a generic-drug application with a paragraph IV certification alleging invalidity, unenforceability, or noninfringement (13).  The innovative drug company may initiate Hatch-Waxman litigation against the generic-drug company in federal court (16).  Doing so within 45 days of notice of the paragraph IV certification triggers a 30-month stay, during which FDA cannot approve the generic-drug application (13).

FDA will not accept generic-drug applications with paragraph IV certifications for the first four years of NCE exclusivity (13).  When a drug with NCE exclusivity also qualifies as a QIDP, this four-year period is extended to nine years.  Thus, by qualifying for NCE and QIDP, an innovative drug company can extend the period during which its products are immune from Hatch-Waxman litigation to nine years (3).

QIDP designations and product approvals

From the enactment of GAIN through September 30, 2017, FDA received 161 requests for QIDP designation.  FDA denied 14 of these requests because, for example, the product was not intended to treat or prevent a serious or life-threatening infection or was a biological product outside the scope of GAIN.  The 147 requests that were granted included QIDP designation for an estimated 74 novel drugs (7).

From the enactment of GAIN through February 2018, FDA approved 12 QIDPs, giving each priority review (7).  These 12 products are listed in Table II, along with the indications receiving the QIDP designation; the new drug application (NDA) holder, number, and approval date; and the types of exclusivity (7, 17).

Ten of the 12 products also received NCE, so the GAIN extension provides them with 10 years of NCE exclusivity and nine years of immunity against Hatch-Waxman litigation.  Two of these 10 products also received ODE, so the GAIN extension provides them with 12 years of ODE in addition to the 10 years of extended NCE exclusivity and nine years of immunity against Hatch-Waxman litigation (3).  The exclusivity determinations for the other two products are pending.

Notably, while all 10 of the approved QIDPs for which FDA has completed exclusivity determinations also received NCE exclusivity, NCE exclusivity is not a requirement for QIDP designation (3).  In addition, according to FDA’s Orange Book, the extended regulatory exclusivities for several of these products extend beyond their patent exclusivity:  Dalvance (dalbavancin hydrochloride) powder for injection; Cresemba (isavuconazonium sulfate) capsule; Cresemba (isavuconazonium sulfate) powder for injection; and Solosec (secnidazole) granule (17).

Conclusion

GAIN provides significant incentives for the development of antibacterial and antifungal drug products to treat serious or life-threatening infections.  Drug companies should consider whether any of their products may qualify as QIDPs under GAIN so they can benefit from the expedited review provisions and exclusivity extensions that other products are already enjoying.

References

1. CDC, Antibiotic Resistance Threats in the United States, 2013 (2013), www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf
2. Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, tit. VIII, § 801, 126 Stat. 993, 1077-79 (2012), establishing § 505E of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355f.
3. 21 U.S.C. § 355f.
4. FDA, Final Rule, Establishing a List of Qualifying Pathogens Under the Food and Drug Administration Safety and Innovation Act, 79 Federal Register 32,464-81 (June 5, 2014) (amending 21 C.F.R. § 317.2), www.gpo.gov/fdsys/pkg/FR-2014-06-05/pdf/2014-13023.pdf.
5. 21 C.F.R. § 317.2.
6. FDA, Draft Guidance, Qualified Infectious Disease Product Designation, Questions and Answers, Guidance for Industry (CDER, January 2018), www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM594213.pdf.
7. Department of Health & Human Servs., Generating Antibiotic Incentives Now, Required by Section 805 of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144 (Feb. 2018), https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM595188.pdf.
8. 21 U.S.C. § 360n-1.
9. 21 U.S.C. § 360ff.
10. FDA, Priority Review, www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm (last updated Jan. 4, 2018).
11. 21 U.S.C. § 356.
12. FDA, Fast Track, www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm (last updated Jan. 4, 2018).
13. 21 U.S.C. § 355.
14. 21 U.S.C. § 360cc.
15. 21 U.S.C. § 355a.
16. 35 U.S.C. § 271.
17. FDA, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (February 2018), www.accessdata.fda.gov/scripts/cder/ob/index.cfm.

About the Authors

Glen Cheng, MD, Regulatory Counsel, Office of Regulatory Policy, Center for Drug Evaluation and Research, FDA.  This article was prepared while Dr. Cheng was employed at Finnegan, Henderson, Farabow, Garrett & Dunner, LLP.  The opinions expressed in this article are the author's own and do not reflect the view of FDA, the Department of Health and Human Services, or the United States government.

Shana K. Cyr, PhD, Partner, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP.  Dr. Cyr focuses on complex patent disputes related to pharmaceuticals, biologics, combination products, and diagnostics.  Her experience includes traditional patent litigation, Hatch-Waxman litigation related to abbreviated new drug applications and 505(b)(2) applications, proceedings before the International Trade Commission, inter partes reviews, inter partes reexaminations, interferences, and appeals to the U.S. Court of Appeals for the Federal Circuit.  Dr. Cyr also counsels clients on issues at the intersection of patent and FDA law.

Jennifer H. Roscetti, Partner, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP.  Ms. Roscetti counsels clients in all aspects of intellectual property law with a focus in the pharmaceutical and chemical arts.  She has extensive litigation experience representing pharmaceutical patent holders in U.S. district court and appellate proceedings involving the Hatch-Waxman Act governing the approval of pharmaceutical products.  Ms. Roscetti also advises clients on the interplay of U.S. patent law and FDA approval for marketing pharmaceutical products.