Regulatory Radar: 21st Century Cures Act, Limited Population Pathway

FDA’s role in promoting development of new antibiotic therapeutics – More to GAIN (Generating Antibiotic Incentives Now)

In February of 2017, the World Health Organization (WHO) published a list of the most important resistant bacteria at a global level which urgently need new treatments. In total, 12 pathogens were identified and assigned into one of three priority categories by need: Critical, High and Medium. The table below shows the resulting classification of these pathogens.

WHO Priority Pathogens by Need for New Treatment

CriticalAcinetobacter baumanniiCarbapenem-resistant
Pseudomonas aeruginosaCarbapenem-resistant
Third generation cephalosporin-resistant
HighEnterococcus faeciumVancomycin-resistant
Staphylococcus aureusMethicillin-resistant
Vancomycin intermediate and resistant
Helicobacter pyloriClarithromycin-resistant
Salmonella spp.Fluoroquinolone-resistant
Neisseria gonorrhoeaeFluoroquinolone-resistant
Third generation cephalosporin-resistant
MediumStreptococcus pneumoniaePenicillin-non-susceptible
Haemophilus influenzaeAmpicillin-resistant
Shigella spp.Fluoroquinolone-resistant

At present, only a limited number of novel antibiotics are in development; however, the number of patients failing to respond to existing antibiotic therapies is on the rise, with estimates of more than 2 million people in the U.S. infected with resistant bacteria annually, directly resulting in at least 23,000 deaths per year1.

The need for new antibiotic therapeutics has been recognized for some time and has prompted legislative action. For example, the 21st Century Cures Act includes incentives to promote the development of new antibiotic therapeutics. While the Cures Act just took effect in December of 2016, it was preceded by the Generating Antibiotic Incentives Now (GAIN) Act, signed into law in 2012. Prompted at the time by a slowdown in the development of antibiotics and a rise in antibiotic resistant pathogens, the GAIN Act directed FDA to grant special incentives to sponsors of antibacterial products intended to treat serious or unmet needs. Such incentives included eligibility for designation as a fast-track product and an additional five years to be added to certain exclusivity periods. Under the GAIN Act, these incentives are limited to products that treat specific pathogens designated by the FDA list of Qualifying Infectious Disease Products (QIDP).

QIDP includes the following 21 pathogens: Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobacter species, Candida species, Clostridium difficile, Coccidioides species, Cryptococcus species, Enterobacteriaceae (e.g., Klebsiella pneumoniae), Enterococcus species, Helicobacter pylori, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N. meningitidis, Non-tuberculous mycobacteria species, Pseudomonas species, Staphylococcus aureus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae.

Since GAIN took effect, FDA has granted 101 out of 109 QIPD requests and, as of December 2015, six drugs with the QIDP designation have been approved for marketing in the United States2:

QIDP Drug Approvals July 2012 – December 2015

Drug NameApproval DateIndicationPriority ReviewFast Track DesignationQPID Exclusivityϯ
DALVANCE® Allergan Inc.May 2016To treat acute bacterial skin and skin structure infectionsYesYesYes
SIVEXTRO® Merck & Co., Inc.June 2014To treat acute bacterial skin and skin structure infectionsYesNo*Yes
ORBACTIV® The Medicines CompanyAugust 2014To treat acute bacterial skin and skin structure infectionsYesNo*Yes
ZERBAXA® Merck & Co., Inc.December 2014To treat complicated intra-abdominal infections, in combination with metronidazole, and complicated urinary tract infections, including pyelonephritisYesYesYes
AVYCAZ® Allergan, Inc.February 2015To treat complicated intra-abdominal infections in combination with metronidazole, and complicated urinary tract infections in patients who have limited or no alternative treatment options, including pyelonephritisYesYesPending (as of Oct 2016)
CRESEMBA® Astellas Pharma U.S., Inc.March 2015To treat adults with two types of invasive fungal infections (aspergillosis and invasive mucormycosis)YesYesYes

* Sponsor did not request.
ϯ DALVANCE® SIVEXTRO®, ORBACTIV® and ZERBAXA® received NCE and QIDP exclusivity. CRESEMBA® received NCE, orphan drug and QIDP exclusivity.

The Cures Act provides FDA with the flexibility to approve antimicrobial drugs based on a limited population if the drug treats a life-threatening infection (Subtitle E − Antimicrobial Innovation and Stewardship, Sec 3042). The concept of a limited population approval path for antibiotics was first introduced in 2012, presented in a briefing to Congress by Dr. Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research.

Limited population approval will aide development given that the number of subjects with rare infections, including those caused by resistant bacteria, is often small which hampers the conduct of clinical trials. Under this pathway, FDA can approve a new antibiotic based on a small study, for use only in patients with confirmed presence of one specific organism. The path resembles that of the Orphan Drug path, under which the FDA grants approval for drugs to treat rare diseases (those that affect fewer than 200,000 people). However, under the limited population pathway there are labeling restrictions requiring that the labeling and advertising of an antimicrobial drug approved under this pathway include “Limited Population” along with a proprietary name of the drug.

As required under the Cures Act, FDA has to issue a draft guidance describing criteria, processes and other general considerations for demonstrating the safety and effectiveness of limited population antibacterial and antifungal drugs no later than 18 months after December 13, 2016.

Sections 3041 and 3044 of the Cures Act also include measures to help preserve the effectiveness of existing antibiotics. It requires that the Department of Health and Human Services monitor use of all approved antibiotics and report annually on antibiotic resistance trends at both regional and national levels. Also, it includes measures that will allow FDA to update breakpoint data (data used by health care providers for clinical use) more readily to avoid unnecessary use of antibiotics. Specifically, the Cures Act requires the creation of a website, by December of 2017, which contains a list of any appropriate new or updated susceptibility test, interpretive criteria standards and interpretive criteria. The labeling of an antimicrobial drug marketed before the establishment of this Interpretive Criteria Website will have to be updated no later than one year after availability of this website with a reference to the Interpretive Criteria Website to replace the prior susceptibility test and interpretive criteria. The labeling of antimicrobial drugs approved on or after the date of the establishment of the website will require a reference to this website instead of susceptibility test interpretive criteria.

It is hopeful that the GAIN and 21st Century Cures Act together will incentivize sponsors to invest in new antimicrobial treatments and pave the way for in-time approval, while maintaining an acceptable risk-benefit balance to address the looming public health crisis.

For available general FDA guidance on developmental paths of antibiotic therapies, refer to FDA’s Draft Guidance from July 2013, Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases.3

Do you have any questions? Please reach out to NSF’s experts Marinka Tellier or Andy Papas. Visit our website to learn more about NSF's pharma biotech services.

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1CDC Antibiotic / Antimicrobial Resistance
2Government Oversight and Accountability Report A-17-189, January 2017
3FDA Draft Guidance for Industry

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