According to the Centers for Disease Control and Prevention (CDC), more than 2.8 million people a year are sickened by antibiotic-resistant infections, and more than 35,000 people die as a result [1]. Antibiotic resistance is on the rise as bacteria continue to grow impervious to currently available antibiotics. Antibiotic-resistant microbes can spread quickly across communities, the food supply, and healthcare facilities and can share their ability to become resistant with other microbes that have not been exposed to antibiotics. When microbes are resistant to antibiotics, not only does this limit the ability to fight routine infections but it also erodes the ability to provide treatments that may immunocompromise patients, such as cancer treatments or organ transplants, and to safely perform more routine procedures that require a certain level of sterility, such as joint replacements.

It is critical for drugmakers to develop treatments for antibiotic-resistant infections. However, it is difficult to identify patients with highly resistant bacterial infections and to enroll them in sufficient numbers for traditional, large-scale clinical trials [2]. Historically, there was also little incentive to develop new antibiotics because these drugs tend to generate smaller revenue compared with “blockbuster” drugs such as those for high blood pressure treatment, which are taken by many more people daily [3].

Generating Antibiotic Incentives Now (GAIN) and the Qualified Infectious Disease Product (QIDP) designation and the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD), described below, were designed by the FDA to streamline development and encourage investment into targeting infections that lack effective therapies [4].

GAIN and the QIDP Designation

In 2012, GAIN was signed into law as part of the Food and Drug Administration Safety and Innovation Act [3]. GAIN established the QIDP designation, which extends the exclusivity period during which certain antibiotics—those that treat serious or life-threatening infections—can be sold without generic competition by 5 years. This 5-year market protection is in addition to any existing exclusivity (e.g., 5 or 3 years under Hatch-Waxman, 7 years under orphan drug designation, and 6 months for pediatric exclusivity). Important highlights of the FDA Draft Guidance on QIDP designation [5] include:

• A sponsor may request a QIDP designation any time prior to submission of a marketing application.
• FDA will consider a drug to be “intended to treat a serious or life-threatening infection” if it is intended to diagnose, prevent, or treat such an infection.
• Biologic products and devices are not eligible for QIDP designation. However, the regenerative medicine advanced therapy (RMAT) designation is intended to incentivize the development of biologic products for the treatment of serious conditions [6].
• Drugs that are intended to treat a serious or life-threatening bacterial or fungal infection caused by a pathogen that is not included on the list of qualifying pathogens may be eligible for designation as a QIDP.

Between 2012 and 2017, FDA designated 147 QIDPs; the number of QIDP designation requests has grown steadily each year [7]. The 5 most common indications that have received QIDP designation include acute bacterial skin and skin structure infection, complicated urinary tract infection, community-acquired bacterial pneumonia, hospital and/or ventilator-associated bacterial pneumonia, and complicated intra-abdominal infections. Between 2012 and 2017, 12 drugs with QIDP designation were approved by the FDA, including Solosec (secnidazole) granules for treatment of bacterial vaginosis in adult women and Vabomere (meropenem and vaborbactam) injection for treatment of complicated urinary tract infections.

The FDA grants fast track and priority status to drugs that fall under GAIN, which undergo an expedited regulatory approval process. As part of GAIN, FDA was required to issue a new guidance on the development of pathogen-focused antibiotics and to compile a list of “qualifying pathogens” that have the potential to pose a serious threat to public health, which is updated every 5 years [8].

LPAD

Although GAIN and QIDP provided a financial incentive and more clarity to spur antibiotic drug development, there was still a need to further incentivize antibiotic drug development for serious conditions in which only a small number of patients—a limited population—are likely to be diagnosed [2].

In 2016, the FDA responded to this need by adding the LPAD program to the Federal Food, Drug, and Cosmetic (FD&C) Act through section 3042 of the 21st Century Cures Act [9]. The goal of this program was to aid approval of antibacterial and antifungal drugs to treat serious and life-threatening infections in a limited population of patients with unmet needs by streamlining approaches to clinical development, which could involve smaller, shorter, or fewer clinical trials. Given that clinical programs might have fewer subjects, trials, or shorter study duration as compared with other indications, drugs approved under the LPAD program are required to have prominent labeling stating “Limited Population” on all labeling and advertising so that healthcare providers can identify the patients for whom the FDA determined the benefits of the drug outweigh the risks. The FDA has the authority to pre-review all promotional materials for these products to ensure that messaging is clear that the drug’s approval was based on a benefit-risk assessment on a limited population. This is because the benefit-risk calculation for the sickest patients who lack other treatment options and who might otherwise die from infection is different from the risk of broader populations with more easily treatable infections [2].

Important highlights of the FDA Draft Guidance on the LPAD program [10] include:

• The LPAD program requires FDA to take into account in its determination of safety and effectiveness the severity, rarity, or prevalence of the infection a drug is intended to treat and the lack of alternative treatment in the limited population a drug is intended for.
• FDA anticipates that early and frequent communications between the Agency and sponsors interested in pursuing approval under the LPAD program for their products can help reduce overall product development timelines. Sponsors interested in the LPAD program should clearly state their intentions during discussions with FDA.
• FDA will make the determination of whether a drug meets the criteria for the LPAD program at the time of the drug’s approval.

In the past 4 years since the LPAD was added to the FD&C, two drugs have been approved under the program [9]:

• Arikayce (amikacin liposome inhalation suspension), was approved for the treatment of lung disease caused by Mycobacterium avium complex, in patients with the disease who do not respond to conventional treatment (refractory disease) based on a single randomized controlled trial of 89 subjects using sputum cultures as a surrogate endpoint.
• Pretomanid Tablets in combination with bedaquiline and linezolid was approved for the treatment of a specific type of highly treatment-resistant tuberculosis of the lungs based on a study of 107 subjects versus a historical control.

Rho has provided regulatory strategy and submission support for products that have utilized these programs and other programs meant to spur development in infectious disease such as the tropical disease priority review voucher program [11]. Our regulatory experts can help guide sponsors through GAIN and the QIDP, LPAD, and other regulatory programs so more drugs that treat life-threatening infections can be developed and save lives.

References:
1. CDC. Antibiotic Resistance Threats in the United States, 2019: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
2. Pew. LPAD: A Regulatory Pathway to Develop Antibiotics and Fight Drug-Resistant Infections, 2015: https://www.pewtrusts.org/en/research-and-analysis/articles/2015/06/lpad-a-regulatory-pathway-to-develop-antibiotics-and-fight-drug-resistant-infections
3. Pew. GAIN: How a New Law is Stimulating the Development of Antibiotics, 2013: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics
4. FDA News Release. FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation, 2018: https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-serious-lung-disease-using-novel-pathway-spur-innovation
5. FDA. Qualified Infectious Disease Product Designation Questions and Answers Guidance for Industry, 2018: https://www.fda.gov/media/111091/download
6. FDA. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance for Industry, 2019: https://www.fda.gov/media/120267/download
7. Department of Health and Human Services (2018) Report to Congress on Generating Antibiotic Incentives Now (GAIN): https://www.fda.gov/media/110982/download
8. FDA. Establishing a list of qualifying pathogens under the Food and Drug Administration Safety and Innovation Act. Final rule. Federal Register, 2014: https://www.govinfo.gov/content/pkg/FR-2014-06-05/pdf/2014-13023.pdf
9. FDA. Limited Population Pathway for Antibacterial and Antifungal Drugs – the LPAD Pathway, 2019: https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway
10. FDA. Limited Population Pathway for Antibacterial and Antifungal Drugs Guidance for Industry, 2018: https://www.fda.gov/media/113729/download
11. FDA. Tropical Disease Priority Review Voucher Program, 2018: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program

Yael Symes, PhD, Integrated Product Development Associate, has over 10 years of experience in writing and editing scientific documents, including 9 publications in peer-reviewed journals. She has participated in the authoring and preparation of clinical protocols, modules of NDAs and INDs, clinical study reports, and other regulatory documents in a variety of therapeutic areas. Her therapeutic area experience includes oncology, infectious diseases, respiratory diseases, ophthalmology, and pain. Dr. Symes received a fellowship for her graduate training in cancer prevention and control from the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center and received her PhD in Health Behavior at the University of North Carolina at Chapel Hill Gillings School of Global Public Health. Her PhD was focused on examining psychosocial predictors of smoking cessation (e.g., health-related quality of life) and e-cigarette use in cancer survivors. Dr. Symes is a current member of the Regulatory Affairs Professionals Society (RAPS) and the North Carolina Regulatory Affairs Forum (NCRAF).

Kathleen Candando, PhD, Research Scientist, authors regulatory submission documents and contributes to regulatory strategy and product development services. Dr. Candando has more than 10 years of experience in writing, reviewing, and editing scientific documents and frequently leads authorship of regulatory submissions including US IND and NDA modules, clinical study reports, clinical study protocols, and orphan drug designation applications. Dr. Candando’s therapeutic experience is broad and includes multiple areas of allergy and immunology, infectious diseases, oncology, and neurology.

Meagan Spychala, DrPH, Assistant Vice President of Patient Engagement and Program Strategy, has over 15 years of clinical development experience, providing scientific and technical oversight on trials of varying phase, sizes, therapeutic areas/indications, and complexities. Meagan holds a DrPH and MS in biostatistics from the University of North Carolina at Chapel Hill and a BS in mathematics from Washington and Lee University. She has extensive knowledge of all facets of clinical development inclusive of study design, protocol writing, risk management, trial implementation, and regulatory submissions to support marketing applications. Dr. Spychala is able to provide a big-picture view of the clinical development landscape having provided oversight to individual trials and multi-trial programs. She recognizes the uniqueness of each clinical trial, and understands the importance of each patient in the development program. Dr. Spychala engages with sponsors as well as the patient advocacy community to develop the relationships needed to support patient and family-centric clinical research. 

Joseph Watson, PhD, RAC, Research Scientist, has experience in both regulatory submissions and clinical document preparation, with over 15 years of experience in scientific writing and editing clinical and nonclinical documents, including numerous publications in peer-reviewed journals. Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates. His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology.

Kevin Barber, PhD, RAC, PMP, Vice President of Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has led the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products in therapeutic areas including dermatology, nephrology, urology, women’s health, CNS/neurology, cardiovascular diseases, virology, oncology, immunology, infectious diseases, blood products, and gene therapy. Dr. Barber has significant experience preparing and filing regulatory submissions, including more than 45 US INDs and more than 40 marketing applications in the US, Canada, Europe, Latin America, Australia, and New Zealand. He also has experience with medical device and in vitro diagnostic development programs and regulatory submissions including pre-IDE meetings, IDEs, 510(k)s, and PMAs.