Antibiotics are among the most important medications in the modern healthcare toolbox and are essential safeguards against global pandemics. However, antibiotics can be challenging to develop, and more and more we are finding that the drugs we have come to rely upon to keep us healthy are not working as well as they once did, or sometimes, not at all.
The Rise of Antibiotic Resistance
The ability of bacteria to reduce or completely abolish antibiotic efficacy is called resistance. Resistance can exist toward a single antibiotic, such as penicillin, or toward a number of antibiotics, which is referred to as multidrug resistance or MDR (e.g., to the beta-lactam family of antibiotics).
Resistance develops due to selective pressure on bacterial populations, which can occur when antibiotic concentrations and/or treatment durations are insufficient to clear the infection completely but instead drive resistance evolution. Resistance has been a concern in antibiotic development since penicillin was discovered (reviewed in Lobanovska 2017). Alarmingly, the rate of bacterial resistance is rising rapidly and is considered one of the greatest modern health threats.
The Centers for Disease Control (CDC) estimates that 2 million people in the US annually are infected with resistant bacterial infections, leading to 23,000 otherwise avoidable deaths and over $20 billion in excess healthcare costs. There is a critical need for new antibiotics to fight resistant microbes, such as methicillin resistant Staphylococcus aureus (MRSA), Clostridium difficile, which causes life-threatening diarrhea, and carbapenem-resistant Enterobacteriaceae (CRE), which causes death in >50% of systemic infections.
Ways that US Agencies are Targeting Antibiotic Resistance
US federal and regulatory agencies take a number of approaches to tackle antibiotic resistance. One strategy is encouraging healthcare professionals to accurately diagnose diseases and prescribe targeted antibiotics to reduce over-prescription of broad-spectrum antibiotics and promote antibiotic stewardship. Another strategy is to launch public awareness campaigns (e.g., US Antibiotic Awareness Week) to encourage patients to complete all antibiotic regimens as prescribed and to only use antibiotics for bacterial infections that are diagnosed by a physician.
Arguably one of the most important ways to address resistance is to aggressively develop novel antibiotics and uncover new mechanisms of action to kill both Gram positive and negative bacteria before resistance becomes widespread. However, despite the critical need for new antibiotics and the rising rates of resistance, very few antibiotics are under active development with only a handful of large pharmaceutical companies investing in new research and development. In 2017, WHO released a report underscoring the lack of innovative treatments that could add value to current antibiotic intervention strategies.
Recognizing the critical need to stop the rise of antibiotic resistance, US government and health authorities, such as the Food and Drug Administration (FDA), the CDC, and the National Institutes of Health (NIH), are providing financial support and regulatory guidance for this important research.
Regulatory Support for Novel Antibiotic Research
FDA Guidance on Antimicrobial Drug Development
To provide the best chances of successful antibiotic development, the FDA updated their guidance on Microbiology Data for Systemic Antibacterial Drugs (released Jan 2018). The current revision provides insight in several key areas of antimicrobial development, which are informed by the evolving landscape and research in the field:
Activity Spectrum: The activity spectrum is defined as the number of bacteria that are susceptible to a tested drug. The FDA recommends testing the activity spectrum early in preclinical development with a large number of bacteria isolated from clinical cases within the last three years (“clinical isolates”). Current focus is on the “ESKAPE” pathogens: Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter as these are the most common causes of life-threatening infections. Activity should be tested against at least 100 isolates, depending on the organism. Such testing will allow definition of the clinical application.
Mechanism of Action & Resistance Studies: A known mechanism of action (MOA) is not always essential in small molecule drug development; however, studies that demonstrate MOA and evaluate resistance mechanisms will need to be completed to demonstrate clinical usefulness. This information should be included in regulatory documents, ideally in initial investigational new drug (IND) applications but definitely prior to beginning Phase 2 clinical trials.
Pre-clinical Animal Models: Animal models should mimic human disease as closely as possible and should include susceptible and resistant bacterial infections. Consider evaluating biofilm formation, if applicable (such as in wound therapy). The best practice is to measure survival, bacterial burden in blood and tissue, and antibacterial activity in relevant tissues. Animal models may also allow development of early pharmacokinetic and pharmacodynamic models to aid in dose selection and regimen.
Regulatory Pathways to Support Antibiotic New Molecular Entities
To provide additional regulatory and financial incentives for pharmaceutical companies to develop novel antibiotics and antifungals, the FDA Safety and Innovation Act put into effect by Congress established the Qualified Infectious Disease Product (QIDP) regulatory designation pathway. QIDP designation is given to products that treat life-threatening infections, and drug products that pursue approval with the QIDP pathway receive the following incentives:
- Fast track designation: provides actions that expedite development
- Priority review designation: allows for review of the New Drug Application (NDA) in 6 months, compared to 10 months for standard review.
- 5-years of additional exclusivity: added to any exclusivity upon approval.
Requests for QIDP designations should be submitted to the FDA as an IND or pre-IND communication. Reach out to Nuventra’s regulatory consultants to discuss submission of a QIDP request.
Financial Support for Antibiotic Development
In addition to regulatory guidance and incentives, US agencies such as the CDC, Department of Defense (DoD), and NIH provide funding for early stage research into antibiotics with novel MOAs. Antibiotic development is a priority for the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which funds research through grants and contracts.
In addition, the CARB-X program (a global partnership between US and international government agencies and private foundations) has provided substantial research funding for companies with broad antibiotic pipelines with an ongoing mission to support antibacterial development.
The DoD also commits funding to antibiotic research through their CDMRP funding programs and Broad Agency Announcements (BAAs; also utilized by other government agencies like CDC), with an eye toward infectious pathogens that can be potentially weaponized.
The need for novel antibiotics is substantial as rates of bacterial resistance rise and the current toolbox of effective antibiotics dwindles. Government agencies are supporting the development of novel antimicrobials with new regulatory pathways, improved guidance, and financial assistance. Leveraging these resources can improve the chances of success for clinical development and eventual approval.
Related FDA Guidance Documents
- Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases (FDA Guidance)
- Limited Population Pathway for Antibacterial and Antifungal Drugs (FDA Guidance)
- Microbiology Data for Systemic Antibacterial Drugs (FDA Guidance)
- Qualified Infectious Disease Product Designation Questions and Answers (FDA Guidance)