Implications of the 21st Century Cures Act on Antibiotic Drug Development
Experts weigh in on what Congress is doing to tackle the threat of antibiotic resistance.
21st Century Cures Act Measures Aimed at Combating Antimicrobial Resistance
- Establishing the limited population antimicrobial drug regulatory pathway
- Encouraging monitoring of antimicrobial resistance and increase stewardship efforts
- Improving availability of contemporary susceptibility break points
The Centers for Disease Control and Prevention estimates that each year at least 2 million Americans develop infections due to drug-resistant pathogens, which result in approximately 23,000 deaths annually.
Antibiotics are a critical medical resource with the potential to cure life-threatening infections. However, the ability of bacteria to evolve rapidly, which is exacerbated by the inappropriate use of antibiotics, often leads to the development of antibiotic resistance.
As resistance develops and spreads globally, healthcare providers are left with a limited ability to effectively treat multidrug-resistant infections.
Therefore, it is important to continually replenish the armamentarium of antibiotics. Unfortunately, the development of new antibiotics has fallen far behind the rising incidence of antibiotic-resistant infections.
Factors that contribute to the relative lack of new agents are complex, with one significant challenge being the lack of an existing approval pathway for antibiotics that are intended to treat serious and rare pathogens. The 21st Century Cures Act (Cures Act), signed into law in December 2016 by President Barack Obama, outlines such a pathway and proposes several additional measures to combat antibiotic resistance.
The Cures Act introduces the Limited Population Antibacterial Drug (LPAD) regulatory pathway, which builds on ideas presented in US Food and Drug Administration (FDA) 2013 draft guidance on developing antibiotics for patients with unmet needs, and provides the FDA flexibility in the approval of antibiotics intended for limited patient populations.
For example, multidrug-resistant pathogens are relatively rare and primarily infect patients who are often too sick to be enrolled in trials, such that large clinical studies may prove infeasible. As a potential solution, LPAD may allow for smaller descriptive clinical datasets supplemented by robust nonclinical data. LPAD directs the FDA to consider the benefit—risk profile in the intended population, the availability of alternative treatment options, and the severity and rarity of the infection that the antibiotic is intended to treat. The LPAD pathway also requires specific language (“This drug is indicated for use in a limited and specific population of patients”
) in any antibiotic label or promotional material for a drug approved via this pathway to indicate that the safety and effectiveness have been demonstrated only with respect to a limited population. Moreover, promotional material will need to be submitted to the FDA at least 30 calendar days prior to distribution to the public. Although many of the details surrounding the FDA’s implementation of LPAD will not be available until a draft guidance is issued within the next 18 months, the overall vision, in the words of Robert Califf, MD, former commissioner of the FDA, is that the pathway “...will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections, where unmet need exists due to lack of available therapies.”
In addition to LPAD, the Cures Act encourages widespread monitoring for antibiotic resistance and increased efforts to reduce inappropriate uses of antibiotics. The legislation establishes a mechanism for healthcare facilities at the Department of Defense, Department of Veterans Affairs, and Indian Health Services to routinely report and evaluate aggregate antibiotic resistance rates within each facility. Healthcare facilities, such as hospitals, nursing homes, and outpatient clinics will also receive educational materials and guidance to support implementation of antibiotic stewardship programs. Importantly, an annual public report will be issued that summarizes national and regional trends in antibiotic resistance, as well as progress on stewardship activities. The first report is expected this year.
Lastly, the Cures Act includes provisions to help improve the availability of information on pathogen susceptibility to a given antibiotic (interpretive susceptibility criteria or “breakpoints”) and keep breakpoints up-to-date. Specifically, any new or updated interpretive susceptibility criteria standards will be evaluated every 6 months. Such an infrastructure may better enable clinicians to select antibiotics that are most likely to lead to positive clinical outcomes for their patients, as well as ensure consistency in methodologies used to establish breakpoints across all antibiotics and antibiotic classes regardless of the date of approval. Furthermore, break-points will be posted to a website, which will be established this year, and a reference or hyperlink to the site will be included in the FDA-approved package insert.
A deeper understanding of the antibiotic resistance landscape and more frequent review of breakpoints will position clinicians, drug developers, scientists, and the FDA to more appropriately address the rising tide of resistance and optimize patient care.
In summary, several key sections of the Cures Act impact antimicrobial development and clinical use. The language in the legislation supports more stringent resistance monitoring and stewardship activities aimed at combating resistance. Most notably, LPAD represents both a congressional acknowledgment of the public health crisis and significant progress in the formation of a clinical-regulatory pathway that enables drug companies to develop antibiotics for patient populations that currently have unmet medical needs.
Dr. Stork is a senior associate in Regulatory Affairs at Achaogen. She completed her PhD in molecular biology at Stanford University.
Dr. Komirenko is a clinical sciences fellow at Achaogen. She completed her PharmD at the University of California, San Francisco. She is an active member of the Society of Infectious Disease Pharmacists (SIDP).
Dr. Mohr is vice president of Medical Affairs at scPharmaceuticals and president and founder of Medical Affairs Strategic Solutions. He is an active member of SIDP.
Dr. Boucher is associate professor of medicine at Tufts University School of Medicine and director of the Infectious Diseases Fellowship Program and Tufts Medical Center. She is an active member of SIDP.
- Centers for Disease Control and Prevention. Antibiotic/antimicrobial resistance. CDC website. www.cdc.gov/drugresistance/. Updated March 8, 2017. Accessed March 10, 2017.
- Projan SJ, Shlaes DM. Antibacterial drug discovery: is it all downhill from here? Clin Microbiol Infect. 2004;10(suppl 4):18-22.
- Shore C. The importance of better drug design for antibiotic innovation. The Pew Charitable Trusts website. www.pewtrusts.org/en/research-and-analysis/analysis/2017/03/08/the-importance-of-better-drug-design-for-antibiotic-innovation. Published March 8, 2017. Accessed March 10, 2017.
- 21st Century Cures Act. H.R. 34, 114th Cong. (2015).
- US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases. FDA website. www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm359184.pdf. Published July 26, 2013. Accessed March 10, 2017.
- Califf RM. 21st Century Cures Act: making progress on shared goals for patients. FDA website. https://blogs.fda.gov/fdavoice/index.php/2016/12/21st-century-cures-act-making-progress-on-shared