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Implications of the 21st Century Cures Act on Antibiotic Drug Development

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.1 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.2 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.3 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.4
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Drug (LPAD) regulatory pathway, which builds on ideas presented in US Food and Drug Administration (FDA) 2013 draft guidance on developing antibiotics for patients with unmet needs, and provides the FDA flexibility in the approval of antibiotics intended for limited patient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.5 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”4) 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.”6

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