FDA Supports Streamlined Trials for New Antimicrobials

The critical need for new medicines to combat infectious diseases is prompting FDA to join with other federal

health agencies and the biomedical research community to advance the science, regulatory policies, and reimbursement strategies to promote innovation in this area. A main strategy is to design research programs for antimicrobials intended for limited use by patient populations exposed to lethal pathogens. The development and approval of new antibiotics traditionally involves large confirmatory clinical trials that are long and costly, but appropriate for therapies that are widely used and can generate a sufficient return on investment to sponsors. To remain effective against lethal pathogens, however, new antimicrobials need to be prescribed very sparingly, cutting revenues in the process. Hence, a different research model is needed to limit research costs while overcoming obstacles in identifying and enrolling sufficient numbers of patients with target pathogens.

These challenges have curbed industry investment in developing new antimicrobials. The Pew Charitable Trusts reports that as of June 2018 only 42 new antibiotics were in clinical development to treat serious bacterial infections (see bit.ly/2O1fiFF). Just one in five, moreover, are likely to succeed, and only a handful have potential to address serious resistance problems, such as gram-negative bacteria, which cause particularly hard-to-treat infections.

To address this crisis, FDA Commissioner Scott Gottlieb recently unveiled a 2019 Strategic Approach for Combatting AMR (antimicrobial resistance) at a meeting Sept. 14 organized by Pew (see bit.ly/2xCQTfz). The plan includes policies and programs to encourage development of new drugs, diagnostic tests, and vaccines; to promote responsible stewardship of antimicrobials in animals and humans; to improve surveillance of antimicrobial use and resistance; and to advance research for developing new tools, standards, and policies in this area. Gottlieb noted that FDA expects that preclinical and clinical programs for certain new infectious disease therapies will follow streamlined approaches to clinical development, including smaller, shorter, or fewer clinical trials.

FDA previously outlined such an approach in issuing draft guidance in June to help manufacturers utilize the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) in developing new therapies (see: bit.ly/2OF3IgF). The LPAD program was authorized by the 21st Century Cures Act, but has been challenging for both sponsors and FDA to implement. The guidance describes how sponsors may seek approval of qualifying products that treat small numbers of seriously ill patients based on data from streamlined research programs.

New reimbursement strategies also are needed to support the development of products that would be prescribed and used on a highly limited basis. To maintain a robust pipeline for antibiotics, Gottlieb recognized at the Pew meeting the need to “change the perception that the costs and risks of antibiotic innovation are too high relative to their expected gains.”

FDA is exploring a subscription-based model that charges hospitals a flat rate or licensing fee for access to a certain number of doses each year of a new antimicrobial. Other innovative reimbursement strategies could involve milestone or add-on payments for new technology. By creating a predictable revenue stream, this kind of “pull incentive,” Gottlieb explained, would “create natural markets for drugs targeted to rare but dangerous, multi-drug resistant pathogens that can threaten human health. 

To advance regulatory science in this area, the Office of Antimicrobial Products in the Center for Drug Evaluation and Research (CDER) has requested input from stakeholders on developing an annual list of science initiatives likely to spur development of new antimicrobial products.

In addition, the Center for Biologics Evaluation and Research (CBER) is supporting development of non-traditional alternatives to small molecule drugs, including bacteriophages, live biotherapeutics, and fecal microbiota for transplant. CBER also is exploring vaccines to prevent infections caused by microbes resistant to current treatment, which ideally would reduce the risk of infections that require treatment with new antimicrobials. Equally important at FDA is support for developing new in vitro diagnostics able to detect disease rapidly, identify appropriate treatment, and track resistance.