On August 1, 2017, the U.S. Food and Drug Administration released its draft guidance titled Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases, detailing proposals for streamlined development of certain antibacterial drugs. Acknowledging the difficulties inherent in the development of antibacterial therapies, and especially therapies for the treatment of rare or acute infections, the FDA notes that “it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness.” The bulk of the guidance discusses ways in which more flexible approaches to clinical trial design may be utilized in order to more rapidly advance treatments for severe or life-threatening infections, especially those involving drug-resistant bacteria. The guidance is not, however, targeted at the development of drugs with slight improvements in efficacy or those with a functional spectrum not appreciably different from existing drugs.
In order to be eligible for consideration for a streamlined development program under this guidance, a drug candidate should target a specific infection, and especially a serious infection for which there are few or no available treatments. The guidance notes that this includes, generally, drugs presenting a novel mechanism of action, those using added inhibitors to overcome resistance, alterations in the structure of an existing drug to overcome resistance, or other characteristics that lead to markedly enhanced effectiveness against severe or life-threatening infection. The guidance specifically notes that drugs with a limited spectrum, including drugs showing efficacy against only a single species, are considered to be candidates for streamlined development.
“Streamlined Development” generally involves fewer, smaller, or shorter clinical trials, focused on patients with serious infections and few or no treatment options. Sponsors will be required to provide the ordinary suite of preclinical data. However, under a streamlined development program, efficacy may be demonstrated more readily by applying less stringent requirements than might normally be applied. For example, the FDA suggests using a larger noninferiority margin than might otherwise be considered (in noninferiority trials against existing treatments) or a less stringent statistical finding of superiority (in superiority trials against existing treatments). Notably, the guidance contemplates trials using limited numbers of patients suffering from specific infections, and especially trials targeting only a single species of bacteria.
While the risk/benefit analysis favors rapid development of drugs to treat severe or life-threatening infections for which there are limited existing treatment options, the guidance notes that FDA does not intend to relax safety standards for drugs subject to streamlined development. However, given the small numbers of patients available for clinical trials, FDA will necessarily be more flexible in the number and types of patients to be included in premarketing safety databases. The guidance also contemplates heavier reliance on PK/PD assessments to determine possible safety issues, as well as labeling requirements detailing the limited safety data available. Postmarketing monitoring, as well as the potential for postmarketing clinical studies, provide avenues for additional safety evaluation of drugs approved under streamlined development. The guidance notes that the FDA may require a risk evaluation and mitigation strategy if necessary to ensure that the benefits of the drug continue to outweigh any risks that are uncovered.
The FDA notes that it does not intend to create a novel approval path for this group of antibacterial therapies, but rather that the guidance, “reflects the FDA’s commitment to expediting the availability of drugs for serious diseases for patients as soon as it can be concluded that the drug’s benefits exceed its risks.” The present guidance seems to affirm the FDA’s commitment to fostering innovation in the antibacterial space in order to meet a growing need for drugs targeting difficult-to-treat infections. Flexibility on the part of the FDA in clinical trial design, and the prospect of more rapid approval may make the task of developing treatments for rare, severe, or acute infections more attractive. Researchers in the antimicrobial space should consider the streamlined development described in this guidance as a possible way to expedite their path to the clinic.