FDA finalizes guidance on drug development for diabetic foot infections

The US Food and Drug Administration (FDA) finalized its advice to drugmakers developing treatments for diabetic foot infections without bone and joint involvement, focusing mainly on phase 3 efficacy trial considerations.

The final guidance document, published in the Federal Register on 17 June 2024, replaces the October 2023 draft guidance (RELATED: FDA offers guidance on development of antimicrobials for diabetic foot infections, Regulatory Focus 17 October 2023). After reviewing the public comments on the draft, FDA determined that no revisions were needed to the guidance, according to the Federal Register notice.

The 23-page guidance document does not include information on drug development for acute bacterial skin and skin structure infections, which are addressed in a separate guidance document.

Trial types and populations

FDA encouraged drug sponsors to discuss study designs and investigational approaches with agency officials before the launch of a trial. Both non-inferiority and superiority trial design are considered acceptable, but the trials should be “active-controlled, prospective, randomized, and double-blinded,” according to the guidance.

The trial population for efficacy trials should include patients with diabetic foot infections of various depths and differing extents of involvement. Since surgical incisions and wound debridement can have an impact on treatment outcomes, FDA advised sponsors to plan surgical debridement during the first 48 hours after trial randomization and to avoid topical antibacterial drugs. Minor bedside procedures, such as suture removal or superficial debridement of devitalized tissue, is allowed under the guidance.

FDA noted that “ideally,” patients would not have received prior antibacterial drug therapy for their current infectious episode if they are enrolled in a noninferiority trial, since prior therapy could bias the findings. However, the agency said it would consider enrollment of a small number of patients (no more than 25% of the patient population) who had received less than 24 hours of potentially active antibacterial therapy before enrollment.

FDA also advised sponsors to consider inclusion of some specific populations, including geriatric subjects (without an upper age limit), obese subjects (body mass index of at least 30 kg/m2), and patients with renal insufficiency. Exclusions for comorbidities should also be avoided unless they are necessary for patient safety, FDA wrote.

Concurrent antibacterial therapy and adjunctive measures

Under ideal circumstances, concurrent antibacterial drug therapy would only be part of an add-on trial where it is part of the therapy being studied, FDA advised. However, there are situations where concurrent antibacterial drug therapy can be considered. It can be administered as rescue therapy, though that would generally be considered a failure of the study drug. Additionally, it may be acceptable in the case of concomitant antibacterial drugs for bacteria that are not susceptible to the study drug.

“Sponsors should discuss with the FDA any plans for concomitant antibacterial drug therapy in advance of trial initiation. The ability to maintain study blinding with the use of concomitant antibacterial drug therapy should be addressed,” FDA wrote in the guidance.

Since it can be difficult to determine the contribution of adjunctive measures, such as off-loading and debridement, to the overall treatment, FDA suggested that sponsors prespecify and document any adjunctive measures that are included in the protocol.

The final guidance also included suggestions related to endpoints, the timing of trial assessments, clinical microbiology considerations, and statistical and labeling considerations among others.

Final Guidance

FDA finalizes guidance on drug development for diabetic foot infections

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