FDA offers guidance on development of antimicrobials for diabetic foot infections

The US Food and Drug Administration (FDA) released new draft guidance on developing antimicrobial drugs specifically intended to treat diabetic foot infection, a focused area that is not included in the agency’s existing development guidance for drugs targeting skin infections.

Diabetic foot infections (DFIs) are often complicated problems that display different clinical characteristics than other skin infections, require specialized management, and can lead to serious sequelae, including amputation, according to the draft guidance released on 17 October 2023.

“The guidance for industry ‘Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment’ does not address DFI due to the differences between DFI and other [acute bacterial skin and skin structure infections]… therefore, a separate guidance was deemed necessary,” FDA wrote.

DFIs can involve a single pathogen, or several, including methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative organisms, some of which may be antibiotic resistant. Patients with impaired circulation may develop necrotic wounds infected by anaerobic pathogens. Poor circulation also impedes wound healing and increases the risk for even small, superficial wounds to progress to deep ulcers before patients seek medical attention. By that time, the patient can be on the verge of serious complications, such as bone infections, that can eventually result in amputation.

But treatment requires far more than dispensing an antimicrobial. These patients may need wound debridement, ischemic reperfusion, adjustments of their glycemic control regimen, and specialized dressings to stop the infective process and begin healing, according to the guidance.

Drug development

In the early phase of drug development, sponsors need to provide proof that the candidate demonstrates adequate penetration to the outer skin layer. The FDA wants to be onboard for this evaluation, the draft guidance notes, recommending that sponsors get regulatory input on how these penetration studies should be conducted.

Clinical trials should enroll patients with either Type 1 or 2 diabetes and a moderate-to-severe DFI with the initial site below the ankle, with or without osteomyelitis. The cohort should also include patients with impaired circulation and neuropathy. Trials should exclude patients with mild infections, the guidance recommends, because they could “potentially drive results toward noninferiority as these infections are associated with a higher incidence of spontaneous resolution.”

Both noninferiority and superiority trials are acceptable to support an application and two successful studies will generally be required, but a single trial is acceptable in some cases.

“A single adequate and well-controlled trial supported by other independent confirmatory evidence, such as a trial in another related infectious disease indication [e.g., acute bacterial skin and skin structure infections], can potentially provide evidence of effectiveness in support of an indication for the treatment of DFI,” FDA wrote.

Safety should be assessed in at least 500 subjects. If the candidate drug is already approved for other indications in the same or a greater dose than proposed, the safety data from those supporting trials can provide part of the required DFI safety data, according to the draft guidance.

Endpoints

The primary endpoint should be clinical resolution of all signs and symptoms of infection with no need for additional therapy. Secondary endpoints can include a composite of death, unplanned amputation and infectious complications at 21 days post-randomization. Other secondary endpoints may include clinical response at the end of therapy, all-cause mortality at a preplanned timepoint, rates of rescue therapy, unplanned surgical debridement or amputation or death. Microbiological cure may also be included.

“For new drugs that have an important clinical benefit compared with existing therapies, depending on the benefit demonstrated, a smaller preapproval safety database may be appropriate,” FDA wrote. “Sponsors should discuss the appropriate size of the preapproval safety database with the FDA during clinical development.”

During clinical trials, patients should not use any other concomitant antibacterials, including topical or oral medications, although minor prespecified procedures needed for wound care can be performed. These include suture removal, needle aspiration, superficial debridement of devitalized tissue or routine wound care.

The minimum duration of treatment in the trials should generally be 7 to 14 days. For subjects who require a prolonged course of antibacterial drug therapy, the sponsor should define criteria for prolonging study drug treatment and discuss with the FDA before proceeding, according to the guidance.

For drugs that have both intravenous (IV) and oral formulations, a switching study can be performed and be part of the primary efficacy assessment. “If an IV-to-oral switch is incorporated into the protocol, the sponsor should specify the objective criteria necessary to permit the switch and discuss the criteria with the FDA before study initiation,” according to the guidance.

The FDA is accepting comments on the draft guidance through 8 December 2023. Comments can be submitted via regulations.gov with the docket number FDA-2023-D-4067.

FDA draft guidance

FDA offers guidance on development of antimicrobials for diabetic foot infections

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