FDA proposes guidance for developing drugs for disseminated coccidioidomycosis

The US Food and Drug Administration (FDA) has published a draft guidance on developing drugs intended to treat disseminated coccidioidomycosis from Coccidioides immitis and C. posadasii. It focuses on clinical trial participant selection, trial design, and recommended endpoints for patients treated for disseminated coccidioidomycosis. It also builds on topics discussed during an August 2020 public workshop.

“To support approval, FDA expects that drugs will provide benefit on a clinically meaningful endpoint,” FDA wrote in the draft guidance.

For early clinical studies, FDA recommended sponsors use tolerability, pharmacokinetics, and preliminary clinical efficacy in proof-of-concept studies to lay the groundwork for phase 3 trials. The agency further noted that trials evaluating combination antifungal treatments should contain “nonclinical assessments of potential interactions between the drugs,” such as antagonism and synergy.

According to FDA, sponsors should also consider and discuss the treatment timing and duration for antifungal therapy, both as a single treatment and in addition to the standard of care for disseminated coccidioidomycosis, and the potential need for a dose-ranging study design to identify optimal doses for a phase 3 trial with regulators.

FDA recommended that sponsors conduct two randomized, double-blind, controlled phase 3 trials, or a single trial that shows “robust evidence of efficacy with confirmatory evidence” of an antifungal therapy in treating disseminated coccidioidomycosis. It also said a superiority trial design can be used for phase 3 trials, and sponsors should consider factors such as comparing the investigational therapy to standard of care, or together as an add-on to standard of care compared to standard of care plus placebo.

Trial population considerations

The guidance states that early clinical studies should attempt to enroll patients “at lower risk of mortality, or limited sites of dissemination” based on the degree of uncertainty of clinical efficacy with a new investigational therapy, or patients with refractory disease or who will not tolerate standard of care therapy.

For phase 3 trials, FDA said sponsors should enroll patients with a confirmed diagnosis of disseminated coccidioidomycosis using “typical symptoms and radiographic abnormalities” as well as enzyme immunoassay and immunodiffusion or complement fixation testing.

“The diagnosis of disseminated coccidioidomycosis should be confirmed based on the presence of C. immitis or C. posadasii in culture of bone, joint or tissue lesions, sputum, bronchial wash, or lung tissue or pleural fluid, or identification of endosporulating spherules in histological preparations,” the agency added.

FDA acknowledged that trials may have different endpoints for patients with different types of disseminated coccidioidomycosis, such as those with nonmeningeal coccidioidomycosis or coccidioidal meningitis. In such cases, the agency said sponsors may choose to limit enrollment based on the types of disseminated coccidioidomycosis, patient comorbidities, and whether patients have refractory disease.

“Given the differences between the disease forms of disseminated coccidioidomycosis, the labeled indication will reflect the patient population studied and may not cover all forms of disseminated coccidioidomycosis,” the agency added.

Endpoint considerations

In terms of endpoints, FDA said that primary endpoints should assess clinical outcomes, while secondary endpoints can examine factors such as serological markers and radiological data.

“As disseminated coccidioidomycosis is a heterogeneous disease, endpoints should represent the outcomes that are most meaningful to the target population, can be improved with treatment, and are expected to be sensitive to detect a treatment effect,” the agency clarified.

According to FDA, clinical outcomes for primary efficacy endpoints can include patient-reported outcome measures of disease symptoms, clinical-reported outcomes, and performance outcomes. While the agency did not recommend a specific patient-reported outcome instrument for trials, it referred sponsors to its guidance series on patient-focused drug development for additional information on clinical outcome development and modification.

“Given the heterogeneous nature of disseminated coccidioidomycosis, determination of which subset of symptoms to investigate will depend on what aspect or aspects of the condition the study drug is expected to improve as well as symptomatology associated with the site of dissemination,” FDA said.

The FDA stated that patients with disseminated coccidioidomycosis can present with a range of symptoms, and trials may benefit from employing a “personalized endpoint approach,” citing an example of a patient reporting their most bothersome symptom at baseline and measuring the change in that symptom as a component of the primary efficacy endpoint. Despite a patient having a personalized endpoint, outcome assessments should still be standardized across a clinical trial to identify new and worsening symptoms and limitations in the trial, the agency added.

“FDA recognizes that there are challenges with this approach, including that as one symptom resolves, other symptoms may emerge as more bothersome,” the guidance said.

According to FDA assessment of a primary endpoint will likely differ based on the trial population and treatment chosen.

“Given the protracted nature of disseminated coccidioidal infections, the primary outcome assessment should be performed after at least 6 to 12 months of study drug treatment,” the agency added.

Secondary endpoints can have a “microbiological endpoint” as a key secondary endpoint, including a negative culture or decrease in complement fixation titers, according to FDA, but can also include a clinical efficacy outcome with the agency noting a secondary endpoint could be a decrease in quantitative complement fixation titers at 6 months or 12 months. Serum complement fixation titers should be assessed every 1-3 months for up to 1 year, the agency added.

Stakeholders can comment on the draft guidance on www.regulations.gov under docket no. FDA-2025-D-1308 through17 November 2025.

Draft guidance
Federal register notice

FDA proposes guidance for developing drugs for disseminated coccidioidomycosis

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