Commenters ask FDA to allow rare disease classification for disseminated coccidioidomycosis drugs

Stakeholders are asking the US Food and Drug Administration (FDA) to treat disseminated coccidioidomycosis as a rare disease for trial design and regulatory purposes.

In September, FDA published a draft guidance that proposed sponsors conduct two phase 3 randomized clinical trials to establish efficacy of future drugs being considered as a treatment for disseminated coccidioidomycosis, or a superiority trial design in situations where the treatment would be used in addition to standard of care (RELATED: FDA proposes guidance for developing drugs for disseminated coccidioidomycosis, Regulatory Focus 18 September 2025).

However, stakeholders who responded to the draft guidance argue that requirements would be too burdensome when developing a treatment for disseminated coccidioidomycosis, a condition that they said should be considered a rare disease based on the number of cases that occur in the US each year. The Coccidioidomycosis Study Group noted there are between 1,100 and 1,800 cases of chronic pneumonia and disseminated coccidioidomycosis reported in the US annually.

“This small proportion of the total requires clinical trials in the field to be performed in a similar manner to diseases of much higher incidence (e.g. candidiasis, aspergillosis), adding a considerable burden to trial design,” the group said.

The Coccidioidomycosis Study Group explained that there is no standard of care for treatment of disseminated coccidioidomycosis, and there has never been a completed phase 3 trial for the disease. Due to the severity and high fatality rate of some forms of disseminated disease, such as coccidioidal meningitis, the benefit of a treatment would be quickly apparent and obviate the need for a phase 3 trial, it argued.

The Mycology Advocacy, Research, and Education (MyCARE) Foundation echoed in its comment that requiring two phase 3 trials is not feasible for a drug intended to treat disseminated coccidioidomycosis.

“The limited number of eligible patients, the heterogeneity of disease manifestations, and ethical considerations surrounding prolonged placebo exposure make this design both impractical and unethical,” the group said.

Instead, MyCare said FDA should allow for single adequate and well-controlled trials, non-inferiority designs in the absence of a drug with no clinical superiority but improved quality of life and safety, and trials with an adaptive or Bayesian design.

“For many patients, a non-inferior therapy with fewer side effects and better tolerability would represent a significant and meaningful advance,” the foundation said.

The inclusion of a culture confirmation requirement is also a barrier to trial enrollment, it added.

“Culturing Coccidioides poses significant biosafety risks to laboratory personnel and is rarely performed outside of reference centers,” MyCARE wrote. “We recommend that diagnostic confirmation by culture be optional and that molecular, serologic, and histopathologic methods be accepted as sufficient for enrollment and endpoint confirmation.

This modification would expand access, accelerate enrollment, and increase patient safety,” It added.

Rare disease classification

In terms of patient populations, the Coccidioidomycosis Study Group said that “most difficult manifestations of disseminated coccidioidomycosis” should be targeted for treatment instead of patients with more treatable manifestations of the disease. The vast majority of primary coccidioidal pneumonia cases do not require treatment, it noted, and the focus should be on those patients with more severe disease.

“We understand the FDA has strict requirements to follow regarding drug approval but this may not fully serve patients with coccidioidomycosis who fail currently available therapy,” the group said. “We are hopeful study designs akin to those used for rare malignancies, metabolic diseases, or other high mortality rare conditions may be acceptable and provide a pathway for limited use approval.”

MyCARE echoed this sentiment and said, “We urge the FDA to explicitly recognize disseminated coccidioidomycosis as an ultra-rare disease for regulatory and trial design purposes.”

Disagreement on outcome focus

FDA’s draft guidance states that clinical outcomes should be assessed as primary endpoints, with secondary endpoints focusing on serological markers, radiological data, or an endpoint that is a meaningful improvement in an outcome relevant to the target population. This could include, but is not limited to the addition of a “personalized endpoint approach” where a most bothersome symptom is documented at baseline and tracked over the trial period.

The Coccidioidomycosis Study Group said that they are concerned that primary outcomes would be focused “solely toward patient symptoms and patient reported outcomes,” and that there is a need for objective response measures such as serologic results, cerebrospinal fluid indices, and radiographic findings.

MyCARE asked FDA to consider patient-centered outcomes alongside clinical outcomes. It argued that patient-reported outcomes can identify potential side effects associated with long-term antifungal therapy, such as pain, fatigue, cognitive dysfunction, and emotional distress.

“These chronic effects can profoundly impair function and quality of life even in the absence of measurable disease progression,” MyCARE said. “We therefore urge the FDA to explicitly state that patient-reported outcomes (PROs), functional measures, and quality-of-life metrics can be considered co-primary or key secondary endpoints, placing patient quality of life on par with clinical outcomes.”

A group of ophthalmology and uveitis specialists from the Jules Stein Eye Institute and David Geffen School of Medicine at UCLA in Los Angeles said they would like to see ocular endpoints included in clinical trials as secondary or exploratory outcomes. Ocular coccidiomycosis is underreported, they explained, which is likely due to the critical state of a patient hospitalized with disseminated coccidioidomycosis.

“[P]rompt aggressive therapy is required to prevent irreversible damage to the eye and severe vision loss,” they said.

Additional side effect profile

There also needs to be an acknowledgement of the side effects associated with long-term use of antifungal medications, MyCARE said. Although treatments can be successful clinically, long-term use can cause issues such as neurocognitive defects, chronic fatigue, memory loss as well as hepatic and renal toxicity, it noted.

“We urge the FDA to explicitly include side-effect profiles, as well as disease impact on patients and caregivers, as meaningful patient-relevant outcomes that can influence benefit-risk assessments,” the foundation wrote.

Basilea Pharmaceutica International also provided a comment responding to FDA’s draft guidance, but it is not viewable by the public because it contains confidential business information.

Draft guidance

Commenters ask FDA to allow rare disease classification for disseminated coccidioidomycosis drugs

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