A significant regulatory debate has erupted over the FDA’s September 2025 draft guidance for disseminated coccidioidomycosis (Valley Fever). The conflict highlights a central tension in modern drug development: how to apply "gold standard" evidence requirements to diseases that technically fit the "rare" profile but lack the official designation.
For sponsors and CROs, this feedback period offers a critical window into the FDA's evolving flexibility regarding trial design, endpoints, and the definition of "feasibility."
The Conflict: Two Phase 3s vs. 1,800 Patients
In September, the FDA proposed a traditional regulatory bar for disseminated coccidioidomycosis: two Phase 3 randomized clinical trials (RCTs) to establish efficacy.
Stakeholders, including the Coccidioidomycosis Study Group and the MyCARE Foundation, have pushed back hard. Their argument is mathematical and ethical:
- The Numbers: With only 1,100 to 1,800 cases of disseminated disease reported annually in the US, recruiting for two large-scale RCTs is operationally impossible.
- The Ethics: In severe forms like coccidioidal meningitis, prolonged placebo exposure is widely considered unethical due to high fatality rates.
The stakeholders are formally requesting that the FDA treat this condition as a Rare Disease, arguing that the small patient population demands the flexible architectures seen in oncology and orphan indications: single adequate trials, non-inferiority designs, or Bayesian adaptive models.
The Data Debate: Clinical Outcomes vs. Patient Reality
Beyond trial structure, there is a fundamental disagreement on what to measure.
- FDA Position: Focus on "Clinical Outcomes" (survival, clearance of infection) with PROs as secondary.
- Stakeholder Position: Because current antifungal therapies (azoles) are toxic and require lifelong administration, Quality of Life (QoL) and Side Effect Profiles should be co-primary endpoints. MyCARE argues that issues like "neurocognitive defects, chronic fatigue, and memory loss" are just as critical as survival.
Operationalizing the "Impossible" Trial
Whether the FDA grants the rare disease classification or holds the line, running trials for disseminated coccidioidomycosis will require a decentralized, high-precision approach. The stakeholder request to allow molecular and serologic confirmation (rather than dangerous and difficult fungal cultures) suggests a move toward digital and remote verification.
This is where the infrastructure must evolve to meet the protocol:
- Finding the "Needles in the Haystack"
With ~1,500 patients scattered across the US, no single site will have enough volume. Sponsors need a decentralized platform capable of unifying data from dozens of low-volume community sites. Alethium’s ability to "spin up" lightweight, compliant sites allows sponsors to go where the patients are—often in rural endemic regions—without the overhead of traditional academic center activation. - Elevating PROs to Primary Endpoints
If the FDA accepts the MyCARE recommendation to make Quality of Life a co-primary endpoint, data capture becomes higher stakes. Paper diaries are insufficient for capturing the nuance of "neurocognitive deficits" or "fatigue." Alethium’s Licensed eCOA engine can deploy validated instruments (like PROMIS or specific neuro-QoL scales) directly to patient devices, ensuring that side-effect data is captured with the same rigor as lab values. - Safety Monitoring in High-Toxicity Regimens
Long-term antifungal use carries risks of hepatic and renal toxicity. Managing this risk requires real-time signal detection. Alethium’s Automation Engine can trigger immediate alerts to medical monitors if a patient-reported symptom (e.g., nausea, fatigue) correlates with a lab anomaly, enabling the "risk-informed safety monitoring" that these fragile patients require.
The Takeaway
The industry is watching the FDA’s response to these comments closely. If the agency concedes to a rare disease classification, it opens the door for single-arm, natural history-controlled trials for Valley Fever.
Sponsors should prepare for either outcome by adopting a trial infrastructure that is agnostic to the design but rigorous on the data. In rare disease, where every patient is a statistic of one, operational precision is the only path to approval.
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