Food and Drug Administration public workshop summary—development considerations of antifungal drugs to address unmet medical need

Publication summary

Antifungal development faces a unique set of challenges when compared with other pharmaceutical research, especially in the area of antifungals for severe, invasive, difficult-to-treat, or rare infections, such as those that affect transplant patients and patients with chronic lung diseases. This article summaries discussions involving academia, the pharmaceutical industry, patient groups, and government agencies held during a 2020 US Food and Drug Administration (FDA) workshop to improve the regulatory and clinical trial infrastructure necessary to develop antifungals for invasive fungal infections.

Who this is for

• Antifungal developers, including clinical trial coordinators
• Patient advocacy groups

Key findings

Drawbacks of currently available antifungals

Immunocompromised people are significantly at risk of invasive fungal infections, and infections that are refractory or resistant to available therapies are not uncommon. The limited number of currently available antifungals does not adequately address the drug absorption and spectrum of activity needed for patients with difficult-to-treat infections. Additionally, available antifungals present safety concerns, such as the risk of toxicity and drug-drug interactions. The lack of oral formulations for two classes of antifungals—polyenes and echinocandins—may increase hospitalization time for patients who have to complete parenteral treatment.

The regulatory environment

Several programs exist through FDA, Japan’s Pharmaceuticals and Medical Devices Agency, the European Medicines Agency, and the US National Institute of Allergy and Infectious Diseases to encourage antifungal development, including, in the US, the Qualified Infectious Disease Product designation for drugs that address serious or life-threatening infections, the Tropical Disease Priority Review Voucher for diseases like cryptococcal meningitis, and the Limited Population Pathway for Antibacterial and Antifungal Drugs for patient populations with unmet medical needs.

Clinical trial design challenges

Clinical trials for new and combination antifungals for invasive fungal infections face significant challenges. Patient recruitment and the use of randomized controlled trials may be limited because of the rarity of invasive fungal infections and the difficulty in quickly and accurately diagnosing and determining susceptibility for invasive infections. Proof that a new antifungal is noninferior to existing therapies relies on endpoints such as microbiological cure and all-cause mortality, making noninferiority difficult to demonstrate for complex patients and for infections resistant or refractory to available treatments. Because issues surrounding the demonstration of a new drug as noninferior plague clinical trials so significantly, the authors argue for the necessity of a “trade-off between scientific rigor and trial feasibility.”

Industry case studies. The workshop included speakers from Astellas Pharma and F2G Ltd., who spoke about their experiences in attempting to design and run trials for new antifungals. Cresemba (Astellas Pharma) was tested as a treatment for invasive aspergillosis, invasive candidiasis, and mucormycosis in 44 trials over 13 years, ultimately failing to show noninferiority to caspofungin. Trials for Olorofim (F2G Ltd.), which represents a new class of antifungals, have had to deal with challenges related to measuring the drug’s performance in patients who do not respond to existing therapies.

Antifungal trials for children. Studying new antifungals in children, infants, and premature neonates also represents a challenging area. Because children with invasive fungal infections experience different symptoms, disease course, and drug metabolism compared with adults, antifungal performance in adults cannot be extrapolated to children. Pharmacokinetic and pharmacodynamic data on antifungal performance in children are limited, making it hard to recruit patients and evaluate the safety and efficacy of a new treatment.

Recommendations for improvement

Clinical trial design. Given the difficulty in recruiting an adequate number of participants for clinical trials, regulators may wish to consider accepting smaller-than-usual trials for drugs that address an unmet need or allow coordinators to use pharmacokinetic and pharmacodynamic data from other trials and animal models, especially as outside data, animal models, and clinical trial networks may further an understanding of safe and efficacious dosing in children and infants. Smaller trial sizes may also aid in developing new therapies for Candida auris and other rarer, but life-threatening, fungal pathogens. A greater availability of nonculture-based diagnostic, susceptibility, and biomarker tests will also help to improve clinical trial design and patient recruitment.

Alternative endpoints. Trials for invasive fungal infections in complex and often immunocompromised patients should consider using endpoints other than all-cause mortality and microbiologic cure, with the authors saying that attributable mortality might make more sense as an endpoint and that, for some rare fungal infections, “stable disease” should be considered a successful outcome.