FDA releases draft guidance to spur development of CDI drugs

The US Food and Drug Administration (FDA) has issued new draft guidance with advice for sponsors on developing drugs for treating Clostridioides difficile infection (CDI).
 
The draft provides recommendations for designing these trials and covers trial populations, efficacy and safety endpoints, nonclinical studies, and pharmacokinetic studies. The guidance does not address fecal microbiota transplant products.
 
CDI is an anaerobic, gram-positive, spore-forming bacterium that is a common cause of healthcare-associated diarrhea. The US Center for Disease Control and Prevention (CDC) deemed C. difficile as ‘threat-level urgent’ in its 2019 Antimicrobial Threats Report and estimates that C. difficile leads to the hospitalizations of 223,900 individuals resulting in 12,800 deaths per year.
 
The guidance addresses the development of small molecule drugs and biological products for treating CDI, reducing the recurrence of CDI, treating and preventing the recurrence of CDI, and preventing CDI in patients at risk.
 
Clinical trials should be randomized, double-blinded and use an active control for both CDI treatment and for reducing CDI recurrence.
 
To prove efficacy, sponsors should provide evidence from two adequate and well-controlled trials with one trial demonstrating efficacy for treatment alone and another trial for preventing CDI.
 
To demonstrate safety, sponsors should submit safety data from at least 300 subjects exposed to the proposed investigational drug treatment. Clinical programs for drugs developed solely for preventing CDI may require a larger safety database. Sponsors should also discuss the appropriate size of the premarket safety database with FDA during clinical development.
 
For nonclinical studies, applicants should test the investigational drug in vitro and in animal models before submitting an investigational new drug application (IND). For more information on these studies, FDA advises applicants to consult the International  Council for Harmonisation (ICH) M3(R2) guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials issued in 2010.
 
FDA recommends an intravenous toxicology study in at least one mammalian species to identify potential risks because patients with CDI may have increased oral drug absorption because of the disruption of the intestinal barrier.
 
In terms of the pharmacokinetic considerations, the guidance says drugs developed for CDI indications can be administered either orally or through intravenous routes.
 
Accompanying the guidance is an appendix comparing the clinical success rates and treatment differences in two Phase 3 clinical trials involving three CDI treatments: tolevamer, vancomycin, and metronidazole.
 
Stakeholders can comment on the draft version of the guidance until 27 December 2022 on www.regulations.com under docket no. FDA-2022-D-1261.
 
Draft guidance