The new guidance restructures how study designers should look at trial population, efficacy benchmarks, and safety in clinical trials involving drug development.
The US Food and Drug Administration (FDA) has released new guidance for treating Crohn’s disease and ulcerative colitis for developing drugs for treatment and is now seeking public comment.
The draft guidance for Crohn’s disease includes new recommendations on trial populations to include subjects with confirmed diagnosis of the disease based on endoscopy and histopathology results.
Patients included in trials should have a CDAI score of at least 220 and a simple endoscopic score for Crohn’s disease (SES-CD) of at least 6 at baseline.
The authors also recommend a balanced representation of subjects who were naïve to biologics with subjects who failed prior therapies with 1 or more biologics or other advanced therapies.
For trial design in Crohn’s disease, the authors recommend a randomized, double-blind, placebo-controlled trials that demonstrate beneficial effects observed initially with treatment that is continued long-term to support chronic administration.
Another approach is to conduct a randomized, placebo-controlled induction trial to assess clinical benefit in the short-term.
For efficacy, the authors recommend defining clinical remission as a CDAI score of less than 150 and endoscopic remission as SES-CD of 0-2.
For secondary endpoints, clinical response should be defined as a decrease from baseline of at least 100 points on the CDAI and endoscopic response is a 50 percent reduction from baseline on the SES-CD. Corticosteroid-free remission is subjects who are in clinical remission at the conclusion of a controlled trial and have no corticosteroid exposure during a prespecified period before the assessment.
For safety, the investigators will continue to promote timely enrollment of patients with active disease, while reducing the potential need for escalation of corticosteroids as bridging therapy. The new reccomendations, however, propose a shorter washout period with appropriate justification.
For long-term treatments, a sufficient number of participants should be exposed to the to-be-marketed dosing regimen for at least 52 weeks to characterize the safety profile.
The guidance for ulcerative colitis trials was similar to the Crohn’s disease guidance.
Patients included in a clinical trials should have a score of 5-9 on the modified Mayo Score (mMS), including an endoscopy subscore of at least 2. Sponsors should also enroll patients across the whole range of both moderately and severely active disease categories.
The authors also recommend a balance representation of patients, similar to Crohn’s disease patients.
Drugs that are intended for chronic administration should be part of a total controlled treatment period of at least 1 year to adequately assess both early efficacy and durability of response over time and to adequately characterize the safety profile.
Designers should also demonstrate superiority to an approved therapy and can consider noninferiority studies. However, the investigators recommend sponsors reach an agreement on an acceptable noninferiority margin with the appropriate review division prior to initiating clinical trials.
For efficacy, the recommendation is for clinical remission is for it to be defined as an mMS score of 0-2 including a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and a centrally read endoscopy subscore of 0 or 1.
The authors also recommend colonoscopies be used to document disease activity in all involved segments of the colon and to use centralized readings for endoscopies as the primary approach to score the endoscopic component of the primary and secondary endpoint assessments.
For secondary endpoints, clinical response should be defined as a decrease from baseline in the mMS of greater than or equal to 2 points and at least a 30% reduction from baseline, as well as a decrease in rectal bleeding a subscore of greater than or equal to 1 or an absolute rectal bleeding subscore of 0 or 1.