FDA offers guidance on drug development for ulcerative colitis, Crohn’s disease

Regulatory NewsRegulatory News | 02 May 2022 |  By 

The US Food and Drug Administration (FDA) issued draft guidance documents on drug development for ulcerative colitis (UC) and Crohn’s disease, outlining recommendations on clinical trial design.

Both UC and Crohn’s disease are chronic inflammatory bowel diseases. In the current guidance documents, issued on 29 April 2022, agency officials outline their thinking on clinical trial populations, trial designs, efficacy considerations, and safety assessments. The guidance for UC replaces a 2016 draft guidance on clinical trial endpoints that was later withdrawn (RELATED: Ulcerative Colitis Drugs: FDA Offers Draft Guidance on Clinical Development, Regulatory Focus 08 August 2016).

Trial design options

For UC or Crohn’s disease drug trials, the agency recommends a randomized, double-blind, placebo-controlled design that can demonstrate the effects of both initial and long-term administration. FDA recommends trials be designed either as induction followed by randomized withdrawal maintenance or as a treat-through design. Trials should include a total controlled treatment period of at least one year for drugs that are intended to be administered chronically.

In induction followed by randomized withdrawal maintenance, sponsors conduct a randomized, placebo-controlled induction trial to assess benefit in the short term, followed by a maintenance trial to assess subjects who achieved initial response to the drug. During the maintenance phase, those initial responders are re-randomized to either active treatment or placebo and are evaluated again to assess long-term outcomes.

In a treat-through trial, subjects are randomized at the start of the trial to either a drug dosing regimen or placebo and are treated continuously without re-randomization.

Although a variety of trial designs can be used, FDA suggests that the overall design be discussed with the agency’s review division before starting the trial. Sponsors also should consult FDA on the number of subjects exposed to the treatment drug for at least a year who should be available at the time of the application submission.  

For both UC and Crohn’s disease, the agency encourages active-controlled trials that demonstrate superiority to an approved therapy. For UC drugs, sponsors can consider noninferiority studies but should reach an agreement with FDA on an acceptable noninferiority margin before starting the trial, according to the draft guidance.

Efficacy assessments

For UC drug trials, FDA recommends that clinical remission be used as the primary endpoint. Secondary endpoints can include clinical response, corticosteroid-free remission, endoscopic improvement, endoscopic remission, and maintenance of remission. Sponsors also may consider exploratory endpoints, including histologic response/remission, interim clinical assessments based on noninvasive measures, and additional patient-reported outcome endpoints.

The agency recommended that UC drug developers use colonoscopy to document disease activity in all involved segments of the colon, rather than sigmoidoscopy.

For Crohn’s disease trials, the FDA recommends co-primary endpoints of clinical remission and endoscopic remission to evaluate the drug’s effects on signs and symptoms, as well as underlying mucosal inflammation.

“Coprimary endpoint assessment should include [the Crohn’s Disease Activity Index (CDAI)] to evaluate signs and symptoms and an ileocolonoscopy to evaluate the impact of the drug on mucosal inflammatory changes. Although we currently recommend assessing signs and symptoms using the CDAI in the coprimary endpoint definition, sponsors are also encouraged to explore other methods for assessing clinically relevant signs and symptoms,” according to the draft guidance.

Secondary endpoints include clinical response, endoscopic response, corticosteroid-free remission, maintenance of remission, and a composite endpoint of clinical remission and endoscopic remission. FDA also recommended exploratory endpoints that include histologic response/remission, interim clinical assessments based on noninvasive measures, change from baseline in the simple endoscopic score for Crohn’s disease (SES-CD) score, and additional patient-reported outcome endpoints.

Safety considerations

For both UC and Crohn’s disease trials, FDA has recommended a washout period of five half-lives for prior therapies or undetectable serum levels for trial participants. However, to reduce the need for bridging therapy with corticosteroids, sponsors can propose shorter washout periods, with appropriate justification, according to the agency.

Public comments are open until 28 June 2022 for both guidance documents. Make comments on the UC guidance here and the Crohn’s disease guidance here.

Draft guidance on UC drug development
Draft guidance on Crohn’s drug development


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