Differences Between the 2016 and 2022 Food and Drug Administration Guidance—Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis

Abstract

Background

In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results.

Methods

We compared both documents and critically appraised the changes and implications for future clinical trials.

Results

The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to “normal appearance of mucosa,” which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term “mucosal healing” has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy.

Conclusions

The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Abstract

The 2022 draft guidance for drug development in ulcerative colitis by the Food and Drug Administration has several changes compared to the 2016 guidance; notably, it mandates full colonoscopy, rather than sigmoidoscopy.