for Gastrointestinal Drugs Advisory Committee
Chemoprevention of Sporadic Colorectal Cancer (CRC)
March 19, 2002
individuals who are able and willing to undergo colonoscopic screening or
surveillance, is either partial and/or complete suppression of colorectal
adenomatous polyps a clinically meaningful benefit? Why or why not?
If adenomatous polyp suppression is not a clinically meaningful benefit, what additional
information would be needed to demonstrate that partial or complete suppression
of polyps is of clinical benefit in such individuals?
A chemoprotective agent (CPA) that suppresses polyp growth may become
resistant to drug effects. Additionally, it may preferentially allow small, invasive
lesions to go undetected on colonoscopy while large, indolent lesions are
identified and removed. If polyp suppression is used as an
endpoint in clinical trials of a CPA:
long should the trial be?
should the time interval be between colonoscopic evaluations?
endpoints and follow up are needed to rule out possible resistance to drug
identification and removal of large, indolent lesions?
How should a rebound withdrawal effect be
Given that mortality and invasive
CRC incidence rates are gold
standards for demonstrating clinical benefit, what is the relative importance of
other study endpoints in clinical trials of CPAs, such as:
Lengthening the interval between (or replacement of) colonoscopic
screening or surveillance?
Reduction in the number of procedural
complications associated with polypectomies?
clinically meaningful outcomes?
Should the results of clinical trials in individuals at high risk for CRC
be generalized to individuals at normal risk for CRC? Why or why not? Please
specify the criteria that should be used to classify risk in clinical trials of
clinical trials of CPAs be required to include substantial numbers of
individuals with particular demographic or baseline characteristics (e.g., age,
race, sex) or on particular concomitant therapies (e.g., nonsteroidal
6) In randomized, placebo-controlled clinical trials of CPAs used as an adjunct to colonoscopic screening or surveillance, what would represent a clinically meaningful effect size for:
Reduction of benign adenomas?
Reduction of premalignant lesions?
Reduction of colorectal cancer?
in the time interval between colonoscopies?
Reduction of complications associated with polypectomies?
How should dropouts/censored patients be analyzed?
What is your advice concerning the safety evaluation of a
drug proposed as a CPA in an at-risk population without active disease?
For partial or complete suppression of adenomatous
Should the proportion of patients who experience the
clinically meaningful benefit of polyp suppression exceed the proportion of
patients who experience serious adverse events?
If yes, should the study be powered accordingly? Why or
In order to ensure long term safety of CPAs, what should
the length of the clinical trials be?