# **Questions for Gastrointestinal Drugs Advisory Committee**

## Chemoprevention of Sporadic Colorectal Cancer (CRC)

### March 19, 2002

1)  For 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?

2)  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:

    a.  How long should the trial be?

    b.  What should the time interval be between colonoscopic
        evaluations?

    c.  What endpoints and follow up are needed to rule out possible
        resistance to drug effects? Differential identification and
        removal of large, indolent lesions?

    d.  How should a rebound withdrawal effect be studied?

3)  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:

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a)  Lengthening the interval between (or replacement of) colonoscopic
    screening or surveillance?

b)  Reduction in the number of procedural complications associated with
    polypectomies?

c)  Other clinically meaningful outcomes?

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4)  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 CPAs.

5)  Should 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 anti-inflammatory agents)?

**(GI Advisory Committee Questions Cont'd)**

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:

    a.  Reduction of benign adenomas?

    b.  Reduction of premalignant lesions?

    c.  Reduction of colorectal cancer?

    d.  Increase in the time interval between colonoscopies?

    e.  Reduction of complications associated with polypectomies?

7)  How should dropouts/censored patients be analyzed?

8)  What is your advice concerning the safety evaluation of a drug
    proposed as a CPA in an at-risk population without active disease?

9)  For partial or complete suppression of adenomatous polyps:

    a.  Should the proportion of patients who experience the clinically
        meaningful benefit of polyp suppression exceed the proportion of
        patients who experience serious adverse events?

    b.  If yes, should the study be powered accordingly? Why or why not?

    c.  In order to ensure long term safety of CPAs, what should the
        length of the clinical trials be?