Food and Drug Administration
Center
for Drug Evaluation and Research (CDER)
Arthritis Advisory Committee
June 2,
2004
Questions to the Committee
I. Please discuss the utility of serum uric acid
as a surrogate marker for the chronic treatment of gout.
- If it is an appropriate
surrogate, what level of serum uric acid or amount of change in serum uric
acid level would be considered adequate evidence of efficacy?
- Would an analysis
comparing the mean change in serum uric acid level for the treatment
populations adequately reflect efficacy?
- Would an analysis
comparing the number of individuals in each treatment arm reaching a prespecified level or amount of change adequately
reflect efficacy?
- Are there advantages to
choosing an analysis of either the uric acid levels at last visit or the
uric acid levels over time (based on the area under the curve)?
- Does
the choice of a surrogate as the efficacy endpoint influence the decision
of what is considered acceptable risk?
II. For a drug to be
approved for the treatment of hyperuricemia associated with gout, what additional
information besides uric acid levels are important to collect?
- Please discuss the
clinical endpoints of a reduced number of gout attacks and decreased size
of tophi in trials of uric acid lowering drugs.
- Are there preferred
methods for measuring tophi (i.e. exam or
imaging)?
- Is there more value in
evaluating either the absolute number of gout attacks or the relative
reduction in number of attacks?
III. Individuals with
gout may demonstrate a broad range of uric acid levels.
- Please discuss the
range of uric acid levels that would reflect meaningful inclusion or
exclusion criteria.
- Are there any
advantages to recruiting patients with uric acid in a specified range such
as 8-12 mg/dL (representing similar total body
load of uric acid)?
- Please discuss whether
there a rationale for studying individuals with values of uric acid over
12 mg/dL.
- Is there value in
stratifying patients by uric acid level?
IV. Patients with gout
may have renal insufficiency.
- Discuss the value of
including or excluding such patients in clinical trials.
- If they are to be
included, what range of serum creatinine levels
would be important to consider for inclusion?
Food and Drug Administration
Center
for Drug Evaluation and Research (CDER)
Arthritis Advisory Committee
June 2,
2004
Questions to the Committee (cont.)
V. Uric acid lowering drugs such as allopurinol are sometimes used at doses higher than those
labeled.
- Discuss the utility of
studying multiples (such as 2x the highest dose) of the proposed maximum
efficacious dose of a new drug.
VI. Please discuss what
could be considered an optimal duration for these trials.
VII. Please discuss the
implications of placebo vs. active controls and superiority vs. non-inferiority
designs for clinical trials of uric acid lowering drugs.
- Is there sufficient
data available in the literature to establish a generally accepted
response rate for allopurinol that could be used
for calculating a non-inferiority margin?
VIII. Please discuss the
implications of concomitant therapies.
- Can concomitant drugs
such as colchicine or NSAIDs
be continued during clinical trials for chronic gout?
- Please discuss the
implications of permitting or prohibiting the use of concomitant diuretics
or low dose ASA.
- Is there value in
recommending or prohibiting a particular diet?
- Is it appropriate to
restrict alcohol use?
- Please discuss issues
concerning the enrollment of patients with kidney stones.
- Please discuss
inclusion of
heart/renal transplant patients, especially those on drugs
such as cyclosporine?