**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.

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-   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?

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-   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?