1 Uric acid and Gout James Witter MD, PhD Arthritis Advisory Meeting June 2, 2004

2 Goals of Meeting Address an important, and often ignored, public health issue Gather input regarding issues to consider for clinical trials intended to support the development and approval for drugs that treat gout and/or uric acid Acute situations Chronic situations

3 Gout: The Problem Important unmet medical need acute and chronic pain joint and renal damage Increasing incidence and severity estimates of 8.4 per 1,000 in U.S. female: male = 1:6 increase not related to diuretics Earlier age especially males Increases may be related to obesity insulin resistance syndrome

4 Gout: Approved Treatments Limited options NSAIDs NSAIDsprostaglandins colchicine colchicinemicrotubules oral, IV allopurinol allopurinol xanthine oxidase inhibitor probenecid probenecid renal tubule inhibitor

5 Claims and Labels Although label claims have legal and regulatory uses, their central purpose is to inform health care providers and patients about the documented benefits and risks associated with a product Claims describe clinical benefit Promotion allowed on approved claims Promotion allowed on approved claims Accurate product labels allow for effective risk management

6 Labeling Options? For chronic use: For treatment of hyperuricemia associated with: For treatment of hyperuricemia associated with: Gouty flares Gouty arthritis Tophi Renal calculi For acute or prophylactic use: For the short-term treatment of uric acid- induced gout For the short-term treatment of uric acid- induced gout

7 Approved INDICATIONS: Indocin® (indomethacin) Indocin® (indomethacin) effective in active stages of acute gouty arthritis Benemid® (probenecid) Benemid® (probenecid) for treatment of the hyperuricemia associated with gout and gouty arthritis Zyloprim® (allopurinol) Zyloprim® (allopurinol) the management of patients with signs and symptoms of primary and secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy) not innocuous drug…not for asymptomatic hyperuricemia Colchicine Colchicine for the treatment of gout…relieving pain of acute attacks as interval therapy to prevent acute attacks of gout

8 The Urate Pool ? urine Joint diet Tophus 10 mg/dl 6 mg/dl Jump in! serum level

9 Inclusion Issues Baseline serum uric acid (SUA) prevalence of gout is 30% at 10 mg/dl but only 0.6% at 7 mg/dl prevalence of gout is 30% at 10 mg/dl but only 0.6% at 7 mg/dl poor correlation of SUA to gouty flares poor correlation of SUA to gouty flares Prior flares at target joint number and/or severity diagnosis by crystals crystals physician physician self-report self-reportTophi not nodules (RA) or nodes (OA) size Renal status chronic insufficiency chronic insufficiency

10 Exclusion Issues Other crystal-induced diseases Other crystal-induced diseases Other inflammatory diseases or infection Other inflammatory diseases or infection Renal status Renal statusdiuretics Co-morbid diseases Co-morbid diseasesobesity Special populations Special populationstransplant genetic defects

11 Efficacy Issues Endpoint and Duration Is SUA a valid surrogate? Is SUA a valid surrogate? Number of gouty attacks Number of gouty attacks early events excluded? Change in tophi Change in tophisizenumber Disability/quality-of-life domains Disability/quality-of-life domains Duration Duration 6-12 months (SUA) 6-12 months (SUA) 1-2 years (tophi) 1-2 years (tophi)

12 “Surrogate” Approval Subpart H 21 CFR FDA may grant marketing approval for a new drug product on the basis of adequate and well- controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible mortality.

13 Surrogate Endpoint: Definition A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint

14 Subpart H Approval Caveats Requirement that applicant study the drug further to verify and describe its clinical benefit where there is uncertainty of: the surrogate to clinical benefit the surrogate to clinical benefit observed benefit to ultimate clinical outcome observed benefit to ultimate clinical outcome Post-marketing studies usually underway must be adequate and well controlled must be adequate and well controlled must be carried out with due diligence must be carried out with due diligence

15 Subpart H Withdrawal Caveats FDA may withdraw approval, following a hearing if: Postmarketing clinical study fails to verify clinical benefit Postmarketing clinical study fails to verify clinical benefit Applicant fails to perform the required postmarketing study with due diligence Applicant fails to perform the required postmarketing study with due diligence The promotional materials are false or misleading The promotional materials are false or misleading Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use

16 Current State: Surrogates Blood pressure Lipid lowering agents Blood sugar/HBA1c Bone mineral density HIV load

17 Primary Endpoints SUA are these valid surrogate endpoints? are these valid surrogate endpoints? change in serum concentration change to a selected endpoint (5 or 6 mg/dl) long-term precision of the serum estimate long-term precision of the serum estimate multiple values, at multiple times Target and non-targeted joints evaluated together or separately evaluated together or separatelyTophus imaging modality (MRI) vs. manual methods imaging modality (MRI) vs. manual methods percent vs. complete resolution

18 Design/Statistical Issues Initial titration to minimize flares Placebo control superiority to placebo Active/standard-of-care control non-inferiority how “different” can the test be from control? how “different” can the test be from control? depends on new drug under development depends on new drug under development Dose ranges to achieve target SUA goals Means or responder approach minimal important difference

19 Co-Meds and Diet Issues Prophylactic ASA (low vs. high dose) ASA (low vs. high dose) colchicine colchicine NSAIDs/COX-2 agents NSAIDs/COX-2 agents Etoh use patient diary patient diaryDiet restrictions restrictions

20 How safe is safe? Life-long use daily daily intermittent intermittentCo-medications for gout prophylaxis or treatment for gout prophylaxis or treatment myopathy with colchicine Special populations chronic renal insufficiency chronic renal insufficiency Are ICH guidelines adequate? ( 6 months) 100 (1 year) 1500 (total)

21