1 Uric acid and Gout James Witter MD, PhD Arthritis Advisory
Meeting June 2, 2004
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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
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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
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
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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
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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 drugnot for asymptomatic hyperuricemia
Colchicine Colchicine for the treatment of goutrelieving pain of
acute attacks as interval therapy to prevent acute attacks of
gout
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8 The Urate Pool ? urine Joint diet Tophus 10 mg/dl 6 mg/dl
Jump in! serum level
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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
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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
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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)
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12 Surrogate Approval Subpart H 21 CFR 314.510 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.
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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
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14 Subpart H Approval Caveats 314.510 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
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15 Subpart H Withdrawal Caveats 314.530 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
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16 Current State: Surrogates Blood pressure Lipid lowering
agents Blood sugar/HBA1c Bone mineral density HIV load
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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
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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
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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
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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? 300-600 ( 6 months) 100 (1 year) 1500
(total)
