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GoutGout::Clinical review and trialClinical review and trial

design issuesdesign issuesJoel SchiffenbauerJoel Schiffenbauer

FDA/DAAODPFDA/DAAODP

AAC/June 3 !""#AAC/June 3 !""#

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GoutGout

$ Caused b% de&osition of 'onosodiu'

urate cr%stals around and in the tissues of

the (oint

$ )hree distinct stages: a*as%'&to'atic

h%&erurice'ia+ b*acute inter'ittent gout+

c*chronic to&haceous gout

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Acute inter'ittent goutAcute inter'ittent gout

$ ,nitial e&isode usuall% follows decades of

as%'&to'atic h%&erurice'ia

$Characteri-ed b% intense &ain andinfla''ation .war'th swelling er%the'a*

$ suall% begins as 'onoarticular

involve'ent with first 0)P (oint

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Acute gout cont1dAcute gout cont1d

$ 2atural course varies with

i'&rove'ent/resolution in da%s to one to

two wees

$ During intercritical &eriods (oints are

virtuall% free of s%'&to's although cr%stal

'a% be found

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Standard a&&roaches to thera&%Standard a&&roaches to thera&%

$ Acute gout

4 2SA,D5 several a&&roved

4 Colchicine5a&&roved

4 Corticosteroids .a&&roved* and AC)6 .not

a&&roved*

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)rial design considerations)rial design considerations

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General )rial Design ,nfor'ationGeneral )rial Design ,nfor'ation

htt&://www7fda7gov/cder/guidancehtt&://www7fda7gov/cder/guidance

$ ,C6 89: Statistical &rinci&les for clinical trials

$ ,C6 8": Choice of control grou& and related

issues in clinical trials

$ ;A guidance

$ OA guidance

$ CO2SO;) .Consolidated Standards of;e&orting )rials* reco''endations .:9*

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Acute GoutAcute Gout

$ Gout is

4 a uni?ue 'edical disorder that deservess&ecific studies and its own labeled indication

O;

4 a 'odel of acute &ain

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Diagnostic criteriaDiagnostic criteria

$ ,s docu'entation of cr%stals critical@

4At ti'e of flare@

4An% &revious docu'entation@

$ Are clinical criteria sufficient to serve as

entr% criteria into trial@ For ea'&le AC;

classification of acute gout% arthritis in

which B/! clinical/lab/5ra% criteria 'a%

be utili-ed

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So'e AC; clinical criteriaSo'e AC; clinical criteria

$ 0ore than one attac of acute arthritis

$ 0ai'al infla''ation develo&ed within

one da%

$ Attac of 'onoarticular arthritis

$ First 0)P (oint &ainful or swollen

$ Sus&ected to&hus$ 6%&erurice'ia

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Acute goutAcute gout

$ Superiority vs non-inferiority:

4 Superiority to placebo: preferable but$ are placebo controlled trials ethical?

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Placebo controlled trials@Placebo controlled trials@

$ Pain severit% in gout

$ aseline AS &ain scores show little

difference fro' other &ain studies

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A&&roaches with PlaceboA&&roaches with Placebo

$ Rescue

4 With time to treatment failure as primary

endpoint: early escape design reduces

exposure to sub-optimal therapy

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Alternatives to &lacebo controlledAlternatives to &lacebo controlled

trialstrials

$ Active comparator and superiority

$ Dose controlled studies

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Alternatives to &lacebo controlledAlternatives to &lacebo controlled

trialstrials

$ Active comparator and non-inferiority

4 If non-inferiority hich comparator !dosing

intervals" and hat is non-inferiority margin?

4 Are there historical ade#uately controlled trialsand of similar design to support non-inferiority

studies?

4 If no placebo and non-inferiority$ issue of

sensitivity of trial- ho do e %no that any drugor%s? &ain resolves spontaneously'

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Do'ainsDo'ains

$ Pain

$ ,nfla''ation

$ Function$ Patient/&h%sician global assess'ent of

disease/treat'ent

$ 6;EO