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Presentedby

Eugene Laska, Ph.D.

at theArthritis Advisory Committee meeting

07/30/02

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The goal of a RCT is to characterize The goal of a RCT is to characterize the properties of a treatmentthe properties of a treatment Onset of pain reliefOnset of pain relief Peak effectsPeak effects Duration of pain reliefDuration of pain relief Dose response relationshipDose response relationship Dosing intervalsDosing intervals Adverse effectsAdverse effects

NB: These are all dependent on the severity of painNB: These are all dependent on the severity of pain

NB:Two measures of efficacy, pain intensity and pain relief NB:Two measures of efficacy, pain intensity and pain relief are not necessary. They are highly correlated and add no are not necessary. They are highly correlated and add no new informationnew information

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Characterizing ONSET

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How to measure onset of analgesiaHow to measure onset of analgesia

One stopwatch method: One stopwatch method: meaningfulmeaningful

captures fact that patient obtained meaningful pain captures fact that patient obtained meaningful pain relief (relief (responderresponder) and the time it occurred () and the time it occurred (onsetonset))

Two stopwatches method: Two stopwatches method: perceptibleperceptible,, meaningfulmeaningful – Time to perceptible pain relief less clinically Time to perceptible pain relief less clinically

relevant and susceptible to noiserelevant and susceptible to noise– Complicates the study for no gainComplicates the study for no gain– Artificial data changes (Artificial data changes (adjusting the time of adjusting the time of

the first click if there is no second clickthe first click if there is no second click) are of ) are of questionable statistically validityquestionable statistically validity

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How to quantify onset of analgesiaHow to quantify onset of analgesia

Cure model: H(t) = (1-p) + pS(t) Cure model: H(t) = (1-p) + pS(t) Population comprised of two groups- Population comprised of two groups-

respondersresponders and and non respondersnon responders Estimate the proportion p of patients who respond Estimate the proportion p of patients who respond

(i.e., obtain onset of meaningful pain relief)(i.e., obtain onset of meaningful pain relief) Estimate the survival distribution and median time Estimate the survival distribution and median time

to meaningful pain relief among the respondersto meaningful pain relief among the responders

LASKA EM, SIEGEL C, and SUNSHINE A. Commentary - LASKA EM, SIEGEL C, and SUNSHINE A. Commentary - onset and duration: Measurement and analysis. Clin Pharm onset and duration: Measurement and analysis. Clin Pharm & Ther, 49(1):1-5, January 1991.& Ther, 49(1):1-5, January 1991.

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Regulatory requirement for Regulatory requirement for registration of drug D - onsetregistration of drug D - onset

The proportion of responders on drug D must be The proportion of responders on drug D must be significantly larger than the proportion of responders on significantly larger than the proportion of responders on placebo: pplacebo: pDD> p> pPP

Median onset among responders on drug D < t minMedian onset among responders on drug D < t min

NBNB: Choice of t may depend on pain intensity, model, and setting

NB: Drug D may not have “faster” onset than placebo

NB: The criterion drug D sig > placebo on PID t is too dependent on sample size and variability

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Characterizing DURATION to establish the

DOSING INTERVAL

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How to measure and quantify How to measure and quantify duration of analgesiaduration of analgesia

Time to offset (Time to offset (end of meaningful pain reliefend of meaningful pain relief) using a ) using a stopwatch or Time to rescue medicationstopwatch or Time to rescue medication

Estimate the survival distribution and median time to Estimate the survival distribution and median time to rescue (trescue (tRR) ) among responders.among responders. Do not impute a value Do not impute a value

for those without onsetfor those without onset Report the proportion of responders that rescue at e.g. Report the proportion of responders that rescue at e.g.

6 hr, 12 hr, and 24 hr6 hr, 12 hr, and 24 hr Median time to rescue, among responders who rescue Median time to rescue, among responders who rescue Use standard survival methods and cure modelsUse standard survival methods and cure models

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Regulatory requirement for claiming a Regulatory requirement for claiming a dosing interval of x hrdosing interval of x hr

The proportion of The proportion of respondersresponders on drug D who rescue on drug D who rescue within x hr within x hr 0.5; 0.5; – thus x thus x median time to rescue median time to rescue

At x hr, the proportion of At x hr, the proportion of responders responders on drug D who on drug D who rescue is significantly < the proportion of responders rescue is significantly < the proportion of responders on placebo who rescueon placebo who rescue

NB: Can be evaluated only in models in which the pain can be controlled with a single agent

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Evaluating the DOSING REGIMEN

in MULTI-DAY models

Old bioassay rule Old bioassay rule

Hold doses fixed - study outcomeHold doses fixed - study outcome

Hold outcome fixed - study dosesHold outcome fixed - study doses

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How to demonstrate efficacy of dosing How to demonstrate efficacy of dosing regimen in acute pain after day 1 regimen in acute pain after day 1

Mild to moderate pain models- no prn Mild to moderate pain models- no prn narcotic allowednarcotic allowed– The proportion of patients who require rescue The proportion of patients who require rescue

on Days 2, 3 etc. is < x%on Days 2, 3 etc. is < x%– Demonstrating superior pain relief vs. placebo Demonstrating superior pain relief vs. placebo

should not be required because patients who should not be required because patients who remain are likely to be “placebo responders.” remain are likely to be “placebo responders.” Imputing values for patients who dropped out Imputing values for patients who dropped out on Day 1 statistically questionableon Day 1 statistically questionable

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How to demonstrate efficacy of dosing How to demonstrate efficacy of dosing regimen in acute pain after day 1regimen in acute pain after day 1

Moderate to severe pain models - prn narcotic Moderate to severe pain models - prn narcotic allowedallowed– Contrast the amount of prn narcotic used by patients on Contrast the amount of prn narcotic used by patients on

drug D vs. placebo drug D vs. placebo – The proportion of patients on drug D + narcotics that The proportion of patients on drug D + narcotics that

dropout for lack of pain relief after Day 1 is < x%dropout for lack of pain relief after Day 1 is < x%

NB: amount of narcotic use for dropouts must be handled statistically

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How to demonstrate efficacy of How to demonstrate efficacy of regimen in chronic pain at week Wregimen in chronic pain at week W

Patients with severe chronic pain on placebo often drop Patients with severe chronic pain on placebo often drop out so comparisons to placebo are not likely to be validout so comparisons to placebo are not likely to be valid

Imputation methods are crude at best and do not solve Imputation methods are crude at best and do not solve problem problem

At least x% of the patients on drug D (possibly plus prn At least x% of the patients on drug D (possibly plus prn narcotic) must still be in the trial by week Wnarcotic) must still be in the trial by week W

Conduct a Conduct a withdrawal trialwithdrawal trial i.e., at week W, half of the i.e., at week W, half of the patients on Drug D are randomly reassigned to placebo patients on Drug D are randomly reassigned to placebo -demonstrate superiority of drug D to placebo (in -demonstrate superiority of drug D to placebo (in efficacy or narcotic sparing) in week W+1efficacy or narcotic sparing) in week W+1

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Key points – onset and durationKey points – onset and duration

OnsetOnset –Prob (responder|D) > Prob (responder|placebo) Prob (responder|D) > Prob (responder|placebo) –Median onset among responder on D < tMedian onset among responder on D < t

Duration: Dosing Interval of x hrDuration: Dosing Interval of x hr–Prob (responders who rescue by x hr|D) Prob (responders who rescue by x hr|D)

< Prob (responders who rescue by x hr| < Prob (responders who rescue by x hr|placebo) placebo)

–Prob (responders who rescue by x hr|D) Prob (responders who rescue by x hr|D) 0.5 0.5

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Key points – demonstrating efficacyKey points – demonstrating efficacy

Efficacy after day 1 – acute pain - no prn narcoticEfficacy after day 1 – acute pain - no prn narcotic– Prob (rescue|D) < y (e.g., 0.15)Prob (rescue|D) < y (e.g., 0.15)

Efficacy after day 1 – acute pain - with prn narcoticEfficacy after day 1 – acute pain - with prn narcotic– Prob (dropout|D+narcotic) < y Prob (dropout|D+narcotic) < y – Mean narcotic on D < mean narcotic on placeboMean narcotic on D < mean narcotic on placebo

Efficacy at week W – chronic pain - with prn narcoticEfficacy at week W – chronic pain - with prn narcotic– Prob (cumulative dropout by W|D+narcotic) < y Prob (cumulative dropout by W|D+narcotic) < y – Conduct a withdrawal trial and show mean narcotic Conduct a withdrawal trial and show mean narcotic

on D < mean narcotic on placeboon D < mean narcotic on placebo