the analysis and interpretation of pain clinical trial outcomes: enhancing understanding
DESCRIPTION
The Analysis and Interpretation of Pain Clinical Trial Outcomes: Enhancing Understanding. John T. Farrar, MD, PhD University of Pennsylvania. Surrogate Outcomes. Only three “real” outcomes Birth Death Quality of life. Changing the State of the Brain. What do you see?. Why Do We Care. - PowerPoint PPT PresentationTRANSCRIPT
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The Analysis and Interpretation of
Pain Clinical Trial Outcomes:Enhancing Understanding
John T. Farrar, MD, PhDUniversity of Pennsylvania
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Surrogate Outcomes
Only three “real” outcomes
• Birth• Death• Quality of life
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Changing the State of the Brain
What do you see?
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Why Do We Care
• RCTs - important for most medical therapy• Did not need an RCT for introduction of
penicillin–Pneumococcal pneumonia–No penicillin - Last week 9/10 people died–With penicillin – This week 1/10 people died
• Corollary – if you identify the right group, measurement and design issues statistics will be less controvertial
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Outline of the Presentation
• Measurement must be appropriate
• Handling of missing data is important
• Part 1: How do patients report pain
• Part 2: Analysis
• Part 3: Interpretation
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Pain is a Subjective Experience
• No “objective” direct measure• Not easy to relate to an underlying
neurologic process in an individual• Depend on subjects to accurately
report their experience
• Creates inter-person variation in the reporting of pain that is unavoidable
• Creates observer discomfort about the validity of the measure
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Pain Measures - Intensity Scales
0__1__2__3__4__5__6__7__8__9__10
|____________________________________________| | |
Least Worst
None Mild Moderate Severe Excruciating
Intra-person reliability – Good Inter-person reliability – Poor
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How do Patients DecideIf a Treatment is Useful
• Does the treatment make my symptoms better now?
• Are there any side-effects?• Is the pain relief “good enough”?
>>>> Am I better overall?
>>>> Should I take something else?
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Global Rating of Quality of Life
Overall how would you rate your quality of life: over the last ______:
0 1 2 3 4 5 6 7 8 9 10Worst BestIt can be it can
be
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Global Change in Quality of Life
How has your quality of life changed over the last ______: (or - since the last _____:)
Very Much Worse
Much Worse
A little worse
Very Much better
MuchBetter
A little better
No change
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Another View on Scales
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How Do Patients Use a Numeric Scale(Acute Pain)
• Study data: Randomized clinical trial of oral trans-mucosal fentanyl versus placebo
• Method: Re-analysis of data set stratified on baseline pain intensity score
• Population: 89 cancer pain patients with acute breakthrough pain
• Results =>
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Data Collection Instrument
• Baseline – Pain Intensity 1_2_3_4_5_6_7_8_9_10
• At 15, 30, 45 and 60 minutes– Pain Intensity 1_2_3_4_5_6_7_8_9_10– Pain Relief 0 (none) 1(slight) 2(mod.) 3(lots) 4(comp.)
• Second rescue medication - Time________– Overall Performance
» 0 (none) 1(slight) 2(moderate) 3(lots) 4(complete)
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-10
-8
-6
-4
-2
0
Poor Fair Good Very Good Excellent
Raw
PID
4
5
6
7
8
9
10
Raw Change in Pain Intensity Compared to Global Performance Scale
Global Performance Scale
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-10
-8
-6
-4
-2
0
Poor Fair Good Very Good Excellent
Raw
PID
4
5
6
7
8
9
10-100%
-80%
-60%
-40%
-20%
0%
Poor Fair Good Very Good Excellent
% P
IDPercent Change in Pain Intensity Compared to Global Performance Scale
Global Performance Scale
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How Do Patients Use a Numeric Scale(Chronic Pain)
• Study data - RCTs of pregabalin in multiple diseases
• Method – Compared measured pain intensity (0-10 NRS) and patients global impression of change (PGIC)
• Population - Data on 2,724 subjects from 10 clinical trials of diabetic neuropathy (3), postherpetic neuralgia (3), chronic low back pain (2), fibromyalgia (1) and osteoarthritis (2).
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Reduction of Pain Diary Scores from Baseline to Endpoint
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
Very Much Worse /Much Worse
Minimally Worse No Change Minimally Improved Much Improved Very MuchImproved
PGIC Category
Raw
Cha
nge
Scor
e
BP = 4BP = 5BP = 6BP = 7BP = 8BP = 9
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Percent Reduction of Pain Diary Scores from Baseline to Endpoint
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
Very Much Worse /Much Worse
Minimally Worse No Change Minimally Improved Much Improved Very MuchImproved
PGIC Category
Perc
ent C
hang
e Sc
ore
BP = 4BP = 5BP = 6BP = 7BP = 8BP = 9
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Clinically Important Differencesfor the 0-10 NRS
• Used the global response levels as the metric of a clinical importance response
• Compared change in 0-10 NRS measure over time to this standard
• Determined the clinically important change cut-off by calculating:–Sensitivity, specificity and accuracy–Receiver Operator Characteristic (ROC)
analysis
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Studies of Duloxetine
• Secondary analysis of 5 studies–Diabetic neuropathy – 3–Fibromyalgia – 2
• Total number of patients – 1600• Study period – 12 weeks• Pain measures – 0-10 NRS
–Worst, least, average• Patient global impression of change
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Impr
ovem
ent
BP
I Ave
rage
Pai
n P
erce
ntag
e C
hang
e S
core
-80-70-60-50-40-30-20-10
01020304050607080
Study 1: DPNPStudy 2: DPNPStudy 3: DPNPStudy 4: FMStudy 5: FM
-80-70-60-50-40-30-20-10
01020304050607080
Duloxetine (N=1077)Placebo (N=533)
-80-70-60-50-40-30-20-10
01020304050607080
Male (N=636)Female (N=974)
-80-70-60-50-40-30-20-10
01020304050607080
18-49 (N=434)50-59 (N=547)60-69 (N=431)70+ (N=198)
A B
C D
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
Very much worse/Much worse
A little worse
No change
A little better
Much better
Very much better
PGI CategoryPGI Category PGI CategoryPGI Category
PGI CategoryPGI Category PGI CategoryPGI Category
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Receiver Operator Response Curve Percentage Pain Intensity Difference
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Clinically Important ValuesBPI average
pain (N=1610)
Model BPI average
pain (N=1610)
BPI worst pain
(N=1612)
Raw change Very much better -3.5 -4.0
Raw change Much or very much better -2.5 -3.0
Raw change A little, much, or very much better -2.0 -2.0
Percentage change
Very much better -51% -51%
Percentage change
Much or very much better -34% -34%
Percentage change
A little, much, or very much better -23% -21%
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Part 1: Conclusion
• Patients use the 0-10 NRS scale primarily as a percent scale and is best analyzed as a percent change from baseline pain
• A 30-35% improvement on the 0-10 NRS pain intensity scale is a reasonable cut-off point for a clinically important change
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Two Groups Randomized:Both centered at 20% change at end of the study
0
2
4
6
8
10
12
14
16
-50%
-43%
-35%
-28%
-20%
-13% -5% 3% 10%
18%
25%
33%
40%
48%
55%
63%
70%
78%
85%
93%
100%
108%
115%
123%
130%
138%
145%
ControlCombined Treatment
Percent change from baseline
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Actually Bimodal Distribution
0
2
4
6
8
10
12
14
16
-50%
-43%
-35%
-28%
-20%
-13% -5% 3% 10%
18%
25%
33%
40%
48%
55%
63%
70%
78%
85%
93%
100%
108%
115%
123%
130%
138%
145%
ControlNon-RespondersCombined Treatment
Percent change from baseline
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Actually Bimodal Distribution
0
2
4
6
8
10
12
14
16
-50%
-43%
-35%
-28%
-20%
-13% -5% 3% 10%
18%
25%
33%
40%
48%
55%
63%
70%
78%
85%
93%
100%
108%
115%
123%
130%
138%
145%
ControlRespondersNon-RespondersCombined Treatment
Percent change from baseline
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0
2
4
6
8
10
12
14
16-0
.5
-0.4
-0.4
-0.3
-0.2
-0.1 -0
0.03 0.1
0.18
0.25
0.33 0.4
0.48
0.55
0.63 0.7
0.78
0.85
0.93 1
1.08
1.15
1.23 1.3
1.38
1.45
Control
Responders
Non-Responders
Combined Treatment
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Study Efficiency Mean vs Dichotomous Analysis
0
2
4
6
8
10
12
14
16
-50%
-43%
-35%
-28%
-20%
-13% -5
% 3% 10%
18%
25%
33%
40%
48%
55%
63%
70%
78%
85%
93%
100%
108%
115%
123%
130%
138%
145%
ControlRespondersNon-RespondersCombined Treatment
Efficiency = 1.145 (T-test N=30, Chi-sq N=26)Mean of Control Group and Low Probability Responders = 15% Mean of the Treated Group = 34%; Cut-off = 33%
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Group Mean Results – PIDOral Transmucosal Fentanyl Citrate (OTFC)
Pain Intensity Differences (with imputed values)
0
1
2
3
4
0 15 30 45 60
Minutes
Better^|||||||^
OTFCPlacebo
p<.001 at all time points
Farrar JT, et al Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. Journal of the National Cancer Institute 1998; 90(8): 611-6
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OTFC Study Outcomes: Relative Risk Comparison
At 60 minutes
PID >33% %Max TotPAR Relative Risk 1.89 1.56 Conf. Interval 1.59 – 2.17 1.30 – 1.93
p-value <0.0001 <0.0001
PR >1 Perf >1
Relative Risk 1.73 1.56 Conf. Interval 1.42 – 1.95 1.34 – 1.95
p-value <0.0001 <0.0001
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OTFC Looked at Density Plots
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Density Function
CumulativeDistributionFunction
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OTFC Placebo Proportion of Responders (at different cut off points - for 30 minutes)
Pro
porti
on o
f Res
pond
ers
Percentage Pain Intensity Difference
Cumulative Distribution of Responders Graph
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%Percent of Pain Intensity Difference
OTFC #1
Placebo
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Mean Value Does Not Provide a Unique Answer to the Clinical Question
• Mean value for the change in pain intensity over time is 10%. This would be observed if:
• 1) every patient in the treatment group improved by 10%, or
• 2) if 50% of the treatment group got better by 20% and 50% had no improvement, or
• 3) if 50% of the treatment group got better by 40% and 50% got worse by
20%.
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FDA Primary Data Analysis
• Data source–Neuropathic pain RCTs (n=15)– Indications
» Post-herpetic neuralgia (n=7)» Diabetic peripheral neuropathy (n=8)
–Pharmaceuticals» Pregabalin (n=11)» Gabapentin (n=2)» Duloxetine (n=2)
–Primary outcome measure» Change in 0-10 NRS pain score
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Representative Data
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Method
• Each RCT was analyzed using absolute and percent change of the mean pain score.
• List of the analytic methods compared for each trial for between group analyses (active treatment vs. placebo)– T-test– Wilcoxon rank sum test– Kolmogorov-Smirnov test – ROC based - AUC comparison– Ordinal logistic regression– Log rank
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T = T-test with equal varianceRS = Wilcoxon rank sum testROC = AUC comparison
KS = Kolmogorov-Smirnov OL = Ordinal logistic regressionLR = Log rank
T = RS ROC KS OL LR
pbo - - - - - -p150 0.2445 0.1865 0.1847 0.5362 0.2230 0.2664
rank 4 2 1 6 3 5p600 0.0003 0.0006 0.0003 0.0003 0.0011 0.0001
rank 2 5 4 3 6 16 7 5 9 9 6
pbo - - - - -p150 0.1542 0.1101 0.1071 0.2919 0.1055 0.0795
rank 5 4 3 6 2 1p600 0.0002 0.0003 0.0002 0.0005 0.0004 0.0000
rank 3 4 2 6 5 18 8 5 12 7 2
dif
total rank
pctchg
Test
total rank
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Rank Totals
T = T-test with equal varianceRS = Wilcoxon rank sum testROC = AUC comparisonKS = Kolmogorov-Smirnov OL = Ordinal logistic regressionLR = Log rank
T = RS ROC KS OL LR
rank totals 117 109 64 165 108 130
rank totals 105 127 79 156 99 125
Test
dif
pctchg
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Conclusions
• Tools for measuring pain have high inter-person variability and lower intra-person variability
• Mean values do not provide a unique answer to the clinical question of how many people get better
• Responder analysis accurately reflect the number of people in each treatment group that reach a level of change in that study
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Conclusions (cont)
• To the degree that the test group is an accurate representation of the general population the response rates in the treated group will reflect what the clinician is likely to see, regardless of the reason for the response.
• Both mean value and the responder analysis provide useful information and should be presented.
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THANK YOU
Research Group• Chris Rowan• Kevin Haynes• Andrea Troxel• Brian Strom• Rosemary Polomano
Additional Collaborators• Robert Dworkin• Dennis Turk• Nathaniel Katz• Michael Rowbotham• Russel Portenoy• John Messina• Michael Poole• Mitchell Max• Jesse Berlin