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CCEB The Analysis and Interpretation of Pain Clinical Trial Outcomes: Enhancing Understanding John T. Farrar, MD, PhD University of Pennsylvania.

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Presentation on theme: "CCEB The Analysis and Interpretation of Pain Clinical Trial Outcomes: Enhancing Understanding John T. Farrar, MD, PhD University of Pennsylvania."— Presentation transcript:

1 CCEB The Analysis and Interpretation of Pain Clinical Trial Outcomes: Enhancing Understanding John T. Farrar, MD, PhD University of Pennsylvania

2 CCEB Surrogate Outcomes Only three “real” outcomes BirthBirth DeathDeath Quality of lifeQuality of life

3 CCEB Changing the State of the Brain What do you see?

4 CCEB Why Do We Care RCTs - important for most medical therapyRCTs - important for most medical therapy Did not need an RCT for introduction of penicillinDid 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 controvertialCorollary – if you identify the right group, measurement and design issues statistics will be less controvertial

5 CCEB Outline of the Presentation Measurement must be appropriateMeasurement must be appropriate Handling of missing data is importantHandling of missing data is important Part 1: How do patients report painPart 1: How do patients report pain Part 2: AnalysisPart 2: Analysis Part 3: InterpretationPart 3: Interpretation

6 CCEB Pain is a Subjective Experience No “objective” direct measureNo “objective” direct measure Not easy to relate to an underlying neurologic process in an individualNot easy to relate to an underlying neurologic process in an individual Depend on subjects to accurately report their experienceDepend on subjects to accurately report their experience Creates inter-person variation in the reporting of pain that is unavoidableCreates inter-person variation in the reporting of pain that is unavoidable Creates observer discomfort about the validity of the measureCreates observer discomfort about the validity of the measure

7 CCEB Pain Measures - Intensity Scales 0__1__2__3__4__5__6__7__8__9__10 0__1__2__3__4__5__6__7__8__9__10 |____________________________________________| |____________________________________________| | | Least Worst | | Least Worst None Mild Moderate Severe Excruciating  Intra-person reliability – Good Inter-person reliability – Poor

8 CCEB How do Patients Decide If a Treatment is Useful Does the treatment make my symptoms better now?Does the treatment make my symptoms better now? Are there any side-effects?Are there any side-effects? Is the pain relief “good enough”?Is the pain relief “good enough”? >>>> Am I better overall? >>>> Am I better overall? >>>> Should I take something else?

9 CCEB Global Rating of Quality of Life Overall how would you rate your quality of life: over the last ______: Worst Best It can be it can be

10 CCEB 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 Much Better A little better No change

11 Another View on Scales

12 CCEB How Do Patients Use a Numeric Scale (Acute Pain) Study data: Randomized clinical trial of oral trans-mucosal fentanyl versus placeboStudy data: Randomized clinical trial of oral trans-mucosal fentanyl versus placebo Method: Re-analysis of data set stratified on baseline pain intensity scoreMethod: Re-analysis of data set stratified on baseline pain intensity score Population: 89 cancer pain patients with acute breakthrough painPopulation: 89 cancer pain patients with acute breakthrough pain Results =>Results =>

13 CCEB Data Collection Instrument BaselineBaseline –Pain Intensity 1_2_3_4_5_6_7_8_9_10 At 15, 30, 45 and 60 minutesAt 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________Second rescue medication - Time________ –Overall Performance »0 (none) 1(slight) 2(moderate) 3(lots) 4(complete)

14 CCEB Raw Change in Pain Intensity Compared to Global Performance Scale Global Performance Scale

15 CCEB Percent Change in Pain Intensity Compared to Global Performance Scale Global Performance Scale

16 CCEB How Do Patients Use a Numeric Scale (Chronic Pain) Study data - RCTs of pregabalin in multiple diseasesStudy data - RCTs of pregabalin in multiple diseases Method – Compared measured pain intensity (0-10 NRS) and patients global impression of change (PGIC)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).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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19 CCEB Clinically Important Differences for the 0-10 NRS Used the global response levels as the metric of a clinical importance responseUsed the global response levels as the metric of a clinical importance response Compared change in 0-10 NRS measure over time to this standardCompared change in 0-10 NRS measure over time to this standard Determined the clinically important change cut-off by calculating:Determined the clinically important change cut-off by calculating: –Sensitivity, specificity and accuracy –Receiver Operator Characteristic (ROC) analysis

20 CCEB Studies of Duloxetine Secondary analysis of 5 studiesSecondary analysis of 5 studies –Diabetic neuropathy – 3 –Fibromyalgia – 2 Total number of patients – 1600Total number of patients – 1600 Study period – 12 weeksStudy period – 12 weeks Pain measures – 0-10 NRSPain measures – 0-10 NRS –Worst, least, average Patient global impression of changePatient global impression of change

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22 CCEB Receiver Operator Response Curve Percentage Pain Intensity Difference

23 Clinically Important Values

24 CCEB 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 painPatients 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 changeA 30-35% improvement on the 0-10 NRS pain intensity scale is a reasonable cut-off point for a clinically important change

25 CCEB Two Groups Randomized: Both centered at 20% change at end of the study Percent change from baseline

26 CCEB Actually Bimodal Distribution Percent change from baseline

27 CCEB Actually Bimodal Distribution Percent change from baseline

28 CCEB

29 CCEB Study Efficiency Mean vs Dichotomous Analysis Efficiency = (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%

30 CCEB Group Mean Results – PID Oral Transmucosal Fentanyl Citrate (OTFC) 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

31 CCEB OTFC Study Outcomes: Relative Risk Comparison At 60 minutes

32 OTFC Looked at Density Plots

33 Density Function Cumulative Distribution Function

34 CCEB OTFC Placebo Proportion of Responders (at different cut off points - for 30 minutes) Proportion of Responders Percentage Pain Intensity Difference Cumulative Distribution of Responders Graph

35 CCEB 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%.

36 CCEB FDA Primary Data Analysis Data sourceData 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

37 Representative Data

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40 CCEB Method Each RCT was analyzed using absolute and percent change of the mean pain score.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)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

41 T = T-test with equal variance RS = Wilcoxon rank sum test ROC = AUC comparison KS = Kolmogorov-Smirnov OL = Ordinal logistic regression LR = Log rank

42 CCEB Rank Totals T = T-test with equal variance RS = Wilcoxon rank sum test ROC = AUC comparison KS = Kolmogorov-Smirnov OL = Ordinal logistic regression LR = Log rank

43 CCEB Conclusions Tools for measuring pain have high inter- person variability and lower intra-person variabilityTools 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 betterMean 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 studyResponder analysis accurately reflect the number of people in each treatment group that reach a level of change in that study

44 CCEB 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.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.Both mean value and the responder analysis provide useful information and should be presented.

45 CCEB THANK YOU Research Group Chris RowanChris Rowan Kevin HaynesKevin Haynes Andrea TroxelAndrea Troxel Brian StromBrian Strom Rosemary PolomanoRosemary Polomano Additional Collaborators Robert DworkinRobert Dworkin Dennis TurkDennis Turk Nathaniel KatzNathaniel Katz Michael RowbothamMichael Rowbotham Russel PortenoyRussel Portenoy John MessinaJohn Messina Michael PooleMichael Poole Mitchell MaxMitchell Max Jesse BerlinJesse Berlin


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