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3873S1_09_Lu

VIEWS: 3 PAGES: 19

									 Time-Specific Measurements
vs. Time-Weighted Average for
  Pain in Chronic and Acute
       Analgesia Trials


             Laura Lu, Ph.D
   Office of Biostatistics, CDER, FDA

               Analgesic ACM 7/29/02    1
                  Outline
• Time-specific measurements and time-
  weighted average (TWA)
• Issues in chronic analgesia trials
  – interpretation of drug benefit
  – data imputation
• Issues in acute analgesia trials
  – interpretation of drug benefit
  – data imputation
• Summary
                                         2
                                     Change from Baseline in Pain
Change from Baseline in Pain Score




                                     60


                                     40


                                     20



                                          0   2    4          8             12
                                                  Time Post-Randomization
                                                                                 3
                                     Change from Baseline in Pain
Change from Baseline in Pain Score




                                     60


                                     40


                                                            d2        d3           d4
                                     20            d1
                                              t1       t2        t3        t4
                                          0        2        4         8           12
                                                        Time Post-Randomization
                                                                                        4
   Time-Weighted Average
         (TWA)

           AUC
TWA=
     t1  t 2  t3  t 4
         =    d   w
     ti  ti 1
wi 
        2t
                           5
  Chronic Analgesia Trials

• Interpretation of drug benefit

• Data imputation



                                   6
          Drug Benefit
• End-of-the-trial (time-specific)
  measurement: drug effect at the end of
  the trial

• TWA: average effect through the trial

• Consistency of drug benefit over time

                                           7
Inconsistent Drug Effect




       Time
                           8
Imputation for Missing Values
• End of the trial measurements: last-
 observation-carried-forward (LOCF)
  – imputes measurement at withdrawal time to
    later period

• TWA: no imputation?
  – uses average treatment effect before
    withdrawal time to represent (impute)
    average effect in overall treatment period
                                                 9
   Imputation for Missing Value
                    (continued)

• Both methods imply assumptions: later
  evaluations of drug efficacy is similar to that
  of earlier evaluation.

• Results generally favor drug with imputation
  than without imputation due to different
  drop-out mechanisms in treatment groups
  (drop-out rates and drop-out reasons).
                                               10
            Improvement?
• Continuing efficacy evaluation even after a
  patient’s withdrawal can provide additional
  treatment information (ITT analysis).


• Responder analysis?
  – time to respond
  – percentage of responder
  – duration of response

                                           11
    Acute Analgesia Trials

• Interpretation of drug benefit

• Data imputation



                               12
           Drug Benefit
• Single-dose trial
  – onset
  – duration
  – pain curves


• Multiple-dose trial
  – duration of effect

                          13
               Drug Benefit
                   (continued)

• In single-dose trials, time specific pain
  measurements provide more information
  about onset and duration. TWA (SPID,
  SPRID) does not.

• In multiple-dose trials, time-specific
  measurements and TWA face similar issues
  as those in chronic analgesia trials.
                                              14
   Data Imputation for Time-
   Specific Measurements in
       Single-Dose Trial
• Last-observation-carried-forward
  (LOCF)

• Baseline-observation-carried-forward
  (BOCF)

• Worst-observation-carried-forward
  (WOCF)
                                         15
                         Observed Curves

                                             --- placebo
Pain Intensity




                                             __ testing drug




                 0



                     4     8    12     16   20     24
                               Hours
                                                           16
                 Observed and Imputed Curves

                                           --- placebo
Pain Intensity




                                           __ testing drug




                 0



                     4   8    12     16   20     24
                             Hours
                                                         17
             Summary
• Chronic analgesia trial:
  – end-of-the-trial measurement and TWA
    represent different aspects of drug effect
  – consistent drug benefit through the trial is
    important


• Acute analgesia trial: time-specific
  measurements are more informative than
  TWA (SPID, SPRID) in single-dose trials.
                                                   18
              Summary

• Continuing efficacy evaluation even after
  a patient’s withdrawal can provide
  additional treatment information for
  drug effect.

• Responder analysis

                                        19

								
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