Analgesic ACM 7/29/021 Time-Specific Measurements vs. Time-Weighted Average for Pain in Chronic and Acute Analgesia Trials Laura Lu, Ph.D Office of Biostatistics, CDER, FDA

2 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

3 Change from Baseline in Pain Change from Baseline in Pain Score Time Post-Randomization

4 Change from Baseline in Pain Change from Baseline in Pain Score Time Post-Randomization t1t1 t2t2 t3t3 t4t4 d1d1 d2d2 d3d3 d4d4

5 Time-Weighted Average (TWA) TWA= =

6 Chronic Analgesia Trials Interpretation of drug benefit Data imputation

7 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

8 Inconsistent Drug Effect Time

9 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

10 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).

11 Improvement? Continuing efficacy evaluation even after a patients withdrawal can provide additional treatment information (ITT analysis). Responder analysis? –time to respond –percentage of responder –duration of response

12 Acute Analgesia Trials Interpretation of drug benefit Data imputation

13 Drug Benefit Single-dose trial –onset –duration –pain curves Multiple-dose trial –duration of effect

14 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.

15 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)

16 Observed Curves 0 Pain Intensity --- placebo __ testing drug Hours

17 Observed and Imputed Curves 0 Pain Intensity --- placebo __ testing drug Hours

18 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.

19 Summary Continuing efficacy evaluation even after a patients withdrawal can provide additional treatment information for drug effect. Responder analysis