Question

You are on the Data Safety and Monitoring Board (DSMB) for a trial of a new drug (vs. standard medication) for the treatment of rheumatoid arthritis. You are participating in a DSMB meeting where an interim analysis is being reviewed and discussed.

The trial has enrolled about half of the total sample size. The primary endpoint is 8 week change-from-baseline in a measure of overall pain/disability. The sponsor chose an O’Brien-Fleming type I error spending function for the primary endpoint, and data are trending toward greater improvement in the new drug group, though not yet statistically significant at this interim analysis.

However, there is an emerging safety issue: there is an excess of pneumonia in the new drug arm (p-value = 0.03, uncorrected for type I error due to multiple tests of the data), and pneumonia is an unexpected adverse event. There was no pre-specified type I error spending function for pneumonia.

What do you recommend?

Keep in mind that one of the DSMB’s responsibilities is to monitor the integrity of the trial (is it still feasible to answer the primary question of interest on pain/disability). Another of the DSMB’s responsibilities is to monitor participant safety (has the risk/benefit ratio changed for persons enrolled in this trial, or for future users of the new medication if it receives regulatory approval). You could recommend stopping for safety, stopping for futility, continuing to the next scheduled interim analysis, continuing with more frequent interim analyses, instituting an ad hoc alpha spending rule for pneumonia, deferring the decision until you get more information on the severity of the pneumonias, etc. There is not one correct answer here!

Answer 1

*Incorrect answer is-
-you could recommend stopping for safety,stopping for futility,continuing to the next scheduled interim analysis,continuing with more frequent interim analyses,instituting an ad hoc alpa spending rule for pneumonia,diferr in the decision until you get more information on the severity of the pneumonia etc.

*Recommendations regarding modification of the design and conduct of the study could be-
-suspension or termination of the study or of one or more study arms because of serious concerns about subject's safety,inadequate performance or rate of enrollment.