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Keywords:

  • incident user cohort;
  • observational study;
  • postmarket;
  • group sequential monitoring;
  • signal refinement;
  • surveillance

ABSTRACT

Purpose

This manuscript describes the current statistical methodology available for active postmarket surveillance of pre-specified safety outcomes using a prospective incident user concurrent control cohort design with existing electronic healthcare data.

Methods

Motivation of the active postmarket surveillance setting is provided using the Food and Drug Administration's Mini-Sentinel Pilot as an example. Four sequential monitoring statistical methods are presented including the Lan–Demets error spending approach, a matched likelihood ratio test statistic approach with the binomial MaxSPRT as a special case, the conditional sequential sampling procedure with stratification, and a generalized estimating equation regression approach using permutation. Information on the assumptions, limitations, and advantages of each approach is provided, including how each method defines sequential monitoring boundaries, what test statistic is used, and how robust it is to settings of rare events or frequent testing.

Results

A hypothetical example of how the approaches could be applied to data comparing a medical product of interest, drug A, to a concurrent control drug, drug B, is presented including providing the type of information one would have available for monitoring such drugs.

Summary

We have described the current state of methodology for postmarket surveillance of pre-specified safety outcomes. We describe the limitations and advantages of the approaches while acknowledging areas for future development. Copyright © 2012 John Wiley & Sons, Ltd.