Statistical approaches to group sequential monitoring of postmarket safety surveillance data: current state of the art for use in the Mini-Sentinel pilot

• Published in: Pharmacoepidemiology and drug safety 2012-01, Vol.21 (S1), p.72-81
• Main Authors: Cook, Andrea J., Tiwari, Ram C., Wellman, Robert D., Heckbert, Susan R., Li, Lingling, Heagerty, Patrick, Marsh, Tracey, Nelson, Jennifer C.
• Format: Article
• Language: English
• Subjects: Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records - statistics & numerical data; group sequential monitoring; Humans; incident user cohort; Models, Statistical; observational study; Outcome Assessment (Health Care); Pilot Projects; postmarket; Product Surveillance, Postmarketing - methods; Prospective Studies; Regression Analysis; signal refinement; surveillance; United States; United States Food and Drug Administration
• ISSN: 1053-8569; 1099-1557
• DOI: 10.1002/pds.2320

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.