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David J. Graham, MD,MPH; Carol R. Drinkard, MPH,PhD; Deborah Shatin, PhD; Yi Tsong, PhD; Margaret J. Burgess

JAMA. 2001;286:831-833.

Context  Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000.

Objective  To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone.

Design, Setting, and Participants  Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations.

Main Outcome Measures  Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims.

Results  Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use.

Conclusions  The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

Author Affiliations: Office of Postmarketing Drug Risk Assessment (Dr Graham) and Office of Biostatistics (Dr Tsong), Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Md; and Center for Health Care Policy and Evaluation, UnitedHealth Group, Minneapolis, Minn (Drs Drinkard and Shatin and Ms Burgess).

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