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.
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
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.
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
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.