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Health Care Policy and Law
January 2019

Assessment of Pregabalin Postapproval Trials and the Suggestion of Efficacy for New Indications: A Systematic Review

Author Affiliations
  • 1Studies of Translation, Ethics, and Medicine, Biomedical Ethics Unit, McGill University, Montreal, Quebec, Canada
  • 2School of Public Health, University of California, Berkeley, Berkeley
  • 3Departments of Psychology and Anesthesia, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada
  • 4Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
JAMA Intern Med. 2019;179(1):90-97. doi:10.1001/jamainternmed.2018.5705
Key Points

Question  How often do pregabalin (Lyrica) trials for new indications generate a suggestion of efficacy that is not confirmed by rigorous trials?

Findings  In this systematic review of 238 pregabalin trials for nonapproved indications, a large proportion of indications (63% [17 of 27]) potentially generated uncertainty about the efficacy of pregabalin that was not addressed in confirmatory trials within 5 years.

Meaning  After initial approval, exploratory trial evidence suggesting the value of pregabalin for new indications often went unconfirmed for extended periods of time; this suggestion of efficacy may encourage uptake in off-label prescription and/or clinical practice guidelines.


Importance  After a drug receives regulatory approval, researchers often pursue small, underpowered trials, called exploratory trials, aimed at testing additional indications. If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug’s clinical value (clinical agnosticism). Such findings may encourage the off-label use of ineffective drugs.

Objective  To characterize the relationship between exploratory and confirmatory postapproval trials for the blockbuster drug, pregabalin (Lyrica).

Evidence Review  Ovid MEDLINE and Embase databases were used to identify clinical trials published prior to January 2018 and that tested the efficacy of pregabalin for nonapproved indications. Indications, trial outcomes, publication dates, and trial design elements were recorded. Time elapsed was calculated between the generation of clinical agnosticism about pregabalin (ie, publications reporting positive or inconclusive evidence of efficacy on a primary endpoint) and it being addressed (publication of at least 1 confirmatory trial in the same indication, regardless of outcome).

Findings  There were 238 trials identified that tested the efficacy of pregabalin in at least 33 indications; 5 indications eventually received European Medicines Agency and/or US Food and Drug Administration marketing approval. Sixty-seven percent (22 of 33) of first publications for new indications may have generated clinical agnosticism. Of those indications with at least 5 years of follow-up, 63% (17 of 27) may have generated agnosticism that was not addressed in confirmatory trials within 5 years. As pregabalin development expanded from indications that received regulatory approval to other indications, the linkage of exploratory to confirmatory trial publication diminished.

Conclusions and Relevance  After initial approval, exploratory evidence suggesting the value of pregabalin for new indications often went unconfirmed for extended periods of time. Poor coordination between exploratory and confirmatory testing may represent an important vehicle through which off-label prescription is recommended in clinical practice guidelines and encouraged in the absence of confirmatory trial evidence.

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