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Is the Large Simple Trial Design Used for Comparative, Post-Approval Safety Research?

A Review of a Clinical Trials Registry and the Published Literature

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Abstract

Post-approval, observational drug safety studies face well known difficulties in controlling for confounding, particularly confounding by indication for drug use. A study design that addresses confounding by indication is the large simple trial (LST). LSTs are characterized by large sample sizes, often in the thousands; broad entry criteria consistent with the approved medication label; randomization based on equipoise, i.e. neither physician nor patient believes that one treatment option is superior; minimal, streamlined data collection requirements; objectively-measured endpoints (e.g. death, hospitalization); and follow-up that minimizes interventions or interference with normal clinical practice. In theory then, the LST is a preferred study design for drug and vaccine safety research because it controls for biases inherent to observational research while still providing results that are generalizable to ‘real-world’ use.

To evaluate whether LSTs are used for comparative safety evaluation and if the design is, in fact, advantageous compared with other designs, we conducted a review of the published literature (1949 through 31 December 2010) and the ClinicalTrials.gov registry (2000 through 31 December 2010). Thirteen ongoing or completed safety LSTs were identified. The design has rarely been used in comparative drug safety research, which is due to the operational, financial and scientific hurdles of implementing the design. The studies that have been completed addressed important clinical questions and, in some cases, led to re-evaluation of medical practice. We conclude the design has demonstrated utility for comparative safety research of medicines and vaccines if the necessary scientific and operational conditions for its use are met.

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Acknowledgements

Robert Reynolds, Joanna Lem and Nicolle Gatto are employed by Pfizer, Inc. Sybil Eng is a former employee of Pfizer. All authors are shareholders of Pfizer. Pfizer has sponsored two LSTs described in this article (ZODIAC and VOLUME) and has funded the SCOT Study through an Investigator-Initiated Research (IRR) grant. Robert Reynolds and Sybil Eng represented Pfizer during open meeting sessions of the external ZODIAC Scientific Steering Committee and Data Safety Monitoring Board. Nicolle Gatto represented Pfizer during open meeting sessions of the external VOLUME Scientific Steering and Data Monitoring Committees and previously represented Pfizer as a non-voting observer during open meetings of the independent SCOT Executive Steering Committee. The views expressed are those of the authors and are not necessarily those of Pfizer. The authors thank the drug safety experts who responded to the query regarding safety LSTs.

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Authors and Affiliations

  1. Department of Epidemiology, Pfizer, Inc., 235 E 42nd St, MS 150/3/04, New York, New York, 10017, USA

    Robert F. Reynolds (ScD), Joanna A. Lem & Nicolle M. Gatto

  2. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

    Robert F. Reynolds (ScD) & Nicolle M. Gatto

  3. Global Health Insights, LLC, Montclair, NJ, USA

    Sybil M. Eng

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  1. Robert F. Reynolds
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Reynolds, R.F., Lem, J.A., Gatto, N.M. et al. Is the Large Simple Trial Design Used for Comparative, Post-Approval Safety Research?. Drug-Safety 34, 799–820 (2011). https://doi.org/10.2165/11593820-000000000-00000

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