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BMC Med. 2018 Mar 21;16(1):45. doi: 10.1186/s12916-018-1023-9.

Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study.

Author information

1
Collaboration for Research Integrity and Transparency (CRIT), Yale Law School, 157 Church Street, 17th Floor, Suite 1, New Haven, CT, 06510, USA. joshua.wallach@yale.edu.
2
Center for Outcomes Research and Evaluation (CORE), Yale-New Haven Hospital, 1 Church Street, Suite 200, New Haven, CT, 06510, USA. joshua.wallach@yale.edu.
3
Evidence Synthesis and Modelling for Health Improvement, Institute of Health Research, University of Exeter Medical School, South Cloisters, St. Luke's Campus, Heavitree Road, Exeter, EX1 2LU, UK.
4
Center for Research on Health and Social Care Management, SDA Bocconi, via G. Roentgen, 1 - 20136, Milan, Italy.
5
Department of Surgery, Beth Israel Deaconess Medical Center, Lowry Medical Office Building, 110 Francis Street, Suite 9B, Boston, MA, 02215, USA.
6
Collaboration for Research Integrity and Transparency (CRIT), Yale Law School, 157 Church Street, 17th Floor, Suite 1, New Haven, CT, 06510, USA.
7
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, 60 College Street, P.O. Box 208034, New Haven, CT, 06520-8034, USA.
8
Center for Outcomes Research and Evaluation (CORE), Yale-New Haven Hospital, 1 Church Street, Suite 200, New Haven, CT, 06510, USA.
9
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06520-8092, USA.
10
Department of Health Policy and Management, Yale School of Public Health, 60 College Street, New Haven, CT, 06510, USA.
11
Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, P.O. Box 208093, New Haven, CT, 06520-8093, USA.

Abstract

BACKGROUND:

The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product's actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication.

METHODS:

We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials.

RESULTS:

Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01-2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15-0.16).

CONCLUSIONS:

Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers.

KEYWORDS:

Lifecycle evaluation; Outcomes; Regulation; Surrogate markers; U.S. Food and Drug Administration (FDA)

PMID:
29562926
PMCID:
PMC5863466
DOI:
10.1186/s12916-018-1023-9
[Indexed for MEDLINE]
Free PMC Article

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