Reporting of Noninferiority Trials in ClinicalTrials.gov and Corresponding Publications

Noninferiority clinical trials are designed to determine whether an intervention is not inferior to a comparator by more than a prespecified difference, known as the noninferiority margin. Selection of an appropriate margin is fundamental to noninferiority trial validity, yet a point of frequent ambiguity.^1,2 Given the increasing use of noninferiority trial designs, maintaining high standards for conduct and reporting is a priority.^3,4 Publicly accessible trial registries and results databases promote transparency and accountability by requiring specification of research designs and end points and disclosure of summary results.^1,5

To better understand reporting of noninferiority trials, we examined registration records and results posted on ClinicalTrials.gov, as well as their corresponding publications, for information about the noninferiority margin and statistical analyses, and determined their association with trial and journal characteristics.

Because ClinicalTrials.gov does not require registration of noninferiority-specific information, we searched Ovid MEDLINE for noninferiority trials published between January 2012 and June 2014 using keywords pertaining to noninferior and equivalence, limited to English-language publications. We then selected publications reporting primary analyses of noninferiority trials indexed with a ClinicalTrials.gov identifier, excluding publications without trial registration (n = 163) or registered in other registries (n = 97). For each trial, we abstracted details on trial design (including specification and justification of the noninferiority margin) and results (including reporting of noninferiority statistical analyses) from both ClinicalTrials.gov (searched during July and August 2014) and corresponding publications.

We used χ² tests to compare reporting by trial sponsor, condition, location, intervention, trial design characteristics, and journal impact factor (Table), with a 2-sided type I error level of 0.006 to account for multiple comparisons. Analyses were performed using JMP version 10.0.0 (SAS Institute Inc).

We identified and characterized 344 unique trials registered on ClinicalTrials.gov, published in 338 articles (6 described multiple trials) that reported primary results of noninferiority trials (Table). Consistent with our search strategy, all publications described noninferiority designs and nearly all (n = 340 trials; 98.8%) provided noninferiority margins. However, any justification for choosing margins was provided for only 95 (27.6%). The most commonly cited reasons were previous research (including historical data and meta-analyses) (n = 46) and reliance on expert opinion or clinical judgment (n = 43).

In contrast, on ClinicalTrials.gov, approximately one-quarter (n = 99, 28.8%) described noninferiority designs, among which 15 (4.4% of total) specified noninferiority margins, 9 of which (2.6% of total) were prespecified at initial registration. The ClinicalTrials.gov and published margin values were concordant for all 15.

Nearly all publications reported noninferiority analyses and results (n = 342, 99.4%). On ClinicalTrials.gov, 129 (37.5%) had posted summary results, among which 76 (22.1% of total) reported that noninferiority analyses were performed and provided appropriate confidence intervals or P values to interpret results.

On ClinicalTrials.gov, industry-sponsored trials were less likely to register noninferiority designs compared with nonindustry-sponsored trials (22.9% [95% CI, 17.7%-29.0%] vs 38.1% [95% CI, 30.3%-46.5%], respectively; P = .002), but were more likely to provide results with appropriate details of noninferiority analyses (33.3% [95% CI, 27.3%-40.0%] vs 4.5% [95% CI, 2.1%-9.4%], respectively; P < .001). Location, intervention, masking, and enrollment also were associated with providing results with appropriate details (Table).

This cross-sectional analysis of noninferiority trials published between 2012 and 2014 demonstrated near-complete reporting of noninferiority designs and margins within our sample of publications, but not justification for choosing margins. However, voluntary reporting of noninferiority designs and margins in corresponding ClinicalTrials.gov records was suboptimal, consistent with prior research.⁶ Moreover, among trials with results reported on ClinicalTrials.gov, more than one-third provided insufficient information to interpret noninferiority analyses.

The study was limited to a sample of recently published noninferiority trials registered on ClinicalTrials.gov. Even though ClinicalTrials.gov does not provide specific registration data elements for specifying noninferiority trial designs, it does provide specific elements for reporting noninferiority results. Nevertheless, modifications may improve reporting and temper the possibility of post hoc distortion of design and margins, facilitating transparency and accountability for noninferiority trial conduct.

Our findings raise concerns about the adequacy of noninferiority trial registration and results reporting within publicly accessible trial registries and highlight the need for continued efforts to improve its quality.

Corresponding Author: Joseph S. Ross, MD, MHS, Section of General Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520 (joseph.ross@yale.edu).

Author Contributions: Mr Gopal and Dr Ross had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Gopal, Desai, Ross.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gopal, Ross.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gopal, Ross.

Obtained funding: Tse, Ross.

Administrative, technical, or material support: Desai, Tse.

Study supervision: Ross.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tse reported being an employee of the National Institutes of Health and a program analyst for ClinicalTrials.gov. Dr Ross reported receiving support from Medtronic Inc and Johnson & Johnson to develop methods of clinical trial data sharing, from the Centers for Medicare & Medicaid Services to develop and maintain performance measures that are used for public reporting, and from the US Food and Drug Administration to develop methods for postmarket surveillance of medical devices. No other disclosures were reported.

Funding/Support: Dr Ross is supported by the National Institute on Aging (grant K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. Dr Tse is supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health.

Role of the Funder/Sponsor: None of the sponsors had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Rebecca J. Williams, PharmD, MPH (National Library of Medicine), for her comments on an earlier draft of the manuscript. Dr Williams was not compensated for her contributions to this work.