AMA Manual of Style (10th edition ed.) : A Guide for Authors and Editors

AMA Manual of Style Committee

Publisher:: Oxford University Press

Print Publication Date:: Mar 2007

Print ISBN-13:: 9780195176339

Published to AMA Manual of Style:: Apr 2009

DOI:: 10.1093/jama/9780195176339.001.0001

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Equivalence and Noninferiority Trials

Chapter:: Study Design and Statistics
Author(s):: Margaret A. Winker,
Stephen J. Lurie

20.2.3 Equivalence and Noninferiority Trials

It is sometimes desirable to compare a less expensive treatment or intervention against a treatment or intervention that is already known to be effective. In these cases, it would be unethical to expose participants to an inactive placebo. Thus, these trial designs assess whether the treatment or intervention under study (the “new intervention”) is no worse than an existing alternative (the “active control”).

In equivalence and noninferiority trials, authors must prespecify a margin of noninferiority (Δ), within which the new intervention can be assumed to be no worse than the active control. There are a number of methods for arriving at the value Δ. Because different methods of estimating Δ may be more defensible in some situations than others, authors should provide clear explanations of their method and rationale for arriving at their value for Δ. Noninferiority trials test the 1-sided hypothesis that the effect of the new intervention is no more than Δ units less than the active control. Equivalence trials, which are less common than noninferiority trials, test the 2-sided hypothesis that the effect of the new treatment lies within the range of Δ to −Δ.

Although use of intention-to-treat (ITT) analysis is optimal in trials that test whether one treatment is superior to another, use of such analysis can bias the results of equivalence and noninferiority trials. Thus, in addition to ITT analysis, authors should report results for only participants who completed the trial.

Interpretation of the results depends on the confidence interval for the difference between the new intervention and the active placebo, and whether this confidence interval crosses Δ, −Δ, and 0. See Table 2.

Table 2. Checklist of Items for Reporting Noninferiority or Equivalence Trials (Additions or Modifications to the CONSORT Checklist Are Indicated in Footnotes)^a

Paper Section and Topic	Item No.	Noninferiority or Equivalence Trials
Title and abstract	1^b	How participants were allocated to interventions (eg, “random allocation,” “randomized,” or “randomly assigned”), specifying that the trial is a noninferiority or equivalence trial.
Introduction Background	2^b	Scientific background and explanation of rationale, including the rationale for using a noninferiority or equivalence design.
Methods Participants	3^b	Eligibility criteria for participants (details whether participants in the noninferiority or equivalence trial are similar to those in any trial(s) that established efficacy of the reference treatment) and the settings and locations where the data were collected.
Interventions	4^b	Precise details of the intervention intended for each group, detailing whether the reference treatment in the noninferiority or equivalence trial are identical (or very similar) to that in any trial(s) that established efficacy, and how and when they were actually administered.
Objectives	5^b	Specific objective and hypotheses, including the hypothesis concerning noninferiority or equivalence.
Outcomes	6^b	Clearly defined primary and secondary outcome measures, detailing whether the outcomes in the noninferiority or equivalence trial are identical (or very similar) to those in any trial(s) that established efficacy of the reference treatment and, when applicable, any methods used to enhance the quality of measurements (eg, multiple observations, training of assessors).
Sample size	7^b	How sample size was determined, detailing whether it was calculated using a noninferiority or equivalence criterion and specifying the margin of equivalence with the rationale for its choice. When applicable, explanation of any interim analysis and stopping rules (and whether related to a noninferiority or equivalence hypothesis).
Randomization Sequence generation	8	Method used to generate the random allocation sequence, including details of any restriction (eg, blocking, stratification).
Allocation concealment	9	Method used to implement the random allocation sequence (eg, numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned.
Implementation	10	Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups.
Blinding (masking)	11	Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. When relevant, how the success of blinding was evaluated.
Statistical methods	12^b	Statistical methods used to compare groups for primary outcome(s), specifying whether a 1- or 2-sided confidence interval approach was used. Methods for additional analyses, such as subgroup analyses and adjusted analyses.
Results Participant flow	13	Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the trial protocol, and analyzed for the primary outcome. Describe protocol deviations from trial as planned, together with reasons.
Recruitment	14	Dates defining the periods of recruitment and follow-up.
Baseline data	15	Baseline demographic and clinical characteristics of each group.
Numbers analyzed	16^a	Number of participants (denominator) in each group included in each analysis and whether “intention-to-treat” and/or alternative analyses were conducted. State the results in absolute numbers when feasible (eg, 10 of 20, not 50%).
Outcomes and estimation	17^a	For each primary and secondary outcome, a summary of results for each group and the estimated effect size and its precision (eg, 95% confidence interval). For the outcome(s) for which noninferiority or equivalence is hypothesized, a figure showing confidence intervals and margins of equivalence may be useful.
Ancillary analyses	18	Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those prespecified and those exploratory.
Adverse events	19	All important adverse events or side effects in each intervention group.
Comment Interpretation	20^a	Interpretation of the results, taking into account the noninferiority or equivalence hypothesis and any other trial hypotheses, sources of potential bias or imprecision, and the dangers associated with multiplicity of analyses and outcomes.
Generalizability	21	Generalizability (external validity) of the trial findings.
Overall evidence	22	General interpretation of the results in the context of current evidence.

a From Piaggio et al.¹⁰

b Expansion of corresponding item on CONSORT checklist.⁴^,¹¹

Authors should refer to specific CONSORT guidelines for reporting the design and results of equivalence and noninferiority trials.¹⁰

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AMA Manual of Style Committee

Equivalence and Noninferiority Trials

Margaret A. Winker,

Stephen J. Lurie

20.2.3 Equivalence and Noninferiority Trials