Infectologia.edu.uy

Reporting of Noninferiority
and Equivalence Randomized Trials
An Extension of the CONSORT Statement
The CONSORT (Consolidated Standards of Reporting Trials) Statement, in-
cluding a checklist and a flow diagram, was developed to help authors im-
prove their reporting of randomized controlled trials. Its primary focus was
on individually randomized trials with 2 parallel groups that assess the pos-
sible superiority of one treatment compared with another but is now being
extended to other trial designs. Noninferiority and equivalence trials have
methodological features that differ from superiority trials and present par-
ticular difficulties in design, conduct, analysis, and interpretation. Although
dards of Reporting Trials(CONSORT) statement was the rationale for such trials occurs frequently, those designed and described
specifically as noninferiority or equivalence trials appear less commonly in
the medical literature. The quality of reporting of those that are published is
often inadequate. In this article, we present an adapted CONSORT check-
list for reporting noninferiority and equivalence trials and provide illustra-
tive examples and explanations for those items amended from the original
CONSORT checklist. The intent is to improve reporting of noninferiority and
recommendations for reportingRCTs, including a flowchart of par- equivalence trials, enabling readers to assess the validity of their results and
conclusions.
allel group trials,1-3 aiming to identifytreatment superiority if it really exists.
isting treatment. We use new to refer treatments and patients, although we ten called an active control.
lence trials. First, we explain the ratio- Author Affiliations: Statistics and Informatics Ser-
vices Group, Department of Reproductive Health andResearch, World Health Organization, Geneva, Swit- Rationale for Noninferiority
zerland (Dr Piaggio); Medical Statistics Unit, London or Equivalence Designs
School of Hygiene and Tropical Medicine, London (DrsElbourne and Pocock and Mr Evans) and Centre for Statistics in Medicine, Oxford (Dr Altman), England.
Corresponding Author: Gilda Piaggio, PhD, Depart-
ment of Reproductive Health and Research, World See also pp 1147 and 1172.
Health Organization, 1211 Geneva 27, Switzerland 1152 JAMA, March 8, 2006—Vol 295, No. 10 (Reprinted)
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equally effective and the alternative hy- pothesis is that they differ. A type I er- small.19,24 Given several previous trials, ror is falsely finding a treatment effect ority (⌬) for the treatment effect in a can be estimated from a meta-analysis.
treatment effect being between −⌬ and ⌬. True (2-sided) equivalence thera- the erroneous acceptance of an infe- ence.28,29peutic or prophylactic trials are rare be- Conduct. Trial conduct should
error is the erroneous rejection of a truly Design. A noninferiority or equiva-
ority, the question of interest is not sym- treatment’s efficacy is established20,21 or to respond, and treatment crossovers.
feriority trials but applies also to 2-sided lence trial should be similar to those in Analysis. Although a modified hy-
trial(s) that established the efficacy of ness,10,11 fewer side effects (harms),12 or greater ease of administration,13 for in- riority ⌬ and a null effect. Sample size desired power), and ⌬.22,23 A prestated often increase the risk of falsely claim- odds ratio, risk ratio, or hazard ratio.
vestigated for its equivalence to the stan- uses a “full analysis set” to describe smaller than the “clinically relevant” complete . . . and . . . close as possible” Methodological Issues
bias the trial in either direction.37 The in Noninferiority and
terms on-treatment or per-protocol analy- Equivalence Trials
Noninferiority and equivalence trials pre- sent particular difficulties in design, con- required size of noninferiority trials is Hypotheses. In a superiority trial the
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tection from ITT’s increase of type I er- pears superior,41 although this result is Interpretation. Interpreting a non-
caveats in noninferiority trials as it re- where the CI for the treatment effect lies FIGURE interprets several possible
periority trials. If noninferiority is es- gous, but both margins ⌬ and −⌬ need stop early because of lack of efficacy.19 priate test or CI (ie, not just the point trial, to expedite availability of the new ferior, then stopping the trial (or a par- riority post hoc from a superiority trialunless clearly related to a predefinedmargin of equivalence. That is, both su- Figure. Possible Scenarios of Observed Treatment Differences for Adverse Outcomes (Harms)
in Noninferiority Trials
periority and noninferiority hypoth-eses need explicit specification in the riority against reference treatment, some by also using evidence from earlier trials Such inferences assume assay con-stancy, ie, current and earlier trials are plies no differences in the effect of treat- (New Treatment Minus Reference Treatment) the absence of assay constancy, an ad-justment method has been pro- Error bars indicate 2-sided 95% confidence intervals (CIs). Tinted area indicates zone of inferiority. A, If the CIlies wholly to the left of zero, the new treatment is superior. B and C, If the CI lies to the left of ⌬ and includes zero, the new treatment is noninferior but not shown to be superior. D, If the CI lies wholly to the left of ⌬ and wholly to the right of zero, the new treatment is noninferior in the sense already defined, but it is also inferior efficacy of new treatment relative to pla- in the sense that a null treatment difference is excluded. This puzzling case is rare, since it requires a very largesample size. It can also result from having too wide a noninferiority margin. E and F, If the CI includes ⌬ and cebo require cautious interpretation.
zero, the difference is nonsignificant but the result regarding noninferiority is inconclusive. G, If the CI includes ⌬ and is wholly to the right of zero, the difference is statistically significant but the result is inconclusive re- How Common Are
garding possible inferiority of magnitude ⌬ or worse. H, If the CI is wholly above ⌬, the new treatment is in-ferior.22,43 Noninferiority and
*This CI indicates noninferiority in the sense that it does not include ⌬, but the new treatment is significantly Equivalence Trials?
worse than the standard. Such a result is unlikely because it would require a very large sample size.
†This CI is inconclusive in that it is still plausible that the true treatment difference is less than ⌬, but the new treatment is significantly worse than the standard.
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Checklist
defined aim of equivalence, a preset ⌬, tion, and actually testing equivalence.
checklist2,3 (TABLE), especially items 1
equivalence or noninferiority yielded term equivalence is often inappropri- results of superiority trials; such trials cant or “negative” results published in noninferiority trials is difficult because Title and Abstract
ies in a recent review of 188 cancer trials Title and Abstract: Item 1. How par-
ority or equivalence analysis.50 In a re- ized, or randomly assigned), specifying that the trial is a noninferiority or equiva- Title. “Oral Pristinamycin versus that whereas the objective of testing for Abstract. “Design—Multicentre, par- analyses, only 1 trial specified the mar- Introduction
Background: Item 2. Scientific back-
ground and explanation of rationale, in- Quality of Reporting
cluding the rationale for using a nonin- of Noninferiority and
Equivalence Trials
Example. “Up to 40 million chil- Extension of
fer from vitamin A deficiency. . . . A dose Consort Statement
as safe and potentially effective. . . . In pass the following issues: (1) the ratio- the term equivalence to mean either.
carotene. . . . Beta carotene is also con- sidered to be virtually non-toxic. . . . In there was a reversion of the clinical and nificant tests for superiority. Fifty-one fects interpretation and conclusions.
ciency in the study group. . . . Since beta specific changes, are described below.
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Table. Checklist of Items for Reporting Noninferiority or Equivalence Trials (Additions or Modifications to the CONSORT Checklist are Shown
in Italics)
Paper Section and Topic
Item Number
Descriptor (Adapted for Noninferiority or Equivalence Trials)
How participants were allocated to interventions (eg, “random allocation,” “randomized,” or “randomly assigned”), specifying that the trial is a noninferiority or equivalence trial. Scientific background and explanation of rationale, including the rationale for using a noninferiority or equivalence design.
Eligibility criteria for participants (detailing whether participants in the noninferiority or equivalence trial are similar to those in any trial[s] that established efficacy of thereference treatment) and the settings and locations where the data were collected.
Precise details of the interventions intended for each group, detailing whether the reference treatment in the noninferiority or equivalence trial is identical (or very similar)to that in any trial(s) that established efficacy, and how and when they were actuallyadministered.
Specific objectives and hypotheses, including the hypothesis concerning noninferiority or Clearly defined primary and secondary outcome measures, detailing whether the outcomes in the noninferiority or equivalence trial are identical (or very similar) tothose in any trial(s) that established efficacy of the reference treatment and, whenapplicable, any methods used to enhance the quality of measurements (eg, multipleobservations, training of assessors).
How sample size was determined, detailing whether it was calculated using a noninferiority or equivalence criterion and specifying the margin of equivalence withthe rationale for its choice. When applicable, explanation of any interim analyses andstopping rules (and whether related to a noninferiority or equivalence hypothesis).
Method used to generate the random allocation sequence, including details of any restriction (eg, blocking, stratification).
Method used to implement the random allocation sequence (eg, numbered containers or central telephone), clarifying whether the sequence was concealed until interventionswere assigned.
Who generated the allocation sequence, who enrolled participants, and who assigned Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. When relevant, how the success ofblinding was evaluated.
Statistical methods used to compare groups for primary outcome(s), specifying whether a 1- or 2-sided confidence interval approach was used. Methods for additionalanalyses, such as subgroup analyses and adjusted analyses.
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 theprimary outcome. Describe protocol deviations from trial as planned, together withreasons.
Dates defining the periods of recruitment and follow-up.
Baseline demographic and clinical characteristics of each group.
Number of participants (denominator) in each group included in each analysis and whether “intention-to-treat” and/or alternative analyses were conducted. State theresults in absolute numbers when feasible (eg, 10/20, not 50%).
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 theoutcome(s) for which noninferiority or equivalence is hypothesized, a figure showingconfidence intervals and margins of equivalence may be useful. Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those prespecified and those exploratory.
All important adverse events or side effects in each intervention group.
Interpretation of the results, taking into account the noninferiority or equivalence hypothesis and any other trial hypotheses, sources of potential bias or imprecisionand the dangers associated with multiplicity of analyses and outcomes.
Generalizability (external validity) of the trial findings.
General interpretation of the results in the context of current evidence.
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each group, detailing whether the refer- ence treatment in the noninferiority or equivalence trial is identical (or very simi- Elaboration. The rationale should cite lar) to that in any trial(s) that estab- lished efficacy, and how and when they Outcomes: Item 6. Clearly defined
Example. “[W]e randomly assigned sures, detailing whether the outcomes in the noninferiority or equivalence trial relative to placebo, they should be cited ceive 600 µg misoprostol orally or 10 IU are identical (or very similar) to those in with effect sizes and CIs. If no such trials any trial(s) that established efficacy of exist, other evidence for efficacy of the larly, according to practice. . . . The use reference treatment should be given.
of uterotonic agents [oxytocin, a type of ment, if present, should be given, to jus- tify use of the new treatment, if not in- and the need for blood transfusion . . . ”57 Example. “Over the past decade seven ferior. One aim of the current trial might dence. In the case of “me-too” drugs, overall reduction in the risk of death or tween the control intervention in the trial Participants: Item 3. Eligibility crite-
glycoprotein IIb/IIIa receptors is 38 per- ria for participants (detailing whether cent. Three glycoprotein IIb/IIIa inhibi- 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.
fer.27 Dose changes may occur: if the dose Example. “From Sept 1, 1992, to Dec of the reference treatment is reduced, it might result in reduced efficacy; if it is Elaboration. Any differences in out- increased, possibly leading to tolerabil- Objectives: Item 5. Specific objec-
tives and hypotheses, including the hy- pothesis concerning noninferiority or Example. “[A] bodyweight-adjusted min regimen of alteplase for efficacy and AIDS clinical events, then clinical events Elaboration. Relevant changes in par- ticipants’ characteristics compared with Sample Size: Item 7a. How sample
explained. Clinical trial participants dif- size was determined, detailing whether it was calculated using a noninferiority trials; therefore, such description should or equivalence criterion, and specifying the margin of equivalence with the ratio- might affect response to treatments).
Interventions: Item 4. Precise de-
studies, a primary event rate of 3.1% per 2006 American Medical Association. All rights reserved.
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enrolled. An increased rate of HIV trans- Both ⌬ and ␣ should be prespecified in mission associated with the shorter regi- tistical power with a 1-sided ␣ equal to Numbers Analyzed: Item 16. Num-
and whether “intention-to-treat” and/or year. . . . Assuming an average follow up Elaboration. It is customary to base alternative analyses were conducted. State interim stopping criteria on P values, and these adjusted P values are analo- Example. “Efficacy variables were Statistical Methods: Item 12. Sta-
rate in the control (heparin plus Gp IIb/ sis . . . and on an as-treated basis. In the for primary outcome(s), specifying whether a 1- or 2-sided confidence inter- val approach was used. Methods for ad- level of .05 and 3000 patients per group, Examples. Binary outcome. “The pro- trol [historical control] and a 92% power to satisfy noninferiority criteria relative Elaboration. The margin of noninfe- Outcomes and Estimation: Item 17.
ference, will be estimated using the time to first event . . . The noninferiority mar- cal grounds. Its relation to the effect of gin (⌬) defined in the primary analysis differences . . . Noninferiority of ximela- terval). For the outcome[s] for which non- gatran over warfarin will be accepted [in inferiority or equivalence is hypoth- a 0.025 level test] if the upper bound of esized, a figure showing confidence intervals and margins of equivalence may estimate of the difference between treat- low ⌬. For these studies, an absolute ⌬ Examples. Inferiority of new treat- ment, figure legend. “Relative risk of Continuous outcome. “Regimens were [0.74 and 1.35 on the relative scale].
(A figure similar to case G in the Figure sis of variance, with adjustment for cen- Stopping Rules: Item 7b. When ap-
Elaboration. The upper bound of the 1-sided (1 − ␣) ϫ 100% CI (or corre- whether related to a noninferiority or 2-sided (1 − ␣/2) ϫ 100% CI) for the Example. “Interim safety analyses treatment effect has to be below the mar- gin ⌬ to declare that noninferiority has been shown, with a significance level ␣.
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Financial Disclosures: None reported.
Funding/Support: No funding was received for writ-
ing this article, although Drs Altman, Elbourne, and Piaggio and Mr Evans were supported by the Concluding noninferiority of new drug CONSORT group to attend a meeting in Canada onthis topic. The wider CONSORT group commented from a trial designed to assess superiority. on earlier drafts and endorsed its submission for pub- lication. Dr Altman is supported by Cancer ResearchUnited Kingdom. Dr Piaggio is supported by the UNDP/ UNFPA/WHO/World Bank Special Programme of Re- search, Development and Research Training in Hu-man Reproduction, Department of Reproductive Health and Research, World Health Organization.
Elaboration. In the first example the Acknowledgment: We thank the members of the
CONSORT Group, especially David Moher, MSc,Thomas C. Chalmers Centre for Systematic Reviews, Children’s Hospital of Eastern Ontario, Ottawa; Ken Schulz, PhD, Quantitative Science, Family Health In-ternational, Research Triangle Park, NC; and Susan Eastwood, ELS, Publications and Grants Writing, De- partment of Neurological Surgery, University of Cali- fornia at San Francisco, Emeryville; Peter C. Gøtzsche,MD, Nordic Cochrane Centre, Copenhagen, Den- mark; Barbara Hawkins, PhD, Bloomberg School ofPublic Health, Johns Hopkins University, Baltimore, Md; Interpretation: Item 20. Interpreta-
Tom Lang, MA, Lakewood, Ohio; Ingram Olkin, PhD, Stanford University, Stanford, Calif; David L. Sackett, OC, FRSC, MD, FRCP, Trout Research and Educa-tion Centre, Markdale, Ontario; and David Simel, MD, hypothesis and any other trial hypoth- MHS, Duke University, Durham, NC, and Simon Day, PhD, Licensing Division, Medicines and HealthcareProducts Regulatory Agency, London, England, for cal.61 But even in cases for which a treat- comments on earlier drafts. We also thank Luciano Costa, MD, Division of Medical Oncology, Univer-sity of Colorado Health Science Center, Aurora, for Examples. Concluding noninferiority. “According to our definition of equiva- REFERENCES
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CORRECTIONS
Incorrect Formula: In the Special Communication entitled “Reporting of Nonin-
feriority and Equivalence Randomized Trials: An Extension of the CONSORTStatement” published in the March 8, 2006, issue of JAMA (2006;295:1152- 1160), a formula for a 2-sided confidence interval (CI) used to assess noninferi- ority of a new treatment compared with a standard one with regard to an out- come was incorrect. On page 1158 in the subsection titled “Elaboration” thatreads “the upper bound of the 2-sided (1−␣/2) ϫ100% CI for the treatment effect has to be below the margin ⌬ to declare that noninferiority has been shown . . . ” should read “the upper bound of the 2-sided (1 −2␣)ϫ100% CI for the treatment effect has to be below the margin ⌬ to declare that noninferi- Error in Figure: In the Original Contribution entitled “Long-term Renal Outcomes
in Patients With Primary Aldosteronism” published in the June 14, 2006, issue of 1842 JAMA, October 18, 2006—Vol 296, No. 15 (Reprinted)
2006 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 07/24/2012

Source: http://infectologia.edu.uy/images/stories/pdf/11_arv/may2013/may2013_jama_no_inferioridad_y_equivalencia.pdf