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Superiority-Equivalence-Non-Inferiority Trials:
           What does it all mean?
                  Gerald Gartlehner
What decision-makers want to know

 Is the new treatment
  better than the
  established one ?

 If not, is it equally
  effective and preferable
  for some other reason



Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Overview

           Definitions and concepts
           Challenges of non-inferiority trials
           What does this mean for systematic reviews?
           Language considerations for comparative
            effectiveness reviews




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Proving Efficacy

 1. Showing superiority of one
    (new) treatment over
    another (placebo or active)

 2. Showing equivalence or non-
    inferiority of a new
    intervention relative to an
    already existing efficacious
    treatment

Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
The interpretation of non-inferiority and
                     equivalence can be confusing




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Ranking position: 72




Ranking position: 34
Gerald Gartlehner
Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Superiority game: the winner takes it all….




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Equivalence game – equally good or clearly
                             better
  Equivalence margin: tied or less than 1 goal
   difference




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Non-inferiority game– at least not substantially
                        worse….
   Non-inferiority margin: can‘t lose with more
    than 1 goal difference




                                                                                              Gerald Gartlehner
Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Definitions

 Superiority trial
          Objective: To determine a clinically relevant difference
          between two interventions
 Equivalence trial
          Objective: To determine whether a (new) intervention is
          neither worse nor better than another (established)
          intervention
 Non-inferiority trial
          Objective: To determine whether a (new) intervention is not
          inferior to another (established) intervention
Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Equivalence - Non-Inferiority
             The naïve approach:
              If a head-to-head trial shows no statistically significant
               difference, two interventions are “equivalent”
              Problem – underpowered studies or high variance will
               create “equivalent” treatments

             The statistical approach:
              Define a margin of non-inferiority or equivalence
              If 95% confidence interval of the difference DOES NOT
               cross the margin, the new intervention is non-inferior or
               equivalent

Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Arthroscopy vs. sham arthoscopy in patients
                  with knee osteoarthritis
                                                    favors sham                        favors arthroscopy


                                                                                                   MID




                                        20                   10                 0             10         20
                                        Knee Specific Pain Scale: difference in points

                        Mosley et al. New England J Med, 2002;347:81-88

Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Non-inferiority margin (d)


 The limit of acceptable inferiority:
 Minimal important difference
 Clinical judgement
 Statistical considerations



Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Determining the non-inferiority margin
                             statistically



Standard vs. placebo
2 points (1.5 to 2.5)


New vs. standard




                           2           1         0

                        Maximimum non-inferiority margin: dmax = 1.5
                        Fractional preservation of treatment effect: f = 0.5
                        d = dmax x (1 – f)
                        d = 1.5 x ( 1 – 0.5) = 0.75
Peculiar issues of non-inferiority trials: the
                   backwardness

Null hypothesis and alternative hypothesis are
 reversed
Type I and type II errors are reversed
Per-protocol analyses can be more important than
 ITT analysis (ITT analyses are biased towards finding
 no difference)
P-value is one-sided (0.025)
Assay Sensitivity and Constancy Assumption



        The ability of a trial to distinguish effective from
        ineffective treatments (depends on the effect size
        the trial wants to detect).




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Assay Sensitivity

Assumptions in non-inferiority trials:

 The efficacy of the active control was preserved in
  the non-inferiority study (i.e. that it had assay
  sensitivity).
 If it was not, equivalence or non-inferiority
  conclusions are meaningless (The non-inferior drug
  could have no effect at all).
Constancy Assumption


 Active comparator must be well established and have
  predictable and consistent treatment effects
 Participants must be similar to those in trial
  establishing efficacy
 Outcomes must be similar to those in trials
  establishing efficacy
Biocreep
                                             Effective treatment




                                                                                     Still clinically relevant?


                                        2                   1                   0




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                                      Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Key Points for critical appraisal

Was a non-inferiority margin defined based on
 clinical considerations and statistical reasoning?
Was it established a priori?
Was the study powered based on the non-inferiority
 margin?
Was an ITT and a per-protocol analysis conducted?
Was the trial design (e.g. eligibility criteria)
 consistent with placebo controlled trials of the
 established treatment?
What does this mean for systematic reviews ?

   For meta-analyses – data can be used just as
    from any superiority trial

   For qualitative assessments – language
    considerations




Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Language considerations

 “..there was no statistically significant difference
    between A and B..”
  “..studies failed to show a difference..”
 Can mean:
 1) The evidence shows equivalence
 2) The evidence is inconclusive (because confidence
      intervals are wide-lack of precision)

 AHRQ guidance: Assessing equivalence and non-inferiority [draft]

Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Language considerations

 Better:
 “..treatments A and B had similar mortality rates..”

 Expressing non-inferiority:

 “…treatment A is at least as effective as treatment B for
   [Outcome or study objective]…”




 AHRQ guidance: Assessing equivalence and non-inferiority [draft]
Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at                                  Gerald Gartlehner
Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
Do we need to establish equivalence
        margins for CERs ?

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Superiority, non-inferiority, equivalence studies - what is the difference?

  • 1. Superiority-Equivalence-Non-Inferiority Trials: What does it all mean? Gerald Gartlehner
  • 2. What decision-makers want to know Is the new treatment better than the established one ? If not, is it equally effective and preferable for some other reason Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 3. Overview  Definitions and concepts  Challenges of non-inferiority trials  What does this mean for systematic reviews?  Language considerations for comparative effectiveness reviews Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 4. Proving Efficacy 1. Showing superiority of one (new) treatment over another (placebo or active) 2. Showing equivalence or non- inferiority of a new intervention relative to an already existing efficacious treatment Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 5. The interpretation of non-inferiority and equivalence can be confusing Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 7. Gerald Gartlehner Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 8. Superiority game: the winner takes it all…. Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 9. Equivalence game – equally good or clearly better  Equivalence margin: tied or less than 1 goal difference Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 10. Non-inferiority game– at least not substantially worse….  Non-inferiority margin: can‘t lose with more than 1 goal difference Gerald Gartlehner Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 11. Definitions Superiority trial Objective: To determine a clinically relevant difference between two interventions Equivalence trial Objective: To determine whether a (new) intervention is neither worse nor better than another (established) intervention Non-inferiority trial Objective: To determine whether a (new) intervention is not inferior to another (established) intervention Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 12. Equivalence - Non-Inferiority The naïve approach:  If a head-to-head trial shows no statistically significant difference, two interventions are “equivalent”  Problem – underpowered studies or high variance will create “equivalent” treatments The statistical approach:  Define a margin of non-inferiority or equivalence  If 95% confidence interval of the difference DOES NOT cross the margin, the new intervention is non-inferior or equivalent Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 13. Arthroscopy vs. sham arthoscopy in patients with knee osteoarthritis favors sham favors arthroscopy MID 20 10 0 10 20 Knee Specific Pain Scale: difference in points Mosley et al. New England J Med, 2002;347:81-88 Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 14. Non-inferiority margin (d) The limit of acceptable inferiority: Minimal important difference Clinical judgement Statistical considerations Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 15. Determining the non-inferiority margin statistically Standard vs. placebo 2 points (1.5 to 2.5) New vs. standard 2 1 0 Maximimum non-inferiority margin: dmax = 1.5 Fractional preservation of treatment effect: f = 0.5 d = dmax x (1 – f) d = 1.5 x ( 1 – 0.5) = 0.75
  • 16. Peculiar issues of non-inferiority trials: the backwardness Null hypothesis and alternative hypothesis are reversed Type I and type II errors are reversed Per-protocol analyses can be more important than ITT analysis (ITT analyses are biased towards finding no difference) P-value is one-sided (0.025)
  • 17. Assay Sensitivity and Constancy Assumption The ability of a trial to distinguish effective from ineffective treatments (depends on the effect size the trial wants to detect). Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 18. Assay Sensitivity Assumptions in non-inferiority trials:  The efficacy of the active control was preserved in the non-inferiority study (i.e. that it had assay sensitivity).  If it was not, equivalence or non-inferiority conclusions are meaningless (The non-inferior drug could have no effect at all).
  • 19. Constancy Assumption  Active comparator must be well established and have predictable and consistent treatment effects  Participants must be similar to those in trial establishing efficacy  Outcomes must be similar to those in trials establishing efficacy
  • 20. Biocreep Effective treatment Still clinically relevant? 2 1 0 Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 21. Key Points for critical appraisal Was a non-inferiority margin defined based on clinical considerations and statistical reasoning? Was it established a priori? Was the study powered based on the non-inferiority margin? Was an ITT and a per-protocol analysis conducted? Was the trial design (e.g. eligibility criteria) consistent with placebo controlled trials of the established treatment?
  • 22. What does this mean for systematic reviews ? For meta-analyses – data can be used just as from any superiority trial For qualitative assessments – language considerations Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 23. Language considerations “..there was no statistically significant difference between A and B..” “..studies failed to show a difference..” Can mean: 1) The evidence shows equivalence 2) The evidence is inconclusive (because confidence intervals are wide-lack of precision) AHRQ guidance: Assessing equivalence and non-inferiority [draft] Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 24. Language considerations Better: “..treatments A and B had similar mortality rates..” Expressing non-inferiority: “…treatment A is at least as effective as treatment B for [Outcome or study objective]…” AHRQ guidance: Assessing equivalence and non-inferiority [draft] Österreichische Cochrane Zweigstelle (ÖCZ) ∙ www.cochrane.at Gerald Gartlehner Department für Evidenzbasierte Medizin und Klinische Epidemiologie, Donau-Universität Krems
  • 25. Do we need to establish equivalence margins for CERs ?

Editor's Notes

  1. For example: The null hypothis becomes the alternative hypothesisType I error becomes type II error and vice versaITT is suddenly not as good as per protocol analysesThere is some backwardness that can be very confusing – so I tried to come up with a simple analogy to capture the basic concepts of superiority-non-inferiority –and equivalence and I ended up with soccer: