Julious, Steven A

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Julious Steven A

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The ABC of non-inferiority margin setting: an investigation of approaches

Steven A Julious

Springer - Publisher Connector

POSTER PRESENTATION Open Access
The ABC of non-inferiority margin setting: an
investigation of approaches
Steven A Julious
From Clinical Trials Methodology Conference 2011
Bristol, UK. 4-5 October 2011
Objectives
To assess the efficacy of a new investigative treatment a
non-inferiority study is undertaken when it is no longer
ethical to have a placebo control. Instead an active con-
trolled trial is undertaken. The objective is thus to show
that the new treatment is no worse than the active
control.
In analysing a non-inferiority trial, the following ABC
needs to be considered [1]:
1. The Assay sensitivity of the active control in both
the placebo controlled trials and in the active controlled
non-inferiority trial is the same.
3. Bias is minimised through steps such as ensuring
that the patient population and the primary efficacy
endpoint are essentially the same for the placebo-con-
trolled trial and the active-controlled trial.
2. Constancy assumption of the effect of the common
comparator. Such that for two trials in sequence: Trial 1
and Trial 2 the control effect of Treatment B vs. Placebo
in Trial 1 is assumed to be the same as the control
effect of Treatment B vs. ‘Placebo’ in Trial 2
This presentation will describe how this ABC can be
considered.
Methods
A major issue in designing a non-inferiority study is the
setting of the non-inferiority limit. The Food and Drug
Administration (FDA) discuss setting a limit so it would
be possible to demonstrate superiority over placebo.
This comparison would need to be done indirectly as
placebo is not given concurrently. A margin could be
set for non-inferiority therefore which will enable super-
iority to placebo to be demonstrated
The European regulators discuss surveying experts to
quantify the margin. An approach that uses both the
objective observed data and subjective opinion to set a
non-inferiority margin would useful which lends to
Bayesian approaches.
Results
There is an issue with indirect comparisons if they are
done retrospectively as the effect over placebo may not
be as great today as when a placebo controlled trial was
last undertaken [2]. The presentation will give a number
of examples where the effect of treatment has fallen
over time. This is known as placebo creep and could
bias the estimate of effect over placebo. Comparison will
be made of simple indirect and Bayesian approaches to
set non-inferiority margins
Conclusions
When making indirect comparison over time to deter-
mine a non-inferiority margin, if there is a suspicion of
placebo creep then the simple ABC for setting a margin
may fail and approaches such as a simple Bayesian
approach may need to be considered.
Published: 13 December 2011
References
1. Julious SA: The ABC of non-inferiority margin setting from indirect
comparisons. Pharmaceutical Statistics 2011, DOI: 10.1002/pst.517.
2. Julious SA, Wang SJ: Issues with indirect comparisons in clinical trials
particularly with respect to non-inferiority trials. DIJ 2008, 42(6):625-33.
doi:10.1186/1745-6215-12-S1-A34
Cite this article as: Julious: The ABC of non-inferiority margin setting:
an investigation of approaches. Trials 2011 12(Suppl 1):A34.
Julious Trials 2011, 12(Suppl 1):A34
http://www.trialsjournal.com/content/12/S1/A34 TRIALS
© 2011 Julious; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.


Crossref

Issues with indirect comparisons in clinical trials particularly with respect to non-inferiority trials. DIJ

The ABC of non-inferiority margin setting from indirect comparisons. Pharmaceutical Statistics

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The ABC of non-inferiority margin setting: an investigation of approaches

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