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Non-inferiority trials: a cautionary tale
F. Maignen (PharmD, MSc, MSc, GradStat)
November 2015
Before we start the presentationThree principles for the analysis of clinical trials:•Per protocol analysis: The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.•Intent-to-treat analysis: subjects allocated to a treatment group should be followed up, assessed and analysed as members of that group irrespective of their compliance to the planned course of treatment.•Assay sensitivity: Property of a clinical trial defined as the ability to distinguish an effective treatment from a less effective or ineffective treatment.
Clinical trials: different hypotheses
• Interventional clinical trials with different primary objectives
• The analysis of the trial will look at the treatment difference between the control and the tested treatment
H0 Control = Tested treatmentTested treatment – Control = 0
Ha Control ≠ Tested treatmentTested treatment – Control > 0
H0 │Treatment - Control │> Δ Ha │Treatment - Control │< ΔH0 Treatment – Control < - Δ Ha Treatment – Control > - Δ
Hypothesis testing
1. Superiority (difference)2. Equivalence3. Non-inferiority
H0 Control = Tested treatmentTested treatment – Control = 0
Ha Control ≠ Tested treatmentTested treatment – Control > 0
H0 │Treatment - Control │> Δ Ha │Treatment - Control │< ΔH0 Treatment - Control < - Δ Ha Treatment - Control > - Δ
Why non-inferiority trials?Superiority trials may not be feasible or inappropriate:•Ethical reasons: unethical to use a placebo arm•Practical reasons:
– superiority is unlikely or difficult to establish (sample size)– product of similar efficacy but has other advantages (e.g.
safety, me-toos, generics and biosimilars)– Inappropriate: dose-finding studies
Underlying idea of non-inferiority trials
• Superiority trials: absence of evidence is not evidence of absence (D. Altman)
• Misnomer: the tested product is less efficacious than the comparator in such a way that the loss of efficacy is not clinical relevant (i.e. not greater than a pre-specified non-inferiority margin –Δ)
• Non-inferiority = hypothesis testing NOT a design. A trial can include both or a switch between superiority and non-inferiority testing (e.g. dose-finding study or pivotal trial in a sense or another).
Non-inferiority trials: interpretation
0-Δ
Analysis: Tested product - Control
Tested productmore efficacious thancomparator
Tested productless efficaciousthan comparator
Non-inferiority trials: interpretation
Analysis: Tested product - Control
0-Δ
Non-inferiority trials: interpretation
Tested productclinically inferiorto comparator
Analysis: Tested product - Control
0-Δ
Tested productnon-inferiorto comparator
Non-inferiority trials: interpretation
0-Δ
One-sided?
Two-sided?
Non-inferiority: interpretation
0-Δ
Non-inferiority: interpretation
0-Δ
Non-inferioritynot shown
Non-inferiorityshown
Superiority
Bonus
0-Δ Δ
Equivalence shown
Equivalence not shown
Equivalence not shown
What are the pitfalls when conducting non-inferiority trials?
Consider impact of protocol deviations and lack of compliance on the hypothesis testing:
H0 Control = Tested treatment Ha Control ≠ Tested treatment
H0 Treatment - Control < - Δ Ha Treatment - Control > - Δ
Protocol deviations and poor compliance
Tested product(superior)
Control
Control
Tested product(inferior)
Superiority testing
Non-inferiority testing
What are the pitfalls when conducting non-inferiority trials?
Therefore protocol deviations and lack of compliance will:
H0 Control = Tested treatment Ha Control ≠ Tested treatment
H0 Treatment - Control < - Δ Ha Treatment - Control > - Δ
Superiority: favour H0Reject an “effective” product
Non-inferiority: favour HaAccept a “less effective” product
Assay sensitivity
• In superiority trials: (assuming that error rate is controlled) the fact that a difference of efficacy between treatments is observed in a proof of sensitivity of the trial
• Therefore, intention-to-treat analysis is CONSERVATIVE in superiority trials.
• It is not the case in non-inferiority trials.
Golden rules of non-inferiority trials
• The trial must be appropriately conducted and protocol deviations must be avoided i.e. the intention-to-treat and the per protocol analyses must give identical results
• Treatment compliance must be (measured and) ensured.
Methodological aspects• The non-inferiority margin must be pre-
specified (numerous rules and guidelines exist) IN ALL CASES (even when switching hypotheses).
• Assay sensitivity should be checked– Direct or indirect evidence that the control is
showing usual efficacy– Comparing the trial with earlier trials which
demonstrated the efficacy of the control– Compliance, ITT, PP.
Non-inferiority: relative treatment effect
0-Δ
Non-inferiority
Superiority
ReadingSwitching between superiority and non-inferiority. British Journal Clinical Pharmacology, 52, 219-228.ICH E10 (www.ich.org)BMJ Endgames (P. Sedgwick) on non-inferiority. -BMJ 2011;342:d3253 doi: 10.1136/bmj.d3253-BMJ 2013;347:f6853 doi: 10.1136/bmj.f6853Analysis by intention to treat BMJ 2011;342:d2212 doi: 10.1136/bmj.d2212Analysis by per protocol BMJ 2011;342:d2330 doi: 10.1136/bmj.d2330
