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OBJECTIVES
Define the purpose of noninferiority trials.
List reasons for conducting noninferiority trials.
Describe the null hypothesis and alternative hypothesis specific to
noninferiority trials.
Analyze the establishment of a noninferiority margin for
appropriateness.
Interpret the meaning of confidence intervals.
Compare ITT and PP populations in terms of noninferiority trials vs
RCTs.
Identify characteristics of trial design that introduce bias in
noninferiority trials and describe their effect on results and
conclusions.
Appropriately interpret results of a noninferiority trial
NONINFERIORITY
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
REASONS
Unethical to use placebo
Worth potential decrease in efficacy
WHAT TYPE OF TRADE OFFS ARE
YOU WILLING TO ACCEPT?
Differences in:
Efficacy?
Dosing?
Route of administration?
Decreased pill burden?
Adverse effects?
Monitoring requirements?
Drug interactions?
Cost?
REASONS FOR NONINFERIORITY
TRIAL DESIGN
Potentially compromised efficacy may be a favorable
trade-off for
Patients
Less drug monitoring
Easier drug administration
Investigators
Smaller sample-size requirement
Depends on the size of noninferiority margin
Comparison to placebo is unethical
ISSUES
Cannot assess drug efficacy only similarity to control
May need a larger sample size to detect a small
difference
Gold standard ITT can produce false results in a
noninferiority study
Serial application of noninferiority margins could
theoretically lead to creeping erosion of the control
referent if each standard bearer is progressively
(albeit slightly) less active than its predecessor [9]. The
size of the beneficial effect over placebo could then
shrink toward the null over time as new
comparators replace the prior standard [16, 18].
Type of study?
Type of analysis?
Meaningful outcome?
Good methodology?
Enough patients?
CONCEALED ALLOCATION
&
BLINDING