NONINFERIORITY TRIALS

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].

DiNubile MJ. Noninferior antibiotics: When is not bad good enough?

Open Forum Infectious Disease. 2016.
NULL HYPOTHESES
What does it mean?
Where can it be used?
Placebo controlled trials
Active controlled trials
NULL VS ALTERNATIVE
HYPOTHESIS
 CONCEPTS IN NONINFERIORITY
TRIAL DESIGN
Null and alternative hypotheses of noninferiority trials are
reversed from superiority trials
Superiority trials
Null hypothesis
there is no difference between interventions
Alternative hypothesis
there is a difference between interventions, but the differences
might not be clinically meaningful
good enough concept
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
NONINFERIORITY
MARGIN
INTERPRETATION OF CONFIDENCE
INTERVALS IN SUPERIORITY TRIALS
 INTERPRETATION OF CONFIDENCE
INTERVALS IN EQUIVALENCY TRIALS
 INTERPRETATION OF CONFIDENCE
INTERVALS IN NONINFERIORITY TRIALS
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
Kaji AH, et al. JAMA. 2015;313(23):2371-2372.
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
DiNubile MJ. Noninferior antibiotics: When is not bad good enough? Open Forum Infectious
Disease. 2016.
DiNubile MJ. Noninferior antibiotics: When is not bad good enough? Open Forum Infectious
Disease. 2016.
ANALYSIS POPULATIONS
Geisler WM, et al. NEJM. 2015;373(26):2512-2521.
Lee CH, et al. JAMA. 2016;315(2):142-149.
Lee CH, et al. JAMA. 2016;315(2):142-149.
Lee CH, et al. JAMA. 2016;315(2):142-149.
Lee CH, et al. JAMA. 2016;315(2):142-149.
 SYSTEMATIC BIASES IN
NONINFERIORITY TRIALS
Some biases that protect against type I error (i.e., finding no
difference) in superiority trials may promote type I error in
noninferiority trials
Noninferiority trials can show that treatments are equally
effective or equally ineffective
Assay sensitivity is the assumption that both the active
control and investigational drugs would be superior to
placebo had placebo been included in the trial
 SYSTEMATIC BIASES IN
NONINFERIORITY TRIALS
The assumption that the effect of the gold standard
comparator is the same during the noninferiority trial as it
was in early trials is termed the constancy assumption
If the effect changes over time, the conclusion of
noninferiority may be affected
Example: a gold standard comparator that is now less
effective makes it easier to find a comparator noninferior
 SYSTEMATIC BIASES IN
NONINFERIORITY TRIALS
Intention-to-treat analyses make comparator groups
appear to have more similar outcomes
This increases the chance of concluding noninferiority
May promote type I error
Per-protocol analysis results should be reported in
noninferiority trials
Differences in conclusions between intention-to-treat and
per-protocol analyses raise concern for bias
NONINFERIORITY
TO SUPERIORITY
Schernthaner G, et al. Diabetes Care. 2013;36(9):2508-2515.
Schernthaner G, et al. Diabetes Care. 2013;36(9):2508-2515.
Mounsey A, et al. J Fam Pract. 2014;63(3):E4-E8.
TIME FOR MORE
EXAMPLES
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Dryden M, et al. J Antimicrob Chemother 2016;71:3575
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Plapler PG, et al. Drug Design Develop Ther. 2016;10:1987
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Wagenlehner FM, et al. Clin Infect Dis. 2016:63754.
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
Salminen P, et al. JAMA 2015;313:2340
ASSIGNED ARTICLE
Full Evaluation
Barrera CM, et al. Lancet Infect Dis. 2015;16:421.
 WHAT DO YOU NEED TO KNOW
BEFORE YOU EVALUATE THIS STUDY?

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 WHY DID THEY
DO THE STUDY?

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 KEY QUESTIONS

Type of study?
Type of analysis?
Meaningful outcome?
Good methodology?
Enough patients?

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 RANDOMIZATION,

CONCEALED ALLOCATION

&

BLINDING

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.
WHY THE DOUBLE-DUMMY
DESIGN?
 INCLUSION & EXCLUSION CRITERIA

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 ADHERENCE

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 TYPE OF ANALYSIS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 PRIMARY ENDPOINT(S)

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 SECONDARY ENDPOINTS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 STATISTICS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.
 MISSING DATA

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 PATIENT
DEMOGRAPHICS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 SENSITIVITY ANALYSIS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 RESULTS:
PRIMARY ENDPOINT

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 ADVERSE REACTIONS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 LIMITATIONS

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.

 SO WHAT CAN BE CONCLUDED
FROM THIS STUDY?

Barrera CM, et al. Lancet Infect Dis. 2015;16:421.