1. Non-Inferiority Exposed: Uses and Abuses
Ajay J. Kirtane, MD, SM
Center for Interventional Vascular Therapy
Columbia University Medical Center /
New York Presbyterian Hospital

2. Ajay J. Kirtane, MD Off-Label: Data-driven
I/we have no real or apparent conflicts of interest to report.
Off-Label: Data-driven

3. Why perform a non-inferiority trial?
New therapy may offer important advantages over currently available effective therapies
Improved safety
Better tolerability/fewer side effects
Ease of use (2nd generation DES, QD drug, etc.)
Less expensive
Increased market competition (?)
Placebo control trial unethical but still want to demonstrate that the new treatment is better than nothing (“putative placebo”) approach
Adapted from D. Cohen

4. Basic Clinical Trial Designs
Non-Inferiority
Increasingly common as it gets harder and harder to demonstrate incremental gains over successful therapies
Particularly in EBM-rich fields (Cardiology) where we have many effective therapies already
Non-inferiority designs are especially common with device and drug iterations
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5. Basic Clinical Trial Designs
Non-Inferiority: Endpoints
Endpoint selection for non-inferiority trials is similar to that of trials assessing a traditional superiority design
Surrogate endpoint (e.g. late loss)
Clinical endpoint (e.g. rate of target vessel failure)
The choice of endpoint will affect the clinical applicability of the trial
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6. Basic Clinical Trial Designs
A Non-Inferiority Trial
1000 patients randomized to DES A or DES B
50 clinical restenosis events with DES A; 50 with DES B
Basic non-inferiority question: What is the probability that DES B could be worse than DES A?
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7. Basic Clinical Trial Designs
Non-Inferiority Explained
In order to define “worse”, we first need to figure out how much “worse” we are willing to accept
This is defined as the non-inferiority “delta” or “margin” and is almost always ARBITRARY
Let’s set it at 20% for this example
Thus, we want to be sure (or at least 95% confident) that DES B is not 20% worse than DES A
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8. Basic Clinical Trial Designs
Non-Inferiority: Choice of a Delta
The choice of “delta” is the most critical aspect of a non-inferiority trial
This affects not only whether the trial is “positive” or “negative” but more importantly relates to the clinical relevance of the trial findings
The best-chosen deltas reflect a clinical (not statistical) focus
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9. Possible Non-Inferiority Results
Superior
Non-inferior
Non-inferior
Non-inferior?
Inconclusive
Inconclusive
Inconclusive?
Inferior ∆
Relative Risk (or Treatment Difference) with 95% CI
← New Treatment Better New Treatment Worse →

10. Selecting a non-inferiority margin
Critical to pre-specify the non-inferiority margin to avoid Type I error (false positive results)
Potential approaches
Clinical rationale expert opinion (“what is the maximum difference you would tolerate?”)
Regulatory rationale based on previous trials
Statistical + Clinical rationale designed to preserve some minimum proportion of benefit vs. placebo (“putative placebo” approach)
Rule of thumb: Margin cannot be greater than the smallest effect size that the active comparator would be expected to have vs. placebo
Key Point
When reading about a non-inferiority trial, always check the non-inferiority margin
If the margin is “too wide”, the trial results are questionable no matter how strong the p-value
c/o D. Cohen

11. Basic Clinical Trial Designs
Non-Inferiority: DES A vs. DES B
Back to the example (1000 patient study of two DES):
DES A is the gold standard with a TLR rate of 10% (50/500)
DES B is being tested, and has a 10% TLR rate as well (50/500)
The delta is set at 20% (relative)
We will accept DES B as non-inferior to DES A if the upper limit of the confidence interval of the TLR rate of DES B is not 20% worse than the TLR rate of DES A
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12. Basic Clinical Trial Designs
Non-Inferiority: DES A vs. DES B
In a prospective randomized trial this is calculated using relative or absolute risk:
The upper limit of the confidence interval of the relative risk of TLR with DES B (compared to DES A) should not be greater than 1.2
This is essentially the same as demanding that the upper limit of the confidence interval of the difference in TLR rates with DES B (compared to DES A) should not be greater than 2%
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13. DES B vs. DES A: Risk Difference
but upper CI is 3.7%
Inconclusive Results (technically negative trial) 2%
Risk Difference with 95% CI
← DES A Better DES B Worse →

14. Basic Clinical Trial Designs
Non-Inferiority: DES A vs. DES B
Even though the rates of TLR were identical with both stents, we cannot claim non-inferiority at this sample size!
How could we have designed the trial to allow DES B to be non-inferior?
Larger delta (40% relative delta)
Greater sample size
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15. Basic Clinical Trial Designs
Non-Inferiority: DES A vs. DES B
With a 10% rate of TLR in both arms:
Total N
DES A
DES B
Risk
Difference
Upper 95% CI of Risk Difference
500
10%
= 0
5.2%
1000
3.7%
1500
3.0%
2000
2.6%
4000
1.8%
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16. Basic Clinical Trial Designs
Non-Inferiority: DES A vs. DES B
With a 10% rate of TLR with DES A and a 9% rate with DES B, the sample size would have gone down
With a 10% rate of TLR with DES A and a 11% rate with DES B, the sample size would have gone up astronomically
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17. Basic Clinical Trial Designs
Non-Inferiority: Basic Principles Apply
Tighter deltas prevent “inconclusive results” but make it harder to be declared non-inferior
Wider deltas and larger sample sizes make it easier to be declared non-inferior, but larger sample sizes with a wide delta may also result in inconclusive results
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18. Comparator Creep BMS DES 1 DES 2 DES 3 DES 4 Restenosis Rate
c/o D. Cohen

19. Data Quality/Trial Conduct
In a superiority trial, the sponsor has a strong incentive to minimize errors in trial conduct and measurement, since these errors would bias the trial results toward the null
In a non-inferiority trial, the incentives are reversed
Key issues in trial conduct that can bias toward a finding of “non-inferiority”
Enrolling a low risk population unlikely to benefit from either treatment
Non-compliance and crossover
Insensitive outcome measure
Loss to follow-up
Most important practical and theoretical issue with non-inferiority trials
c/o D. Cohen

20. Basic Clinical Trial Designs
Non-Inferiority: Summary
Increasingly common
Always look at the raw event rates and confidence intervals, and ask whether these rates make sense
In some cases, the p-values are less relevant than the actual rates
Watch for deltas that do not make clinical sense, and beware of “creep”
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