# Presentation: 806133

## Challenges of Non-Inferiority Trial Designs

- R. Sridhara, Ph.D.

## Terminology

- Superiority
-     = Drug T better than  Placebo (P) or  	T better than Active Control (C)
- C may or may not have known efficacy
- Non-inferiority (NI)
-       = T not much less effective than C
-        ‘Was Not Different’ or ‘Similar’
- C must have known efficacy

- Pediatric Advisory Committe

- 12/6/06

## Clinical Trials to Demonstrate Efficacy

- Superiority Claim
- First choice
- Direct evidence
- Non-inferiority Claim
- Last choice
- Indirect evidence
- Interpretation could be misleading

- Pediatric Advisory Committe

- 12/6/06

## Non-inferiority Claim Implies:

- The effect of T and C are close
- T and C may be both equally beneficial or
- 	T and C may be both equally not beneficial

- Pediatric Advisory Committe

- 12/6/06

## Assumptions for NI consideration

- C has an effect (compared to placebo, P)
- Therefore, C can not be another experimental therapy in NI trial
- Can reliably estimate C effect size
-        * C effect size compared to P
- Control (C) effect in the future study population will be same as in the historical population.

- Pediatric Advisory Committe

- 12/6/06

## Non-inferiority Trial Design Considerations

- Endpoint  - Overall Survival
- 			 - Progression-free Survival
- 			 - Response Rate
- Control Effect
-  % Retention

- Pediatric Advisory Committe

- 12/6/06

## Non-inferiority or Superiority

- Challenges with Non-inferiority Trial
- How well we know the effect of the control
- How much of the control effect can we afford to give up
- At least ‘’% retention of the control effect necessary to make sure that the new treatment is significantly better than placebo

- Pediatric Advisory Committe

- 12/6/06

## Superiority trial designs with OS as the primary endpoint

- Null Hypothesis, H0: HR(T/C) = 1 vs.
- Alternative, H1: HR (T/C) < 1 if T is better than C

- Pediatric Advisory Committe

- 12/6/06

## Non-inferiority trial designs with OS as the primary endpoint

- H0: HR(T/C) ≥ M vs.
- H1: HR (T/C) = 1 if the two are expected to be similar, Or
- H1: HR(T/C) = 0.95, for example, if the new treatment (T)  is expected to be slightly better
- M is the margin determined based on the active control (C) effect size estimated from historical trials and percentage of the effect to be retained
- HR > 1 implies, T is worse than C

- Pediatric Advisory Committe

- 12/6/06

## Percent Retention and Estimated Active Control Effect Size

- Non-inferiority ≈ “not much less effective”
- ‘X’ is the effect size of the active control; example: Point estimate of HR (C/P) = 0.5 (or HR(P/C) = 2.0) implies an estimate of active control effect size was a 50% reduction in the risk of event (ex: death)
- Percent retention is a percentage of ‘X’ that is retained; example: a 50% retention of the 50% effect size is 25% effect size, i.e., the putative HR(T/P) = 0.75 (or HR(P/T) = 1.33)

- Pediatric Advisory Committe

- 12/6/06

## Estimates of True Control Effect

- Lower 95% C.L.
- ( << 0.025)

- Lower  % C.L.
- ( = 0.025)

- Point Estimate
- ( >> 0.025)

- Pediatric Advisory Committe

- 12/6/06

## Methods for estimating active control effect size: No method is ideal and no particular method is endorsed by the Agency

- All methods assume that the control effect has not changed over time
- Some methods do not consider the variation between and within studies
- Other methods incorporate variation between and within studies

- Pediatric Advisory Committe

- 12/6/06

## Hypothetical Example of a NI Trial with Overall Survival Endpoint

- Suppose HR(P/C) = 2.0                 					   (95% CI: 1.9, 2.1)
- Then, Lower 70% Confidence limit = 1.97

- Pediatric Advisory Committe

- 12/6/06

## Hypothetical example: Estimates of True Control Effect

- Lower 95% C.L. of HR = 1.9

- Lower 70% C.L. of HR: 1.97

- Point Estimate
- HR(P/C) = 2.0

- Pediatric Advisory Committe

- 12/6/06

## Hypothetical Example of a NI Trial with Overall Survival Endpoint

- Suppose we want to retain 50% of 1.97, i.e., HR(P/T) = 1.49, and we can accrue 100 patients per unit time
- If H1: HR(T/C) = 1, then N = 407 events or 1045 patients will be required
- If H1: HR(T/C) = 0.95, then N = 290 events or 836 patients

- Pediatric Advisory Committe

- 12/6/06

## Sample Size Depends On:

- How good the historical data is:
- One randomized study – large confidence interval – more uncertainty about the effect size
- Many randomized studies – smaller confidence interval – unless there were fundamental differences in the conduct of the studies: population, dose, etc.

- Pediatric Advisory Committe

- 12/6/06

## Summary - 1

- Superiority trials provide direct evidence
- New drug can be compared to placebo or control (established or not)
- Non-inferiority trials provide indirect evidence
- New drug must be compared to established control
- Interpretation can be misleading

- Pediatric Advisory Committe

- 12/6/06

## Summary - 2

- For NI trial consideration, active control effect must be well characterized
- Able to estimate effect size
- Control effect is same now as before
- NI trials are generally large
- Sample sizes for a NI trial is dependent on the estimate of control effect, population, % retention and the alternative hypothesis

- Pediatric Advisory Committe

- 12/6/06

## Summary - 3

- In considering NI trial, any potential loss of efficacy must be weighed against risk-benefit ratio
- Failed superiority does not imply non-inferiority

- Pediatric Advisory Committe

- 12/6/06