# Presentation: 647432

## Issues Regarding

**Choice of the Margin**
**in Non-Inferiority Trials**
- February 19, 2002
- Thomas R. Fleming, Ph.D.
*Professor and Chair of Biostatistics*
*University of Washington*

- FDA Anti-Infective Drugs Advisory Committee

## Dual Goal of Non-Inferiority Trials

- 	•  To enable a direct evaluation
-        		 of the clinical efficacy
- 	       		 of EXP relative to A.C.
- 	•  To contribute evidence to
-        		 the evaluation of efficacy
- 	       		 of EXP relative to PLA

## Factors Influencing  the Choice of Margin

- and Interpretation of NI Trial Results

- •  Clinical Relevance of Changes in:
- 	       Benefits,  Risks/Tolerance,
- 			  Convenience,  Resistance,  etc.
- •  Active Control Effect
- •  Quality of the Design & Conduct
- 					of the NI Trial

## Factors Influencing Choice of Margin

- • *Clinical Relevance of Changes in:*
*	**       **Benefits,  Risks/Tolerance, *
*	**	**	**  **Convenience,  Resistance,  etc.*
-   Clinical importance of:
- 	- reduction in efficacy by 
- 	- altered safety/tolerance profile
- 	- altered convenience of administration
- 	- altered resistance or drug/drug interactions

## Factors Influencing Choice of Margin

## *

- Factors Influencing Choice of Margin

-   ***PLA ******–****** AC  Cure Rate***

*****

**(**

**)**

**  –**45%    **–**35%    **–**25%   **–12.5%**       0%

## •  Quality of the Design & Conduct 

- Factors Influencing  Interpretation of Trial Results

- •  *Quality of the Design & Conduct *
*	**	**	**	**	**of the NI Trial*
-    ICH  E9:     “Many flaws in the design or conduct
- 	of the trial will tend to bias the results
- 		toward a conclusion of equivalence”
-      ... it is especially important to minimize
- 	     *incidence of violations in the entry criteria,*
*	**        **non compliance, withdrawals,*
*	**     ****losses to follow-up,  missing data***
*	**         **and other deviations in the protocol*.”

## •   ICH  E9:  ... it is especially important to minimize...

- Factors Influencing  Interpretation of Trial Results

- •   ICH  E9:  ... it is especially important to minimize...
*	**       ****losses to follow-up,  missing data***
*	*
- “ITT”  _vs_  “Evaluable”	(  variability & ****** bias **)
-        •  Absence of targeted microbial at baseline
-        •  Not assessed due to:
- 	**~**  termination due to adverse clinical events
- 	**~**  termination due to perceived drug ineffectiveness
- 	**~**  treatment with prohibited concomitant interventions
- 	**~ **“missing” evaluations

##     Non-inferiority trials

- 	  having scientifically rigorous margins
-   always require very large sample sizes...
- 		      ... fact  or  myth?

-  Sample Sizes in Non-inferiority trials

## Illustration:  AC Antibiotic having 80% Cure Rate

- Relative  in  Non-Cure Rate
- 	            ( for   EXP **–** AC   Cure Rate )

** ****75%********    50%******     25%      **~**          25%    50% 

** ****–**** ****15        ****–**** 10**         **–** 5           0             5           10

## *

**Probability of a Positive Trial**
- 	    as a function of true   **EXP** **–** **AC**  **Cure Rate**

- .025			     .90

**–**15            **–**10             **–**5               **0**                 5     **7.3**    10   **12**

- _Scenario #1_  (Superiority)	      2N  =  **340**  Evaluable pts

## *

**Probability of a Positive Trial**
- 	    as a function of true   **EXP** **–** **AC**  **Cure Rate**

- .025			     .90

**–**15            **–**10             **–**5               **0**                 5     **7.3**    10   **12**

- _Scenario #1_  (Superiority)	      2N  =  **340**  Evaluable pts

- .025            .18              .58	   .90

**–****15**            **–**10         **–5.9**                 **0**                5               10

- _Scenario #2_  (Non-Inferiority)          2N  =  **300 ** Evaluable pts

## *

**Probability of a Positive Trial**
- 	    as a function of true   **EXP** **–** **AC**  **Cure Rate**

- .025			     .90

**–**15            **–**10             **–**5               **0**                 5     **7.3**    10   **12**

- _Scenario #1_  (Superiority)	      2N  =  **340**  Evaluable pts

- .025            .18              .58	   .90

**–****15**            **–**10         **–5.9**                 **0**                5               10

- _Scenario #2_  (Non-Inferiority)          2N  =  **300 ** Evaluable pts

- .025           .367            .90

**–****10**                  **–3.9**        **0**                5              10

- _Scenario #3_  (Non-Inferiority)          2N  =  **672 ** Evaluable pts

## *

**Probability of a Positive Trial**
- 	    as a function of true   **EXP** **–** **AC**  **Cure Rate**

- .025			     .90

**–**15            **–**10             **–**5               **0**                 5     **7.3**    10   **12**

- _Scenario #1_  (Superiority)	      2N  =  **340**  Evaluable pts

- .025            .18              .58	   .90

**–****15**            **–**10         **–5.9**                 **0**                5               10

- _Scenario #2_  (Non-Inferiority)          2N  =  **300 ** Evaluable pts

- .025           .367            .90

**–****10**                  **–3.9**        **0**                5              10

- _Scenario #3_  (Non-Inferiority)          2N  =  **672 ** Evaluable pts

- .025           .238            .703     .90

**–**15           **–10**              **–**5      **–2.1**  0         **3**      5              10

- _Scenario #4_  (Non-Inferiority)	      2N  =  **374 ** Evaluable pts

##   “Bio-creep”   with Repeated NI Trials

- Eg:   *Anti-viral Drugs Advisory Comm  (10/4/01)*
-        Empiric Anti-fungal therapy
- 			   of febrile neutropenic patients
-          •  **Amphotericin B Deoxycholate**
-          •  **Ambisome** vs **Amphotericin B**
- 		49.9% v 49.1%     Mucosis Study Gp #32
-          •  **Voriconazole** vs **Ambisome**
- 		23.7% v 30.1%    95% CI:  (**– **12, **– **0.1)

##        •  ICH E10:      “The determination of the margin

- 	          in a non-inferiority trial   is based on
- 	both statistical reasoning & clinical judgment,
- 	   should reflect uncertainties
- 	           in the evidence on which the choice is based,
-                  and should be suitably conservative.”
-   •   Non-inferiority trials
- 	         having scientifically rigorous margins
- 		          do not necessarily require
- 			                     very large sample sizes.

-  Conclusions