# Presentation: 045452

## Surrogate Endpoints:

** ****The Challenges are**
**Greater than they Seem**
- March 7, 2005
- Thomas R. Fleming, Ph.D.
*Professor and Chair of Biostatistics*
*University of Washington*

- NIDDK Workshop:

## Surrogate Endpoints

-   **Criteria for Study Endpoints**
-   A Correlate does not a Surrogate Make
-   Validation of Surrogates
-   Controversial Issues with AA

## Criteria for Study Endpointsin Clinical Trials

**•**** ****Measurable/Interpretable**
- • **Sensitive**
- • **Clinically relevant**
-     **~** Retinopathy, Nephropathy
-     **~** Major hypoglycemic events: Coma/Seizure

## Use of Surrogate Endpoints

- Treatment Effects on Surrogate Endpoints
-     eg:  **~**  Oncology:  Tumor Burden Outcomes
-             **~**  HIV/AIDS:  CD4, Viral Load
- 	   **~  **Cardiovascular Dis:  B.P., Cholesterol
**	****   ****~   **Type 1 Diabetes:  HbA1c , C-Peptide
-  • Establishes Biological Activity
-  • But Not Necessarily Clinical Efficacy

## Surrogate Endpoints

-   Criteria for Study Endpoints
-   A Correlate does not a Surrogate Make
-   Validation of Surrogates
-   Controversial Issues with AA

##                    Surrogate Endpoint:

-                    Surrogate Endpoint:
- Not in Causal Pathway of Disease Process

- Disease

**            ****Surrogate**	       **True Clinical**
-             **Endpoint**             **Endpoint**
-   **Causal Pathway**

**   **The Surrogate Endpoint is not in the                                                    Causal Pathway of the Disease Process.
**                                                                                                   **

- Disease
- Disease

**                                    ****Biomarker**       **Mother-to-Child**
**                                      ****e.g.,**** ****CD4   ****        ****Trans of HIV**
-                              **HIV Viral Load**
**                                   ****Anti-Islet             ****End-Organ ****	****	****	****Autoantibodies           Diabetic**
- 						 **Complications**
- 		        **β****-Cell Function**
**  **“Correlates”:   Useful for Disease Diagnosis, or                  	Assessing Prognosis and Effect Modification
-   “Valid Surrogates”:   Replacement Endpoints

## Intervention

**Endpoint****	****           Endpoint**

- Disease

**True Clinical**
**  ****Endpoint**

-  **Surrogate**
** ****Endpoint**

- Disease

- Multiple Pathways of the Disease Process

## Intervention

**Endpoint****	****           Endpoint**

- Disease

** ****End-Organ**
**     ****Diabetic**
**Complications**

-            **HbA****1c**
** ****Glycemic Control**

- Disease

- Multiple Pathways of the Disease Process

## Time

**      ****Count                    & Death**

-       IL-2

- Disease

-   IL-2:   known > 200 CD4 cell count increase
-   Unknown whether IL-2 is increasing the level
- 			of functional CD4 cells
-   NIH is sponsoring the evaluation of 6000 patients,
- 	followed for >5 years, in SILCAAT and ESPRIT

## Disease

**  ****Endpoint****	****                Endpoint**

- Intervention

- Interventions having Mechanisms of Action
-       Independent of the Disease Process

## Disease

**Suppression****	****     Survival**

- Intervention

- Interventions having Mechanisms of Action
-       Independent of the Disease Process

## Surrogate Endpoints

-   Criteria for Study Endpoints
-   A Correlate does not a Surrogate Make
-   **Validation of Surrogates**
-   Controversial Issues with AA

## End Stage Renal Disease

- Goal:  Normalize Hematocrit Values
- 	    and reduce Death and MI

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- 60%
- 45%
- 30%
- 15%
-   0%

## End Stage Renal Disease

- Goal:  Normalize Hematocrit Values
- 	    and reduce Death and MI

## End Stage Renal Disease

- High Dose Epogen
- Standard Dose Epogen

- R

- Goal:  Normalize Hematocrit Values
- 	    and reduce Death and MI

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- 60%
- 45%
- 30%
- 15%
-   0%

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- HIGH DOSE EPOGEN

- • **30% ******** death RR**
**   ****for 10 pt ******** in hem.**

- 60%
- 45%
- 30%
- 15%
-   0%

- 60%
- 45%
- 30%
- 15%
-   0%

- 27-30	       30-33	 33-36	          36-39	      39-42

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- HIGH DOSE EPOGEN

- • 30%  death RR
-    for 10 pt  in hem.

- 60%
- 45%
- 30%
- 15%
-   0%

- 60%
- 45%
- 30%
- 15%
-   0%

- 27-30	       30-33	 33-36	          36-39	      39-42

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- HIGH DOSE EPOGEN

- • 30%  death RR
-    for 10 pt  in hem.
- • ****** ****in hematocrit**

- 60%
- 45%
- 30%
- 15%
-   0%

- 60%
- 45%
- 30%
- 15%
-   0%

- 27-30	       30-33	 33-36	          36-39	      39-42

## Patient Distribution & Percent Deaths by Hematocrit %

- 27-30	       30-33	 33-36	            36-39	       39-42

- STANDARD DOSE EPOGEN

- HIGH DOSE EPOGEN

- • 30%  death RR
-    for 10 pt  in hem.
- •  in hematocrit
- • **30% ******** in death RR**

- 60%
- 45%
- 30%
- 15%
-   0%

- 60%
- 45%
- 30%
- 15%
-   0%

- 27-30	       30-33	 33-36	          36-39	      39-42

## End Stage Renal Disease

- High Dose Epogen
- Standard Dose Epogen

- R

-    Goal:  Normalize Hematocrit Values
- 	                   and reduce Death and MI
-     Besarab et al, NEJM 339:584-590, 1998:
- “****** ****in incidence of thrombosis of vascular access sites**”

## How does one

- validate
- a
- surrogate endpoint?

## Validation of Surrogate Endpoints

**Property of a Valid Surrogate**
-       *Effect of the Intervention *
*	**	**        **on the Clinical Endpoint*
- 	      is reliably predicted by the
-         *Effect of the Intervention*
*	**	**        **on the Surrogate Endpoint*

## Prentice’s Sufficient Conditions

- 1.	The surrogate endpoint
- 		must be correlated with
- 			the clinical outcome

- 2.	The surrogate endpoint
- 	     must fully capture
- 		   the net effect of the intervention
- 			    on the clinical outcome

## Z = 1 : Control     ;     Z = 0 : Intervention

*S*(t) : Surrogate Endpoint at t

****** ****(t | Z) = ********0****(t) e******

- 

******(t | Z,*****S*****(t) ) = ********0****(t) e********Z + *********S*****(t)**

- 

- Proportion of **net** intervention effect
- 	explained by the surrogate endpoint:
-   DeGruttola et al,  J Infectious Diseases 175:237-246, 1997

***p***** = 1 -**

****

****

## Meta-analyses

- are required to explore
- the validity
- of surrogate endpoints

## Z = 1 : Control     ;     Z = 0 : Intervention

*S*(t) : Surrogate Endpoint at t

****** ****(t | Z) = ********0****(t) e******

- 

******(t | Z,*****S*****(t) ) = ********0****(t) e********Z + *********S*****(t)**

- 

- Proportion of **net** intervention effect
- 	explained by the surrogate endpoint:
-   DeGruttola et al,  J Infectious Diseases 175:237-246, 1997

***p***** = 1 -**

****

****

## Time        

**                             ****Glycemic Control               Events**
-    		Unintended negative effects
-        		Alternative beneficial effects

- Disease

-  Intervention

- Time

## Validation of Surrogate Endpoints

**Statistical**
-     Meta-analyses of clinical trials data
**Clinical**
-     Comprehensive understanding of the
- 	  **~** Causal pathways of the disease process
- 	  **~** Intervention’s intended and unintended
- 		    mechanisms of action

##   Hazard Ratios for DFS vs Overall Survival

## Endpoint Hierarchy

-   True Clinical Efficacy Measure
**  ***Validated Surrogate Endpoint*    (*Rare*)
**  **Non-validated Surrogate Endpoint that is
-     “reasonably likely to predict clinical benefit”
-   Correlate that is
- 	 solely a measure of Biological Activity

## Illustrations of Valid Surrogates

***Preventing Mother-to-Child Transmission of HIV***
- 	    when using short course antiretrovirals
-      **~**  ***Prevention of AIDS and Death***
-                   often occurring within two years
***Substantial Sustained Reduction in Blood Pressure***
- 	    when using β-blockers or low dose diuretics
**     ****~**  ***Prevention of Fatal and Non-fatal Stroke***

## Hierarchy for Outcome Measures

-   True Clinical Efficacy Measure
**  **Validated Surrogate Endpoint    (*Rare*)
**  ***Non-validated Surrogate Endpoint that is*
*   “**reasonably likely to predict clinical benefit”*
-   Correlate that is
- 	 solely a measure of Biological Activity

## Establishing a Level #3 Outcome Measure

-   *Accurately representing the treatment’s effect*
*        **on the predominant mechanism through which*
*           **the disease process induces clinical risks*
***  ****Lack of large adverse effects on clinical endpoint*
***           ****not captured by the outcome measure*
***  ****Net effect on the clinical endpoint is consistent *
*        **with what would be predicted by*
*	**  **level of effect on the outcome measure*
*  **Targeted effect on outcome measure sufficiently*
*          **strong and durable to predict meaningful benefit*

## Hierarchy for Outcome Measures

-   True Clinical Efficacy Measure
**  **Validated Surrogate Endpoint    (*Rare*)
**  ***Non-validated Surrogate Endpoint that is*
*   “**reasonably likely to predict clinical benefit”*
-   Correlate that is
- 	 solely a measure of Biological Activity

## Surrogate Endpoints

-   Criteria for Study Endpoints
-   A Correlate does not a Surrogate Make
-   Validation of Surrogates
-   **Controversial Issues with AA**

## ’95-’00:  12 Accelerated Approvals

- ’95-’00:  12 Accelerated Approvals
-     *Facts presented to ODAC*:
-             *Of 12 AA, 8 remain unresolved:*
-   *Average time from AA to Completion of    **	**Validation Trial projected to be 10 years*
-   In one case, sponsor enrolled 8 pts/year
-   In 3 cases, Validation Trial indicated 			                  minimal treatment benefit

## ’95-’00:  12 Accelerated Approvals

- ’95-’00:  12 Accelerated Approvals
*Disturbing Issues re Validation Trials**:*
-   *Enrollment difficulties into validation trials*
*  **Cross-ins on the control arm*
*  **Loss of “sense of urgency” by sponsor*
-   Lack of clear vision for proper process
- 	 when the validation trial
- 		 is not conclusively positive

## ’95-’00:  12 Accelerated Approvals

- ’95-’00:  12 Accelerated Approvals
-     *Facts presented to ODAC*:
-             *Of 12 AA, 8 remain unresolved:*
-   Average time from AA to Completion of    	Validation Trial projected to be 10 years
-   *In one case, sponsor enrolled 8 pts/year*
*  **In 3 cases, Validation Trial indicated **	**	**	**              minimal treatment benefit*

## ’95-’00:  12 Accelerated Approvals

- ’95-’00:  12 Accelerated Approvals
*Disturbing Issues re Validation Trials**:*
-   Enrollment difficulties into validation trials
-   Cross-ins on the control arm
-   Loss of “sense of urgency” by sponsor
-   *Lack of clear vision for proper process*
*	**   **when the validation trial *
*	**	**  **is not conclusively positive*

## Hierarchy for Outcome Measures

-   True Clinical Efficacy Measure
**  **Validated Surrogate Endpoint    (*Rare*)
**  **Surrogate Endpoint that is
-     “reasonably likely to predict clinical benefit”
-   *None of the Above:   A Correlate that is*
*	** **solely a measure of Biological Activity*

##    Use of Biological Markers

-   As “Correlates”...
*	**   **Disease Diagnosis, or assessing*
*                **Prognosis or Effect Modification*
* *
-   In Screening or Proof of Concept Trials...
- 	   *Primary Endpoint*
-   In Definitive Trials...
- 	   *Supportive Data *
*	**         **on Mechanism of Action*

## NIDDK Workshop 

-  Surrogate Endpoints
-  **The Next Step **
**	**** ****after the Phase 1 Trial**

## Development Strategies

- After Phase 1:
- 	  What should be the next step?
- 			**~** **Phase 2**
- 			**~** Phase 2B (Intermediate Trial)
- 			**~** Phase 3

## Why Conduct a Phase 2 Trial?

- Obtain improved insights:
***Biological Activity:  Proof of Concept***
***Refinements in dose/schedule***
***Safety***
- Improving adherence to interventions
- Improving quality of trial conduct
- 		- Timely accrual
- 		- High quality study implementation
- 		- High quality data, including retention

## Development Strategies

- After Phase 1:
- 	  What should be the next step?
- 		     **~** Phase 2
- 		      **~** **Phase 2B ****(Screening Trial)**
- 	          **~** Phase 3

## The Randomized Phase 2B “Screening Trial”

- _Illustration_:    Type 1 Diabetes
-   Primary Endpoint:
-                   *Time to Hypoglycemic Events  or *
*                    **End-Organ Diabetic Complications*
*  *Targeted Treatment Effect:
- 			33% reduction in progression rate

## Screening Trial Design

- Phase 3 Trial Design

- -33%                 0%                  33%  44%        67%

- Further
- Studies

- Positive

-  -17%     0%      17%    33%    50%

- Positive

## An Illustration of the Use

- of an Intermediate Trial
- Before a Definitive Trial
- Surgical Adjuvant Therapy
- of Colorectal Cancer

- 5-FU + Levamisole
- Levamisole
- Control

- R

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- NCCTG Trial

- 5-FU+LEV  n=91
- Levamisole  n=85
- Control        n=86

## Screening Trial Design

- Phase 3 Trial Design

- -33%                 0%                  33%  44%        67%

- Further
- Studies

- Positive

-  -17%     0%      17%    33%    50%

- Positive

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- NCCTG Trial

- 5-FU+LEV  n=91
- Levamisole  n=85
- Control        n=86

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- NCCTG Trial

- Cancer Intergroup Trial

- 0     1     2     3     4     5     6     7     8     9

- 100 -
-   80 -
-   60 -
-   40 -
-   20 -
-     0

- Years from randomization

- 5-FU+LEV  n=91
- Levamisole  n=85
- Control        n=86

- 5-FU+LEV  n=304
- Levamisole  n=310
- Control        n=315

## Important Observations

-  Confirmatory trials
-          of promising results from Intermediate Trials
-                    can be performed successfully
-  Confirmatory trials
- 	- can reveal true positives (eg, 5-FU+Lev)
- 	- can reveal true negatives (eg, Levamisole)

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- NCCTG Trial

- Cancer Intergroup Trial

- 0     1     2     3     4     5     6     7     8     9

- 100 -
-   80 -
-   60 -
-   40 -
-   20 -
-     0

- Years from randomization

- 5-FU+LEV  n=91
- Levamisole  n=85
- Control        n=86

- 5-FU+LEV  n=304
- Levamisole  n=310
- Control        n=315

##     Illustration of a Screening Trial with

-     Illustration of a Screening Trial with
-   “Compelling” Results:   HIVNET 012

- • 8/99 Results	*Lancet* 1999; 354: 795-802
- 		 	  _       __**MCT of HIV**__ __	__ _
- 	       _  __N  _	_  6-8 wks  _	  _ 14-16 wks _
- AZT	       302	59 (21.3%)	   65 (25.1%)
- NVP	       307	35 (11.9%)	   37 (13.1%)
- 			1p = 0.0014	   1p = 0.0003

## Screening Trial Design

- Phase 3 Trial Design

- -33%                 0%                  33%  44%        67%

- Further
- Studies

- Positive

-  -17%     0%      17%    33%    50%

- Positive

## Goals in Development of Diabetes Drugs

-   Using Biomarkers to achieve
- 	        a cost-effective research strategy
-   Achieving rapid availability of drugs
-       providing improved benefit-to-risk profile
-   Achieving *reliable* as well as *timely*
- 	evaluation of both efficacy and safety
- 		of new interventions

## Slide 61