# Presentation: 045437

## Surrogate Endpointsas Measures of Efficacy:Complexities & Limitations FDA Advisory Committee November 18, 2002

- Michael D. Hughes, Ph.D.
- Professor of Biostatistics
- Harvard School of Public Health
- mhughes@hsph.harvard.edu
**(with thanks to Professor Tom Fleming)**

## Criteria for Study Endpointsin Clinical Trials

- Measurable/Interpretable
- Sensitive
- 	e.g. Analgesic in terminally ill
- 			   - Pain relief, not survival
- Clinically relevant

## Criteria for Study Endpoints:Clinically Relevant

**Criteria for Study Endpoints:****Clinically Relevant**

## What is a Surrogate Endpoint?

**“**A surrogate endpoint of a clinical trial is a laboratory measurement or physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives.
- 	Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.”
- Ref: Temple. In Nimmo, Tucker, eds. 1995

## Surrogate Endpoints: Why?

- Basic science
- improve understanding of pathogenesis and mechanisms of drug action
- Phase II trials
- for selecting drugs for further development
- Accelerated approval
- preliminary drug approval pending results from clinical outcome trials
- Phase III trials
- replacement for large, long-term clinical outcome trials

## Surrogate Endpoints: Examples

##      Prognostic Marker vs.                                     Surrogate Endpoint

- Critical to distinguish them!
- Prognostic marker
- A variable that predicts the clinical outcome
- Surrogate endpoint
- Effect of an intervention on a surrogate endpoint reliably predicts the effect of the intervention on the clinical outcome
- “A correlate does not a surrogate make”

## “A Correlate Does Not A Surrogate Make”

-    disease process.

**“****A Correlate Does Not A Surrogate Make”**

**Disease**

- Surrogate	       True Clinical
- Endpoint	       Outcome

## “A Correlate Does Not A Surrogate Make”

-    not the clinical outcome.
-   Common example arises when “surrogate” is a
-    measure of symptoms.

**“****A Correlate Does Not A Surrogate Make”**

**Disease**

- Surrogate	       True Clinical
- Endpoint	       Outcome

**Intervention**

## Association or Causation?

- Essential to have a comprehensive understanding of causal pathways of the disease process
- Do changes in measures from brain imaging precede changes in true clinical outcome?
- What is the biological model that these measures are on the causal pathway to the true clinical outcome(s)?
- Even when there is an established model for the causal pathway, the marker may not be a good surrogate endpoint ......

## Model for an Ideal Surrogate Endpoint

- Surrogate	     True Clinical
- Endpoint	     Outcome

**Intervention**

**Disease**

**• ****All mechanisms of action of the intervention on the**
**  ****true endpoint are mediated through the surrogate.**
**Ref: Fleming, DeMets. Ann Intern Med. 1996**

## Even in the Ideal Setting, There May be Problems .....

- Effect of intervention on true clinical outcome could be:
- Underestimated if there is considerable measurement error in surrogate.
- Overestimated if effect on surrogate is not of sufficient size or duration (could it be transient?)
- These problems can arise even when effect on surrogate is statistically significant

## Reasons for Failure of Surrogate Endpoints

- Surrogate		True Clinical
- Endpoint		Outcome

- Intervention

- Disease

**Reasons for Failure of Surrogate Endpoints**

-   Of several causal pathways of disease, the intervention
-    only affects the pathway mediated through the surrogate.
-   Effect on surrogate could look impressive but effect
-    on true clinical outcome could be clinically insignificant
-    if other pathways important.

## Reasons for Failure of Surrogate Endpoints

- True Clinical
- Outcome

- Surrogate
- Endpoint

- Disease

- Intervention

- The surrogate is not in the pathway of the intervention's effect.

**Reasons for Failure of Surrogate Endpoints**

##  Example of a Failed Surrogate Endpoint:

**Chronic Granulomatous Disease**

-  CGD  recurrent serious infections
-  Intervention: Interferon gamma
-  Increase superoxide production and kill bacteria?
-  International CGD Study Group Trial:
- 70% reduction in recurrent serious infections
- BUT essentially no effect on biological markers
-  Effect was mediated through a different
-   pathway from the surrogates or the surrogates
-   were insensitive.

## Problems with Insensitive Surrogates and 

**Surrogates Not on the Causal Pathway**

-  Regulatory approval based on these surrogates
-   will focus drug evaluation on these surrogates
-  If they are poor surrogates for true clinical
-   endpoint, then drugs that have important effects
-   on the clinical endpoint could be missed

## Disease

*Dotted lines* = mechanisms of action that might exist.

- Surrogate		  True Clinical
- Endpoint		  Outcome

- Intervention

**Reasons for Failure of Surrogate Endpoints**

## Example of a Failed Surrogate Endpoint

- _Lipid Research Clinics Trial_	CHD death	Death
- (n= 3806, 7.4y average f-up)			 /m.i.
- Cholestyramine			8.1%		3.6%
- Placebo				9.8%		3.7%
- _W.H.O. Cooperative Trial_		All major	Death
- (n = 10627, 5.3y average f-up)		 	IHD
- Clofibrate				3.1%		3.0%
- Placebo				3.9%		2.4%

- [Ref: JAMA, 1984; Br. Heart J., 1978]

**Two trials with similar reductions in cholesterol **
**	****for active treatment vs. placebo (8.5% and 9%):**

## Example of a Failed Surrogate:Ventricular Arrhythmia After M.I.

- Cardiac Arrhythmia Suppression Trial (CAST)
- Arrhythmia: Risk factor for sudden death
- Antiarrhythmic drugs: Encainide, flecainide
- Antiarrhythmic drugs TRIPLED the death rate
-     relative to placebo.

## Example of a Failed Surrogate:TIMI Flow After Myocardial Infarction

- Diagnosis: blockage of coronary artery leading to myocardial infarction
- Prognostic marker: TIMI flow
- Grade 3 = complete flow;
- Grades 0/1/2 = no/low/partial flow
- Possible surrogate: TIMI flow 90 minutes following medical therapy

## TIMI Flow vs. Mortality

- [Source: K. Anderson, NIH Workshop on Surrogate Endpoints]

**% TIMI 3 FLOW @ 90**
**MINUTES**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**31**

**54**

**8**

**7**

**6**

**5**

**4**

**3**

**2**

**1**

**0**

**7.3**

**6.3**

**SK    tPA**
**GUSTO-1**

**% 30-DAY MORTALITY**

**SK    tPA**
**GUSTO-I**

## TIMI Flow vs. Mortality

- [Source: K. Anderson, NIH Workshop on Surrogate Endpoints]

**% TIMI 3 FLOW @ 90**
**MINUTES**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**31**

**54**

**44**

**61**

**8**

**7**

**6**

**5**

**4**

**3**

**2**

**1**

**0**

**7.3**

**6.3**

**SK    tPA**
**GUSTO-1**

**tPA  rPA**
**RAPID-2**

**% 30-DAY MORTALITY**

**SK    tPA**
**GUSTO-I**

## TIMI Flow vs. Mortality

- [Source: K. Anderson, NIH Workshop on Surrogate Endpoints]

**% TIMI 3 FLOW @ 90**
**MINUTES**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**31**

**54**

**44**

**61**

**8**

**7**

**6**

**5**

**4**

**3**

**2**

**1**

**0**

**7.3**

**6.3**

**7.24**

**7.47**

**SK    tPA**
**GUSTO-1**

**tPA  rPA**
**RAPID-2**

**% 30-DAY MORTALITY**

**SK    tPA**
**GUSTO-I**

**tPA    rPA**
**GUSTO-III**

## Benefits and Risks of Using Surrogate Endpoints for Drug Approval

- Benefits:
- Smaller and/or shorter clinical trials.
- Drugs available sooner
- Risks:
- Drugs have unknown clinical efficacy
- Potential for adverse effects, no effect, minimal beneficial effect on patient relevant outcomes.
- Approval focused on effects on surrogates could mean that clinically effective drugs are missed

## Drug Approval Based on Effects on Surrogate Endpoints

- 	Use of surrogates *will* increase risk that a licensed drug has no or minimal clinical benefit or, worse, an adverse effect.

- Ultimately, drug approval based on effects on a surrogate involves an extrapolation of experience with existing drugs to an untested new drug

## Drug Approval Based on Effects on Surrogate Endpoints

- Minimizing this risk requires detailed understanding of:
- Causal pathways for disease effects on true clinical outcomes
- Intended and unintended mechanisms of action of all interventions which might be evaluated using the surrogate
- Empirical evidence to support the validity of the surrogate