1. 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)

2. Criteria for Study Endpoints in Clinical Trials Measurable/Interpretable Sensitive e.g. Analgesic in terminally ill - Pain relief, not survival Clinically relevant

3. Criteria for Study Endpoints: Clinically Relevant - Screening Evaluation:- Definitive Evaluation: Biological Activity Clinical Efficacy Objective resp. rate Duration of survival Change in viral load Quality of life New targeted- Symptom relief markers of disease- ICU/Hospitalization - e.g. brain imaging - Global assessment measures- Cognitive function

4. 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

5. 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

6. Surrogate Endpoints: Examples

7. 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”

8. The surrogate is not on the causal pathway of the disease process. “A Correlate Does Not A Surrogate Make” Disease Surrogate True Clinical Endpoint Outcome

9. An intervention could affect the surrogate endpoint but 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

10. 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 ……

11. 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

12. 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

13. SurrogateTrue Clinical EndpointOutcome 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.

14. 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

15. 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.

16. 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

17. The intervention has mechanisms of action independent of the disease process. Dotted lines = mechanisms of action that might exist. Surrogate True Clinical Endpoint Outcome Disease Intervention Reasons for Failure of Surrogate Endpoints

18. Example of a Failed Surrogate Endpoint Lipid Research Clinics TrialCHD deathDeath (n= 3806, 7.4y average f-up) /m.i. Cholestyramine8.1%3.6% Placebo9.8%3.7% W.H.O. Cooperative TrialAll majorDeath (n = 10627, 5.3y average f-up) IHD Clofibrate3.1%3.0% Placebo3.9%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%):

19. 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.

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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