Surrogate Endpoints: The Challenges are Greater than they Seem March 7, 2005

1. NIDDK Workshop: 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

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

3. Criteria for Study Endpointsin Clinical Trials •Measurable/Interpretable •Sensitive •Clinically relevant ~Retinopathy, Nephropathy ~Major hypoglycemic events: Coma/Seizure

4. 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

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

6. Surrogate Endpoint: Not in Causal Pathway of Disease Process SurrogateTrue Clinical EndpointEndpoint Causal Pathway Disease

7. The Surrogate Endpoint is not in the Causal Pathway of the Disease Process. • BiomarkerMother-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 Disease Disease

8. Multiple Pathways of the Disease Process Intervention Surrogate True Clinical Endpoint Endpoint Disease Intervention True Clinical Endpoint Disease Surrogate Endpoint

9. Multiple Pathways of the Disease Process Intervention Surrogate True Clinical Endpoint Endpoint Disease Intervention End-Organ Diabetic Complications Disease HbA1c Glycemic Control

10. Time IL-2 CD4 Cell AIDS Events Count & Death 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

11. Interventions having Mechanisms of Action Independent of the Disease Process Intervention Surrogate True Clinical Endpoint Endpoint Disease

12. Interventions having Mechanisms of Action Independent of the Disease Process Intervention Arrhythmia Overall Suppression Survival Disease

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

14. End Stage Renal Disease Goal: Normalize Hematocrit Values and reduce Death and MI

15. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42

16. End Stage Renal Disease Goal: Normalize Hematocrit Values and reduce Death and MI

17. End Stage Renal Disease High Dose Epogen Standard Dose Epogen R Goal: Normalize Hematocrit Values and reduce Death and MI

18. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42

19. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN • 30%  death RR for 10 pt  in hem. 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42 60% 45% 30% 15% 0% HIGH DOSE EPOGEN 27-30 30-33 33-36 36-39 39-42

20. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN • 30%  death RR for 10 pt  in hem. 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42 60% 45% 30% 15% 0% HIGH DOSE EPOGEN 27-30 30-33 33-36 36-39 39-42

21. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN • 30%  death RR for 10 pt  in hem. •  in hematocrit 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42 60% 45% 30% 15% 0% HIGH DOSE EPOGEN 27-30 30-33 33-36 36-39 39-42

22. Patient Distribution & Percent Deaths by Hematocrit % STANDARD DOSE EPOGEN • 30%  death RR for 10 pt  in hem. •  in hematocrit • 30%  in death RR 60% 45% 30% 15% 0% 27-30 30-33 33-36 36-39 39-42 60% 45% 30% 15% 0% HIGH DOSE EPOGEN 27-30 30-33 33-36 36-39 39-42

23. 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”

24. How does one validate a surrogate endpoint?

25. 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

26. 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

27. Z = 1 : Control ; Z = 0 : Intervention S(t) : Surrogate Endpoint at t (1) (t | Z) = 0(t) eZ (2)  (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 - 

28. Meta-analyses are required to explore the validity of surrogate endpoints

29. Z = 1 : Control ; Z = 0 : Intervention S(t) : Surrogate Endpoint at t (1) (t | Z) = 0(t) eZ (2)  (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 - 

30. Time Intervention • HbA1c Major Clinical • Glycemic Control Events • Unintended negative effects • Alternative beneficial effects Disease

31. 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

32. Hazard Ratios for DFS vs Overall Survival

33. 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

34. 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

35. 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

36. 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

37. 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

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

39. FDA Oncology Drugs AC: 3/12-13/03 • ’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

40. FDA Oncology Drugs AC: 3/12-13/03 • ’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

41. FDA Oncology Drugs AC: 3/12-13/03 • ’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

42. FDA Oncology Drugs AC: 3/12-13/03 • ’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

43. 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

44. 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

45. NIDDK Workshop • Surrogate Endpoints • The Next Step • after the Phase 1 Trial

46. Development Strategies After Phase 1: What should be the next step? ~Phase 2 ~Phase 2B (Intermediate Trial) ~ Phase 3

47. 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

48. Development Strategies After Phase 1: What should be the next step? ~Phase 2 ~Phase 2B (Screening Trial) ~ Phase 3

49. 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

50. Screening Trial Design -33% 0% 33% 44% 67% Further Studies Positive Phase 3 Trial Design -17% 0% 17% 33% 50% Positive