Biomarkers are NOT useful Surrogates in Lipid Lowering Trials, but they are great Biomarkers!

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1 Biomarkers are NOT useful Surrogates in Lipid Lowering Trials, but they are great Biomarkers! Robert M Califf MD Vice Chancellor for Clinical Research Duke University

2 CHD Mortality Rate Per 1000 Total Serum Cholesterol: Major Risk Factor for CHD Multiple Risk Factor Intervention Trial (n=361,622) Framingham Study (n=5209) Plasma Cholesterol (mg/dl) Serum Cholesterol (mg/100 ml)

3 Statins and Clinical Outcomes Meta-analysis of statin trials (25 studies and 69,511 patients) RR (95% CI) All-Cause Mortality 0.84 ( ) CHD mortality 0.77 ( ) CHD mortality or nonfatal MI 0.75 ( ) Statin Better No Statin Better Wilt TJ, Arch Intern Med, 2004

4 CHD Reduction in Non-statin Trials of Cholesterol Reduction Method Study Cholesterol Diet Niacin Cholestyramine Surgery Oslo I (P.Leren) 1970 Coronary Drug Project 1975 LRC CPPT 1984 POSCH or LDL-C CHD RRR P-value T-C 14 % 25 % 0.05 T-C 10 % 15 % <0.05 LDL-C 13 % 19 % <0.05 LDL-C 38 % 35 % <0.001 Ileal bypass 1990 Courtesy of T. Pedersen

5 CHD Events (%) The Statin Decade: For LDL: Lower is Better R² = p < S LIPID CARE HPS TNT PROVE IT TIMI 22 IMPROVE IT LDL Cholesterol (mg/dl) Adapted and Updated from O Keefe, J. et al., J Am Coll Cardiol 2004;43:

6 -Am Heart J 149; 2005

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9 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

10 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 treatment on the clinical outcome

11 Percent Change from Baseline to Year 1 Changes In Lipoproteins LDL HDL Triglycerides

12 Incidence (%) Primary CHD Events 15 Estrogen + Progestin Placebo (2763) 1 (2631) 2 (2506) 3 (2392) 4 (1435) 5 (113) Follow-Up, y (No. at Risk) Log Rank p=0.91

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16 Unintended Targets Vesnarinone? neurohormones Calcium Blockers Systolic Function? Neurohormones PD Inhibitors Arrhythmia Epoprostenol Neurohormones

17 Unintended Targets TNF- blockers? neurohormones Moxonidine Systolic Function? Neurohormones Flosequinon Neurohormones Doxazocin Fluid retention

18 Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease Authored by the Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease Edited by Christine M. Micheel and John R. Ball 18

19 Biomarkers are Useful When Used Carefully Discovery and Development of Medical Therapies and Products Comparative Effectiveness Research Formation of Clinical Practice Guidelines Basic Biomedical Research Clinical Practice Public Health Practice Understanding Healthy Nutrition and Lifestyle Choices 19

20 Definitions - Biomarker Biomarker: a characteristic that is objectively* measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n] intervention. Example: cholesterol level. *The committee defines objectively to mean reliably and accurately. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):

21 Definitions Surrogate Endpoint Surrogate Endpoint: a biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Example: blood pressure for trials of several classes of antihypertensive drugs. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):

22 Definitions Clinical Endpoint Clinical Endpoint: a characteristic or variable that reflects how a patient [or consumer] feels, functions, or survives. Example: death. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):

23 Relevance to Drugs, Biologics, and Devices Surrogate Endpoints Successes Blood pressure as a surrogate endpoint for cardiovascular disease clinical endpoints HIV-1 RNA levels as an indicator of complete viral suppression for HIV interventions Failures Arrhythmia suppression as a surrogate endpoint for reduction of cardiac sudden death LDL reduction through hormone replacement therapy as a surrogate endpoint for cardiovascular disease clinical endpoints 23

24 LDL is not a Generic Surrogate Endpoint: Lesson from Hormone Replacement Therapy Postmenopausal hormone replacement therapy (HRT) was thought to protect women from cardiovascular disease based on both observational, epidemiologic data and the apparent beneficial effects of estrogen on lipoproteins and other cardiovascular disease biomarkers. After several clinical trials, HRT was discovered to raise mortality from cardiovascular events and have other adverse unexpected effects. 24

25 Even in the best of circumstances, it is possible for surrogate endpoints to be misleading by either overestimating or underestimating an intervention s effect on clinical outcomes. Time Intervention Disease Surrogate Endpoint True Clinical Outcome Fleming, T. R., and D. L. DeMets Surrogate end points in clinical trials: Are we being misled? Annals of Internal Medicine 125(7):

26 Failures of Surrogate Endpoints Time A Disease Surrogate Endpoint True Clinical Outcome Intervention B Disease Surrogate Endpoint True Clinical Outcome Intervention C Disease Surrogate Endpoint True Clinical Outcome Intervention D Disease Surrogate Endpoint True Clinical Outcome Fleming, T. R., and D. L. DeMets Surrogate end points in clinical trials: Are we being misled? Annals of Internal Medicine 125(7):

27 Biological Complexity Leads to Many Opportunities for Error Pure or multicomponent substance or intervention Component 3 Component 2 Component 1 Component n Outcome 1 Outcome 2 HEALTH STATUS Surrogate Endpoint Outcome 3 Biological Pathways 1, 2, 3, n Outcome n 27

28 Recommendation: Biomarker Evaluation Framework The biomarker evaluation process should consist of the following three steps: Analytical validation: analyses of available evidence on the analytical performance of an assay; Qualification: assessment of available evidence on associations between the biomarker and disease states, including data showing effects of interventions on both the biomarker and clinical outcomes; and Utilization: contextual analysis based on the specific use proposed and the applicability of available evidence to this use. This includes a determination of whether the validation and qualification conducted provide sufficient support for the use proposed. 28

29 Biomarker Evaluation Framework Utilization Discovery Development Validation Qualification: Evidentiary Assessment 29

30 Case Study: LDL and HDL Cholesterol LDL is often considered to be a generically qualified surrogate endpoint for cardiovascular disease for both food-related disease claims and drugs But, the strength of LDL-C as a surrogate endpoint is not absolute (as in HRT example) And, evidence is weak that elevation of HDL from therapeutics decreases cardiovascular disease risk 30

31 Acknowledgments Committee Members JOHN R. BALL (Chair) American Society for Clinical Pathology MICHELLE A. ALBERT Brigham and Women s Hospital and Harvard Medical School FRED APPLE Hennepin County Medical Center and University of Minnesota School of Medicine ROBERT M. CALIFF Duke University School of Medicine VICTOR DE GRUTTOLA Harvard School of Public Health DAVID DEMETS University of Wisconsin Madison ROBERT GERSZTEN Harvard Medical School WILLIAM HARLAN, JR. Consultant ALLAN JAFFE Mayo Clinic RONALD KRAUSS Children s Hospital Oakland Research Institute HARLAN M. KRUMHOLZ Yale University School of Medicine MARIA LOPES-VIRELLA Medical University of South Carolina ROBERTA NESS University of Texas Health Science Center, School of Public Health JENNIFER VAN EYK Johns Hopkins University JOHN A. WAGNER Merck and Company, Inc. ELIZABETH YETLEY (Consultant) Consultant 31

32 Read the Report Online at nap.edu Discussion workshop was held in DC June 21-22, 2010; summary to be published late fall 2010 Contact IOM study director Christine Micheel, , for further information about reports 32

33 Biomarkers, Surrogates and Lipid Lowering Trials When we do things right, we should prescribe treatments when it is proven that the human benefits outweigh the human risks If we want to know if a proposed therapy improves the human condition, we must measure its impact on the human condition longevity, feeling (quality of life, symptoms) or function If we want to hedge our bets on when to do the real test (a proper RCT with clinical outcomes) for the balance of risks and benefits we should use validated and qualified biomarkers, including lipids and imaging 33