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PHYSIOLOGICAL AND LABORATORY MARKERS OF DRUG EFFECT

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  1. PHYSIOLOGICAL AND LABORATORY MARKERS OF DRUG EFFECT Arthur J. Atkinson, Jr., M.D. Senior Advisor in Clinical Pharmacology Clinical Center, NIH

  2. USES OF BIOMARKERS • CLINICAL PRACTICE: • ESTABLISH DIAGNOSIS AND PROGNOSIS • MONITOR RESPONSE TO THERAPY • DRUG DEVELOPMENT: • MANY USES

  3. ANTIHYPERTENSIVE DRUG HYPERTENSION STROKE  BLOOD PRESSURE  OTHER RISK FACTORS TREATMENT OF HIGH BLOOD PRESSURE

  4. DOES TERMINOLOGY MATTER? AT LEAST SOME OF THE CONTROVERSY IN THIS AREA RESULTS FROM CONFUSION IN THE INTERCHANGABLE USE OF THE TERMS: • BIOMARKER • SURROGATE MARKER • SURROGATE ENDPOINT BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.

  5. DEFINITION (clinical) A surrogate endpoint of a clinical trial is a laboratory measurement or a 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. Robert J. Temple

  6. TITLE 21, PART 314, SUBPART H SEC. 314.510 APPROVAL BASED ON A SURROGATE ENDPOINT OR ON AN EFFECT ON A CLINICAL ENDPOINT OTHER THAN SURVIVAL OR IRREVERSIBLE MORBIDITY “FDA MAY GRANT MARKETING APPROVAL FOR A NEW DRUG PRODUCT ON THE BASIS OF ADEQUATE AND WELL-CONTROLLED CLINICAL TRIALS ESTABLISHING THAT THE DRUG PRODUCT HAS AN EFFECT ON A SURROGATE ENDPOINT THAT IS REASONABLY LIKELY … TO PREDICT CLINICAL BENEFIT…”

  7. BIOLOGICAL MARKER Biological Marker: A physical sign or laboratory measurement that occurs in association with a pathological process and that has putative diagnostic and/or prognostic utility.

  8. EXAMPLES OF PHYSIOLOGICENDPOINTS THERAPEUTIC BIOMARKER/ CLINICAL CLASS SURROGATE OUTCOME ANTIHYPERTENSIVE  B.P.  STROKE DRUGS FOR GLAUCOMA  I.O.P.  LOSS OF VISION OSTEOPOROSIS DRUGS  BONE DENSITY  FRACTURE RATE ANTIARRHYTHMIC  ARRHYTHMIAS  SURVIVAL

  9. EXAMPLES OF LABORATORY ENDPOINTS THERAPEUTIC BIOMARKER/ CLINICAL CLASS SURROGATE_OUTCOME ANTIBIOTICS NEG. CULTURE CLINICAL CURE ANTI-DIABETIC  BLOOD GLUCOSE  MORBIDITY LIPID LOWERING DRUGS  CHOLESTEROL  CAD DRUGS FOR PROSTATE CA  PSA TUMOR RESPONSE ANTI-HIV DRUGS  CD4; VIRAL RNA DELAY AIDS

  10. THE MOST WIDELY USED SURROGATE ENDPOINT* BLOOD LEVELS USED AS A SURROGATE FOR CLINICAL EFFICACY AND TOXICITY IN THE EVALUATION OF GENERIC DRUGS * Comment by Carl Peck: CDDS WORKSHOP, McLean, VA, May 13, 1998

  11. DEFINITIONS OF CLINICAL ENDPOINTS Clinical Endpoint: A clinically meaningful measure of how a patient feels, functions or survives. Intermediate Endpoint: A clinical endpoint that is not the ultimate outcome but is nonetheless of real clinical benefit. Ultimate Outcome: A clinical endpoint such as survival, onset of serious morbidity or symptomatic response that captures the benefits and risks of an intervention.

  12. EXAMPLE: LIDOCAINE IN ACUTE MI BIOLOGICAL INTERMEDIATE ULTIMATE MARKER ENDPOINT OUTCOME VENTRICULAR VENTRICULAR SURVIVAL ECTOPY FIBRILLATION

  13. SURROGATE MARKER USE OF THIS TERM IS DISCOURAGED BECAUSE IT SUGGESTS THAT THE SUBSTITUTION IS FOR A MARKER RATHER THAN FOR A CLINICAL ENDPOINT BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.

  14. EVOLUTION OF BIOMARKERS TO SURROGATE ENDPOINTS* Clinical Endpoints (for Efficacy) Surrogate Endpoints (for Efficacy) Biomarkers (for Efficacy) Evidence that a Biomarker is Reasonably Likely to Predict Clinical Benefit Provisional Evaluation of Efficacy and Toxicity Continuing Assessment of Benefit to Risk Ratio Surrogate Endpoints (for Toxicity) Biomarkers (for Toxicity) Clinical Endpoints (for Toxicity) * From Biomarkers Definitions Working Group

  15. VALIDATION OF BIOMARKERS • BIOLOGICAL PLAUSIBILITY • EPIDMIOLOGIC EVIDENCE THAT MARKER IS A RISK FACTOR • MARKER MUST BE CONSISTENT WITH PATHOPHYSIOLOGY • MARKER MUST BE ON INTERVENTION PATHWAY • CHANGES IN MARKER REFLECT CHANGES IN PROGNOSIS • ADVERSE DRUG EFFECTS MUST NOT BE CONFOUNDING • STATISTICAL CRITERIA • CHANGES IN MARKER MUST BE CORRELATED WITH • CLINICAL OUTCOME • BUT CORRELATION DOES NOT EQUAL CAUSATION

  16. ADDITIONAL SUPPORT FOR BIOMARKERS* • SUCCESS IN CLINICAL TRIALS • EFFECT ON SURROGATE HAS PREDICTED OUTCOME WITH • OTHER DRUGS OF SAME PHARMACOLOGIC CLASS • EFFECT ON SURROGATE HAS PREDICTED OUTCOME FOR • DRUGS IN SEVERAL PHARMACOLOGIC CLASSES • OTHER BENEFIT/RISK CONSIDERATIONS • SERIOUS OR LIFE-THREATENING ILLNESS WITH NO • ALTERNATIVE THERAPY • LARGE SAFETY DATA BASE • • SHORT-TERM USE • • DIFFICULTY IN STUDYING CLINICAL ENDPOINT * Temple R: JAMA 1999;282:790-5.

  17. CLASSIFICATION BY EXTENT OF VALIDATION* TYPE 0: NATURAL HISTORY MARKER (PROGNOSIS) TYPE I: BIOLOGICAL ACTIVITY MARKER (RESPONDS TO THERAPY) TYPE II: SINGLE OR MULTIPLE MARKER(S) OF THERAPEUTIC EFFICACY (SURROGATE ENDPOINT – ACCOUNTS FULLY FOR THERAPEUTIC EFFICACY) * Mildvan D, et al.: Clin Infect Dis 1997;24:764-74.

  18. ONLY 2 SURROGATE ENDPOINTS FOR CARDIOVASCULAR DISEASE DRUGS* “THE ONLY SURROGATE ENDPOINTS CURRENTLY USED AS A BASIS FOR APPROVAL OF CARDIOVASCULAR DRUGS ARE BLOOD PRESSURE AND SERUM CHOLESTEROL LEVEL” * Temple R: Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 1999;282:790-95.

  19. UNREALISTIC EXPECTATIONS A surrogate marker is a response variable for which a test of the null hypothesis on no relationship to the treatment groups under comparison is also a valid test of the corresponding null hypothesis based on the true endpoint. Ross L. Prentice

  20. CHOLESTEROL CASE HISTORY • INITIAL CLINICAL UTILITY AS AN EPIDEMIOLOGIC BIOMARKER • PROGRESSION FROM BIOMARKER TO SURROGATE ENDPOINT FOR DRUG DEVELOPEMENT: THE SIMVASTATIN STORY • CAVEATS • FUTURE DIRECTIONS

  21. RELATION OF SERUM CHOLESTEROL TO CORONARY HEART DISEASE DEATH* * From Gotto AM Jr, et al. Circulation 81:1721-1733, 1990

  22. SIMVASTATIN DOSE-RESPONSE STUDY * NUMBER OF 1° CHOL PATIENTS: 43 NUMBER OF STUDY CENTERS 4 STUDY DURATION: 6 weeks SIMVASTATIN DOSE RANGE: ONCE DAILY: 2.5 - 40 mg/day TWICE DAILY: 1.25 - 40 mg bid * Mol MJTM et al. Lancet 1986;ii:936-9

  23. ESTIMATING DOSE RANGE FOR SUBSEQUENT PIVOTAL TRIAL Mol MJTM, et al. Lancet 1986;ii:936-9.

  24. SIMVASTATIN SURVIVAL STUDY * NUMBER OF CHD PATIENTS: 4444 NUMBER OF STUDY CENTERS: 94 MEDIAN FOLLOW-UP DURATION: 5.4 years SIMVASTATIN DOSING: INITIAL: 20 mg/day SUBSEQUENT TITRATION:  [Chol] to 117-200 mg/DL * 4S Study Group. Lancet 1994;344:1383-9

  25. RR = 0.70 (0.58-0.85) KAPLAN-MEIER CURVES FOR ALL-CAUSE MORTALITY * Scandinavian Simvastatin Survival Study Group. Lancet 1994:344;1383-9.

  26. CAVEATS REGARDING CHOLESTEROL AS A SURROGATE ENDPOINT • DOES THE EXTENT OF LOWERING • SERUM CHOLESTEROL CAPTURE ALL • THE BENEFICIAL EFFECTS OF STATIN • THERAPY? • IS SERUM CHOLESTEROL LOWERING • ACTIVITY BY ITSELF AN ADEQUATE • BASIS FOR DRUG APPROVAL?

  27. HMG-CoA REDUCTASE INHIBITOR CORONARY ARTERY DISEASE MI  CHOLESTEROL  OTHER RISK FACTORS, e.g. FAMILY HISTORY SMOKING INFLAMMATION CAD AND MI

  28. RELATION OF SERUM CHOLESTEROL TO CORONARY HEART DISEASE DEATH* * From Gotto AM Jr, et al. Circulation 81:1721-1733, 1990

  29. OBSERVED VS. PREDICTED CHD RATES* * From West of Scotland Coronary Prevention Study Group. Circulation 1998;97:1440-1445.

  30. EFFECT OF PRAVASTATIN ON CRP* CRP mg/dL * Ridker PM, et al. Circulation 1999;100:230-5

  31. BIOMARKERS FOR CHD RISK * * Ridker PM. Ann Intern Med 1999;130:933-7.

  32. CONJOINT BIOMARKERS FOR CHD RISK Binder CJ, et al. Nat Med 2002;8:1218-26.

  33. DOES CRP HAVE BIOLOGICAL PLAUSIBILITY AS A CHD BIOMARKER? • ORIGINALLY ISOLATED AS PROTEIN BINDING TO C-POLYSACCHARIDE OF PNEUMOCOCCI • TRADITIONAL VIEW: NON-SPECIFIC, ACUTE-PHASE REACTANT • SO IS CRP A BYSTANDER OR PARTICIPANT?

  34. ROLE OF CYTOKINES IN PLAQUE FORMATION Li AC, Glass CK. Nat Med 2002; 8:1235-42.

  35. + LIVER IL-6 CRP - + SERUM FACTOR - ASA SIMVASTATIN - PROPOSED PATHOGENIC ROLE OF CRP ENDOTHEL. MCP-1 MCSF + MACROPHAGE DIFFERENTIATION & PLAQUE FORMATION MONOCYTE MIGRATION TO SUBENDOTHELIUM

  36. CAVEATS REGARDING CHOLESTEROL AS A SURROGATE ENDPOINT • DOES THE EXTENT OF LOWERING • SERUM CHOLESTEROL CAPTURE ALL • THE BENEFICIAL EFFECTS OF STATIN • THERAPY? • IS SERUM CHOLESTEROL LOWERING • ACTIVITY BY ITSELF AN ADEQUATE • BASIS FOR DRUG APPROVAL?

  37. PROBUCOL • STRUCTURALLY UNRELATED TO STATINS • FAVORABLE ANTIOXIDANT PROPERTIES • DECREASES LDL BY ENHANCING • CLEARANCE • BUT • DECREASES HDL CHOLESTEROL • PROLONGS QT INTERVAL TOXICITY BIOMARKER - INITIALLY STUDIED ONLY IN MEN

  38. PROARRHYTHMIA ? SURVIVAL LIPID LOWERING AND SURVIVAL* PROBUCOL CORONARY ARTERY DISEASE  LDL MI  *Reinoehl J, et al. Am Heart J 1996;131:1184-91.

  39. BIOMARKERS FOR EFFICACY & TOXICITY • SURROGATE ENDPOINT FOR EFFICACY: SERUM CHOLESTEROL • BIOMARKER FOR EFFICACY: HIGH-SENSITIVITY C-REACTIVE PROTEIN • BIOMARKER FOR TOXICITY: QT-INTERVAL PROLONGATION

  40. FUTURE DIRECTIONS • NO SINGLE BIOMARKER/SURROGATE ENDPOINT IS LIKELY TO “CAPTURE” ALL THE EFFECTS OF A THERAPEUTIC INTERVENTION ON A CLINICAL ENDPOINT • COMBINATIONS OF BIOMARKERS AND SURROGATE ENDPOINTS WILL BE USEFUL IN CIRCUMVENTING THIS LIMITATION • “OMICS” TECHNOLOGIES WILL MAKE • MAJOR CONTRIBUTIONS TO OUR • BIOMARKER REPERTOIRE.

  41. CHOLESTEROL TRANSPORT* * From Barter P, Rye K-A. Clin Exp Pharmacol Physiol 1994;21:663-72.

  42. TaqI-B POLYMORPHISM IN CETP* TaqI-A TaqI-B VARIANT B1B1 ---- B1B2 ---- B2B2 FREQUENCY 35% 49% 16% CETP (µg/ml) 2.29 2.01 1.76 HDL (mg/dl) 34 36 39 * From Kuivenhoven JA, et al. N Eng J Med 1998; 338:86-93.

  43. 52% 33% 15% EFFECT OF CETP Taq1B GENOTYPE ON CAD PROGRESSION AND PRAVASTATIN RESPONSE* CHOLESTEROL ↓= IN ALL GENOTYPES *From: Kuivenhoven JA, et al. N Engl J Med 1998;338:86-93

  44. TAXONOMY OF “-OME’S” GENOME (DNA) “WHAT COULD HAPPEN” TRANSCRIPTOME (mRNA) “WHAT MIGHT BE HAPPENING” PROTEOME (PROTEINS) “WHAT IS HAPPENING” * FROM ANDERSON NL. THE NEXT STEP: EXPLORING THE PROTEOME NIH CONFERENCE, MAY 21, 2001 (http://proteome.nih.gov)

  45. PROTEOME SCAN OF KIDNEY FROM A CYCLOSPORINE-TREATED RAT* *From: Aicher L, et al. Electrophoresis 1998;19:1998-2003.

  46. VALIDATION VIA SPECIES SPECIFICITY* *From: Aicher L, et al. Biochem Pharmacol 1997;53:723-31.

  47. VALIDATION VIA DRUG SPECIFICITY* *From: Aicher L, et al. Biochem Pharmacol 1997;53:723-31.

  48. ROLAN’S LAW OF BIOMARKERS THE EXTENT OF VALIDITY OF A BIOMARKER VARIES INVERSELY WITH ITS INNOVATIVENESS * • CORROLARIES: • BIOMARKERS MORE LIKELY WELL VALIDATED • WHEN DEVELOPING “ME TOO” DRUGS • BIOMARKERS NOT LIKELY AS WELL VALIDATED • WHEN DEVELOPING DRUGS FOR UNMET • MEDICAL NEEDS * Rolan P: Br J Clin Pharmacol 1997;44:219-35.