PHYSIOLOGICAL AND LABORATORY MARKERS OF DRUG EFFECT

Arthur J. Atkinson, Jr., M.D.Senior Advisor in Clinical Pharmacology

Clinical Center, NIH

USES OF BIOMARKERS

• CLINICAL PRACTICE:– ESTABLISH DIAGNOSIS AND PROGNOSIS

– MONITOR RESPONSE TO THERAPY

• DRUG DEVELOPMENT:– MANY USES

TREATMENT OF HIGH BLOOD PRESSURE

STROKEHYPERTENSION

BLOOD PRESSURE

OTHER RISK FACTORS

ANTIHYPERTENSIVE DRUG

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.

DEFINITION (clinical)

A surrogate endpoint of a clinical trial is alaboratory measurement or a physical signused 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

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…”

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.

EXAMPLES OF PHYSIOLOGIC ENDPOINTS

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

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

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

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.

EXAMPLE: LIDOCAINE IN ACUTE MI

BIOLOGICAL INTERMEDIATE ULTIMATE MARKER ENDPOINT OUTCOME

VENTRICULAR VENTRICULAR SURVIVAL ECTOPY FIBRILLATION

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.

SurrogateEndpoints

(for Efficacy) 20.4

Biomarkers (for Efficacy)

Clinical Endpoints(for Toxicity)

Clinical Endpoints(for Efficacy)

Evidence that a Biomarker is

Reasonably Likely to Predict Clinical

Benefit

Provisional Evaluation of Efficacy and Toxicity

Biomarkers (for Toxicity)

Continuing Assessment of Benefit to Risk Ratio

EVOLUTION OF BIOMARKERS TO SURROGATE ENDPOINTS*

* From Biomarkers Definitions Working Group

Surrogate Endpoints

(for Toxicity)

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 CONFOUNDINGSTATISTICAL CRITERIA• CHANGES IN MARKER MUST BE CORRELATED WITH CLINICAL OUTCOME

• BUT CORRELATION DOES NOT EQUAL CAUSATION

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.

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.

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.

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 onthe true endpoint. Ross L. Prentice

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

RELATION OF SERUM CHOLESTEROL TO CORONARY HEART DISEASE DEATH*

* From Gotto AM Jr, et al. Circulation 81:1721-1733, 1990

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

ESTIMATING DOSE RANGE FOR SUBSEQUENT PIVOTAL TRIAL

0.0

10.0

20.0

30.0

40.0

0 20 40 60 80

SIMVISTATIN DOSE (mg/day)

% C

HO

LE

ST

ER

OL

DE

CR

EA

SE

Mol MJTM, et al. Lancet 1986;ii:936-9.

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

KAPLAN-MEIER CURVES FOR ALL-CAUSE MORTALITY

* Scandinavian Simvastatin Survival Study Group. Lancet 1994:344;1383-9.

RR = 0.70 (0.58-0.85)

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?

CAD AND MI

CORONARY ARTERY DISEASE

MI

CHOLESTEROL

OTHER RISK FACTORS, e.g. FAMILY HISTORY SMOKING INFLAMMATION

HMG-CoAREDUCTASEINHIBITOR

RELATION OF SERUM CHOLESTEROL TO CORONARY HEART DISEASE DEATH*

* From Gotto AM Jr, et al. Circulation 81:1721-1733, 1990

OBSERVED VS. PREDICTED CHD RATES*

* From West of Scotland Coronary Prevention Study Group. Circulation 1998;97:1440-1445.

EFFECT OF PRAVASTATIN ON CRP*

* Ridker PM, et al. Circulation 1999;100:230-5

CR

P m

g/d

L

BIOMARKERS FOR CHD RISK*

* Ridker PM. Ann Intern Med 1999;130:933-7.

CONJOINT BIOMARKERS FOR CHD RISK

Binder CJ, et al.Nat Med 2002;8:1218-26.

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?

ROLE OF CYTOKINES IN PLAQUE FORMATION

Li AC, Glass CK. Nat Med 2002; 8:1235-42.

PROPOSED PATHOGENIC ROLE OF CRP

SIMVASTATIN-

-

ASA

-

IL-6 CRP+ LIVER

+ SERUM FACTOR

MONOCYTE MIGRATION TO SUBENDOTHELIUM

MACROPHAGE DIFFERENTIATION & PLAQUE FORMATION

MCSF MCP-1+

ENDOTHEL.

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?

PROBUCOL

• STRUCTURALLY UNRELATED TO STATINS

• FAVORABLE ANTIOXIDANT PROPERTIES

• DECREASES LDL BY ENHANCING CLEARANCE

BUT• DECREASES HDL CHOLESTEROL• PROLONGS QT INTERVAL

- INITIALLY STUDIED ONLY IN MEN

TOXICITY BIOMARKER

LIPID LOWERING AND SURVIVAL*

CORONARYARTERYDISEASE

LDL

PROBUCOL

? SURVIVAL

PROARRHYTHMIA

MI

*Reinoehl J, et al. Am Heart J 1996;131:1184-91.

BIOMARKERS FOR EFFICACY & TOXICITY

• SURROGATE ENDPOINT FOR EFFICACY:

SERUM CHOLESTEROL

• BIOMARKER FOR EFFICACY:

HIGH-SENSITIVITY C-REACTIVE PROTEIN

• BIOMARKER FOR TOXICITY:

QT-INTERVAL PROLONGATION

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.

CHOLESTEROL TRANSPORT*

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

TaqI-B POLYMORPHISM IN CETP*

* From Kuivenhoven JA, et al. N Eng J Med 1998; 338:86-93.

VARIANT B1B1 ---- B1B2 ---- B2B2

FREQUENCY 35% 49% 16%

CETP (µg/ml) 2.29 2.01 1.76

HDL (mg/dl) 34 36 39

TaqI-A

TaqI-B

EFFECT OF CETP Taq1B GENOTYPE ON CAD PROGRESSION AND PRAVASTATIN RESPONSE*

*From: Kuivenhoven JA, et al. N Engl J Med 1998;338:86-93

CHOLESTEROL ↓= IN ALL GENOTYPES

33%

52%

15%

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)

PROTEOME SCAN OF KIDNEY FROM A CYCLOSPORINE-TREATED RAT*

*From: Aicher L, et al. Electrophoresis 1998;19:1998-2003.

VALIDATION VIA SPECIES SPECIFICITY*

*From: Aicher L, et al. Biochem Pharmacol 1997;53:723-31.

VALIDATION VIA DRUG SPECIFICITY*

*From: Aicher L, et al. Biochem Pharmacol 1997;53:723-31.

ROLAN’S LAW OF BIOMARKERS

THE EXTENT OF VALIDITY OF A BIOMARKER VARIES INVERSELY WITH

ITS INNOVATIVENESS *

* Rolan P: Br J Clin Pharmacol 1997;44:219-35.

CORROLARIES:

• BIOMARKERS MORE LIKELY WELL VALIDATED WHEN DEVELOPING “ME TOO” DRUGS

• BIOMARKERS NOT LIKELY AS WELL VALIDATED WHEN DEVELOPING DRUGS FOR UNMET MEDICAL NEEDS