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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
ANTIHYPERTENSIVE
DRUG

 BLOOD
PRESSURE
HYPERTENSION
STROKE
OTHER RISK FACTORS
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 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
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
CLASS
BIOMARKER/
SURROGATE
ANTIHYPERTENSIVE
 B.P.
DRUGS FOR GLAUCOMA
 I.O.P.
OSTEOPOROSIS DRUGS
 BONE DENSITY
ANTIARRHYTHMIC
 ARRHYTHMIAS
CLINICAL
OUTCOME
 STROKE
 LOSS OF VISION
 FRACTURE RATE
 SURVIVAL
EXAMPLES OF LABORATORY ENDPOINTS
THERAPEUTIC
CLASS
BIOMARKER/
SURROGATE_
CLINICAL
OUTCOME
ANTIBIOTICS
NEG. CULTURE
CLINICAL CURE
ANTI-DIABETIC
 BLOOD GLUCOSE
 MORBIDITY
 CHOLESTEROL
LIPID LOWERING DRUGS
DRUGS FOR PROSTATE CA
ANTI-HIV DRUGS
 PSA
 CD4; VIRAL RNA
 CAD
TUMOR RESPONSE
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
MARKER
INTERMEDIATE
ENDPOINT
VENTRICULAR VENTRICULAR
ECTOPY
FIBRILLATION
ULTIMATE
OUTCOME
SURVIVAL
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.
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
Biomarkers
(for Toxicity)
20.4
Provisional Evaluation
of Efficacy and Toxicity
Surrogate
Endpoints
(for Toxicity)
Continuing Assessment
of Benefit to Risk Ratio
Clinical Endpoints
(for Toxicity)
* From Biomarkers Definitions Working Group
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
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 on
the 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
% CHOLESTEROL DECREASE
ESTIMATING DOSE RANGE FOR
SUBSEQUENT PIVOTAL TRIAL
40.0
30.0
20.0
10.0
0.0
0
20
40
60
80
SIMVISTATIN DOSE (mg/day)
Mol MJTM, et al. Lancet 1986;ii:936-9.
SIMVASTATIN SURVIVAL STUDY *
NUMBER OF CHD PATIENTS:
4444
NUMBER OF STUDY CENTERS:
MEDIAN FOLLOW-UP DURATION:
94
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
RR = 0.70
(0.58-0.85)
* Scandinavian Simvastatin Survival Study Group. Lancet 1994:344;1383-9.
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
HMG-CoA
REDUCTASE
INHIBITOR
CORONARY
ARTERY
DISEASE

 CHOLESTEROL
MI
OTHER RISK FACTORS, e.g.
FAMILY HISTORY
SMOKING
INFLAMMATION
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.
CRP mg/dL
EFFECT OF PRAVASTATIN ON CRP*
* Ridker PM, et al. Circulation 1999;100:230-5
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
+
LIVER
IL-6
CRP
+
SERUM FACTOR
-
SIMVASTATIN
ASA
ENDOTHEL.
MCP-1
MCSF
+
MACROPHAGE
DIFFERENTIATION &
PLAQUE FORMATION
MONOCYTE MIGRATION
TO SUBENDOTHELIUM
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 TOXICITY BIOMARKER
- INITIALLY STUDIED ONLY IN MEN
LIPID LOWERING AND SURVIVAL*
PROARRHYTHMIA
PROBUCOL
CORONARY
ARTERY
DISEASE

 LDL
 MI
? SURVIVAL
*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*
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.
EFFECT OF CETP Taq1B GENOTYPE ON CAD
PROGRESSION AND PRAVASTATIN RESPONSE*
52%
33%
15%
CHOLESTEROL ↓= IN ALL GENOTYPES
*From: Kuivenhoven JA, et al. N Engl J Med 1998;338:86-93
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*
SPECIES
RENAL
CYCLOSPORINE
CALBINDIN-D 28kDa NEPHROTOXICITY
RAT


DOG
N.C.
0
MONKEY
N.C.
0


MAN
*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 *
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.