Biomarkers;Biomarkers;Biomarkers;Biomarkers;Qualification, Validation and Use Qualification, Validation and Use

“Pharmacogenomic BMs”Pharmacogenomic BMs

Dr K Prasad MD FRCPMHRA, UK,Member of Pharmacogenomic Working

party of CHMP

©

DisclaimerDisclaimer

The views expressed are those of the presenter The views expressed are those of the presenter and not necessarily of MHRA/ EMA/CHMP…

h d d l h hpero no se han separado de los hechos.

Disculpas por no hablar en español ....... Todavía estoy tratando de aprender

©

Overview

Background

Ch i i f Bi k Characteristics of Biomarkers

Challenges with BMsg

What influences incorporation/use

What Trials and designs for validation/Qualification?!/Q

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Biomarkers are disruptive……

Represent an additional test burden

p

Represent an additional test burden

Need to establish role (and/or cost) in the context of drug development / use

Need Validation of test procedures Need Validation of test procedures

Need Sensitivity and Specificity

Clinical context need to be established.. (Why, When and How should new replace old?) When and How should new replace old?)

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Genomic BMs in Drug labels.

D t f EMA b it

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Data from EMA website

Commonly asked QuestionsCommonly asked Questions;;

Is the marker predictive [Is the marker predictive [of drug effect/ outcomeof drug effect/ outcome]?]?

Are the data consistent? Are the data consistent? (Validity)(Validity)

D h d IMPACT i ? D h d IMPACT i ? (U ili )(U ili ) Do the data IMPACT practice? Do the data IMPACT practice? (Utility)(Utility)

What & How to convey / EnforceWhat & How to convey / Enforce----label (SPC)label (SPC)yy

Tests?Tests?

Is a test necessary ?Is a test necessary ?

Is it specific /special? Is it specific /special? andand Is it specific /special? Is it specific /special? andand

Is it available generally?Is it available generally?

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BiomarkersBiomarkers

Different types Diagnostic, prognostic, predictive, and surrogate

Should be “Fit for purpose”;

Requirements (Regulatory) may differ based on :

IF BM linked to a medicine or not

With the therapeutic fieldTi i f d lTiming of assay development

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Definitions

Qualification “ i l i h h bi k d b i d

http://www.ema.europa.eu/pdfs/human/ich/38063609endraft.pdf

Qualification “ ……. is a conclusion that the biomarker data submitted support the use of the BM in drug discovery, drug development or post approval studies and where appropriate, in regulatory decision making pp pp p g y g(ICH E-16) ”.

Validation; …..establishing documented evidence that a process or system, when operated within established parameters, can perform ff i l d d ibl d bi k ( ± di i l effectively and reproducibly to produce a biomarker ( ± medicinal

product), that meets its pre-determined specifications and quality attributes.

..validity…. traditionally settled by debate, consensus and the passage of time”; ………..AAPS Journal, 2007

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the passage of time ; ………..AAPS Journal, 2007

BM QualificationBM QualificationNew regulatory pathway (CHMP/EMA)

Q lifi i Ad i

“Fit for purpose”

Qualification Advice on further methods development towards qualification,

based on the evaluation of the scientific rationale and on based on the evaluation of the scientific rationale and on available data.

Qualification Opinion on the acceptability of a specific use of the proposed

method (e g use of a biomarker) in a R&D context based method (e.g. use of a biomarker) in a R&D context, based on the assessment of data submitted.

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Validityy Valid

bi k th t i d i l ti l t t t a biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is widespread agreement in the medical for which there is widespread agreement in the medical or scientific community about ……. …… significance of the results.

Probably valid Probably valid ……for which there is a scientific framework or body of

evidence that appears to elucidate the physiologic evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results.

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Useful definitionsf f

SENSITIVITY: PREDICTIVE VALUE:

Sensitivity of a test (marker) is the percentage of all patients with disease who have a positive test

The predictive value of a test (marker) is a measure (%) of the times that the value is the disease who have a positive test

(marker).the times that the value is the true value:

SPECIFICITY:Specificity of a test (marker) is the

f ll i

TEST EFFICIENCY:The efficiency of a test is the

percentage of the times that percentage of all patients without disease who have a negative test.

percentage of the times that the test give the correct answer compared to the total gnumber of tests.

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F A i ti P di ti T tChallengeFrom Association a Predictive Test

Need to Balance neutropenia and efficacy in 7/7 positive

Slide from FDA Website

p ppatients:

Dose reduction of Irinotecan may be unnecessary for 50%, and may have unknown consequences

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and may have unknown consequences

Decision rules (cut off points);pdifficult?!!!

For BMs that quantify physiological states or therapeutic ff i i l hi h h b b l l response, cut off points crucial; higher the better, but lower values

useful

ALT or ALT +Bili for liver injury

DRB1*07 and DQA1*02.

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Clinical Validity

Test result (marker status) correlates with Test result (marker status) correlates with a clinical endpoint

May be established in a retrospective study, but replication needed

Needs analysis of Sn, Sp, PPV, and NPV against a « standard of truth », g ,

Does the test improve PPV and NPV over standard prognostic factors ??over standard prognostic factors ??

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Liver injury – recent exampleAnalgesic productAnalgesic product

T h e m a r k e r s w e r e p r e d i c t i v e f o r C a u c a s i a n p o p u l a t i o n ;not so useful for other populationsnot so useful for other populations.

It was validated in the “Target” study population ( n=18000) using a testing sample and a validation sample.

Probably valid.. But more evidence needed for utility

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Clinical utilityClinical utility

Use of the test improves outcome for the patient p p

Outcome measure should reflect patient benefit

Test informs therapeutic decision

Diff t i i BM tt h d t di i Different scenarios in BM attached to a medicine (predictive BM):

- Drug diagnostic co development- « Rescue » diagnostics (post marketing)

- « Retrofit » diagnostics (patent expiry/generics)

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KRAS storyy

Several Interesting issues; Several Interesting issues; • Prognostic or Predictive

2nd Renewal- suggested that use of Vectibix in mutated KRAS may be detrimental –a Safety BM.

• Relationship with BRAF, NRAS, etc.. (??)De Rook W et al; Lancet oncol De Rook W et al; Lancet oncol,

11:753-62, 2010

H i h l i l k ?oWild type vs mutant KRAS, Impact on PFS;

o Retrospective analysis; (prosp defined)

How to use with multiple markers ?

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TPMT test;

Identified in 1980 (Weinshilboum et al) Identified in 1980 (Weinshilboum et al) Simple test for inheritance of polymorphism TPMT*2 and TPMT*3 alleles- “Recessive” TPMT 2 and TPMT 3 alleles Recessive 1:300 incidence of hymozygotes Use of thiopurines ( 6-Mp, Azathioprine, & others)

EN22214 report on TPMT (

Use of thiopurines ( 6 Mp, Azathiop ine, & othe s) associated with bone marrow suppression.

EN22214 report on TPMT (EU commissioned study –2006)

TPMT--Testing is cost effective!!

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TPMT test; Azathioprine Product labelling amended to include reference to TPMT status; [FDA have approved ( ) f d i i f TPMT ](2004) test for determination of TPMT status]

But variable Perception of UtilityBut variable Perception of Utility British Association of Dermatologistsg

Recommend Pretreatment TPMT determination in all

British Thoracic Society saysy y No requirement for TPMT testing in Interstitial Lung

Disease

British Society of Gastroenterology says TPMT status determination ‘cannot yet be

d d i i h ’

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recommended as a prerequisite to therapy’

Warfarin

Cl it ? /S ifi it

[Posted 08/16/2007] This new information explains that people's genetic makeup may influence

how they respond to the drug. Specifically, people with variations in two Clarity? /Specificityhow they respond to the drug. Specifically, people with variations in two genes

may need lower warfarin doses ………………………………………

than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability g p g yof warfarin to prevent blood from clotting.

The dosage and administration of warfarin must be individualized for each patient according to the particular patient's prothrombin time……………………………….

( )(PT) / International Normalized Ratio (INR) response to the drug. ……Ongoing warfarin therapy should be guided by continued INR monitoring. Is this sufficiently specific clear?

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g Is this sufficiently specific, clear?

Marker, validity and utility

Abacavir Carbemazepine WarfarinAbacavir Carbemazepine WarfarinMarker HLA-B*5701 HLA B* 1502

& HLAB*3101CYP 450 SNPs+

VKORC13

Discovery Retrospective Retrospective Retrospective

Confirmatory id

Prospective study Retrospective Variableevidence Prospective study not

feasible

R li i Y Y iReplication Yes Yes ongoing

Validity Clear evidence Clear evidence of harm Evidence of associationD i lt ti ??Dosing alteration??

Utility Clear Clear Contradictory

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Trials designs for validity/ Trials designs for validity/ UtilityUtility

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Clinical Trial Designs Clinical Trial Designs –– Unselected designUnselected design

ALL subjects

Test as possible

ALL subjects

Data on BMs needed from majority of subjects

PBO Drugin a CT for validation

Interaction analysis between

d treatment and test

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Iressa in NSCLCIressa in NSCLC

Authorised in 2009 in EUMajority of evidence was exploratory / retrospectiveMajority of evidence was exploratory / retrospective

Pooled analysis was considered supportive

CHMP- --Replicated “marker- response interaction ”CHMP Replicated marker response interaction..

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Clinical Trial Designs (2)Clinical Trial Designs (2)Clinical Trial Designs (2)Clinical Trial Designs (2)Enriched or targeted designEnriched or targeted design

Test -No information onefficacy or safety Test

ALL testedALL subjects

efficacy or safety in this group

Test +

Drug PlaceboDrugs would be integrally Drug Placebolinked with availability and use of the biomarker test at the time of approval

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the time of approval.

Targeted DesignHer-2 over-expression

Herceptin: Typical example

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Herceptin

Clarity helps implementation 1/9/2012 K Prasad 27

Clarity helps implementation

‘Marker by Rx-interaction’ Design MARVEL Trial-- erlotinib

Gives the “ideal” comparisonsInformation about all groupsDisadvantage;

Large sample size

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Risk of Rx-ing some Non-responders

Clinical Trial Design –(4)

“Hybrid design”Hybrid design

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C tCaveats

PPV and NPV are influenced by prevalence of the k i h l i marker rates in the population

Predictive values need to be generated in populations that reflect anticipated clinical use.

Enriched design… does not validate the marker (!) or define its utility.

Observational studies provide an opportunity to p pp ymerge retrospective cohorts to evaluate them prospectively….. Question is How best to Use

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them?

Impact on labelImpact on label

SPC extract AbacavirSPC extract

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Carbamazepine Carbamazepine

Possible example of what to include in advice.. But becomes complex

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complex

Limitations of Retrospective data setsLimitations of Retrospective data sets

Often from non-randomised studies (or associations)(or associations)

Inability to replicate the results first result is usually best ---Winner’s curse first result is usually best ---Winner s curseoften -overestimation of effect size underpowered FU studies (sample sizes)underpowered FU studies (sample sizes) Phenotype heterogeneity..

Potential for Bias(es) Potential for Bias(es)

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Conditions/ caveats for Conditions/ caveats for Retrospective data sets ( for validation)

Ideally Data from well conducted RCT/s

Biological sample availability should be from all subjects; or from the majorityj ; j y

Prospectively stated hypothesis

P ti l t t d l i l Prospectively stated analysis plan

Replication ………..…

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Other influences impacting use p g

R and D activityPublic Sector Research

groups in EU, Jpn & USAy Commercial Focus Public sector focus

groups n EU, Jpn & USHopkins M, 2006 Nat Biotech

Awareness Education

Schools /institutions (Medical/Pharmacy)

Health care professionals Health care professionals Public

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For BMs, reality is Validation and Utility

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Utility

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