1
Biomarkers and Clinical CareBiomarkers and Clinical Care
Lessons Learned from Case Studies:Lessons Learned from Case Studies:The Challenges and the Promise of The Challenges and the Promise of
Predictive BiomarkersPredictive Biomarkers
Steven D. Averbuch, MDSteven D. Averbuch, MDVice President, Oncology Transition Strategy & Development and Vice President, Oncology Transition Strategy & Development and
Head, PharmacodiagnosticsHead, Pharmacodiagnostics
Global Clinical ResearchGlobal Clinical Research
Bristol-Myers SquibbBristol-Myers Squibb
2
Disclosure
I am an employee of Bristol-Myers Squibb Company and I own stock in Bristol-Myers Squibb and in other pharmaceutical companies
Bristol-Myers Squibb manufactures and sells Plavix ®® and Erbitux®®
Any reference to information not contained within drug labeling is unintentional.
3
Personalized Medicine A shift from conventional disease oriented approach to biologically
defined personalized approach leads to improved performance of drugs
Test for drug response*
60% benefit from therapy
86% benefit from therapy
Try alternate therapy
High response to therapy Low response to therapy
Pla te 0000066592 Pro c e ss G ro up 0799006 Ma rke r WI7466-1 (#592)
Sta tus:GetGenos PassUser: vish Pass
Unkno wns: #Wells
Passed 84Failed 0
Averages X YXX 2.77 0.14XY 2.78 2.65YY 0.15 2.74
Co ntro ls: (Ma x)
X YNEG - PCR 0.12 0.07Syn 2.68 0.36
6659266592
0
0.5
1
1.5
2
2.5
3
3.5
0 0.5 1 1.5 2 2.5 3 3.5
Neg.
Unknown
Synthetic Temp
A/A
C/C
A/C
Treat
TEST
Don’t Treat?
* Specific blood, tissue or imaging marker that can be used to prospectively identify patients for efficacy, safety and/or dose
4
PharmacodiagnosticsThe Hype Surrounding Personalized Medicine Needs to
be Balanced Against Many Challenges
Research & Development
Regulatory
Commercial / Economics
5
PharmacodiagnosticsThe Hype Surrounding Personalized Medicine Needs to
be Balanced Against Many Challenges Research & Development
– Establishing molecular mechanism and biomarkers– Selecting and optimizing diagnostic platforms– Clinical specimen acquisition– Clinical validation– Potential decrease in therapeutic development productivity– Relevant biomarker science is often out of step with drug
development timing
6
Test Validation
Patient Stratification
Clinical Validation
Clinical Utility
Marketing Authorization
--- Dx DEVELOPMENT---
Co-Development: Drug and PDx Ideal Paradigm
--- MARKER DISCOVERY---
Identify Stratification Markers
Assay Development
Test Development
Ph I
Exploratory discovery
Early discovery
Full discovery Exploratory Development
Full development, Regulatory Approval
Commercial Prep
Launch and LCM
Target ID Lead discovery Pre-clin Ph IIa Ph IIb Ph III File Phase IV
7
Only In Few Cases Have Subgroups Been Defined in Only In Few Cases Have Subgroups Been Defined in Advance With Formal AnalysisAdvance With Formal Analysis
Imatinib and Kit + GIST (prospective, preapproval)
Dasatinib and PH + ALL (prospective, preapproval)
Maraviroc and CCR5 + (tropic) HIV-1 (prospective, preapproval)
Tetrabenazine and 2D6 dosing (prospective, preapproval)
Trastuzumab and HER2+ Br Ca (“prospective”, preapproval)
L. Lesko, FDA
8
How Pharmacodiagnostics can Streamline Clinical Development and Increase
Value
10-12 years 5-7 years
Broad patient population
Traditional clinical trials
Responders only
Pharmacogenomics-based trials
Cost of Development >$1,000 Million <$500 Million
Success Rate 5-10% 25-50%
Patients Per NDA > 2,000 > 600
Value Good BetterSource: Pharma 2010: The Threshold of Innovation.
9
Trial Design to Establish Clinical Utility:An Ideal Situation
A definitive clinical study for a drug used in conjunction with a predictive biomarker allows for assessment of a drug’s safety and efficacy and for verification of the clinical utility of the biomarker in guiding the drug’s use including appropriate patient selection, and consequently enables labeling
10
Only In Few Cases Have Subgroups Been Defined in Only In Few Cases Have Subgroups Been Defined in Advance With Formal AnalysisAdvance With Formal Analysis
Imatinib and Kit + GIST (prospective, preapproval)
Dasatinib and PH + ALL (prospective, preapproval)
Maraviroc and CCR5 + (tropic) HIV-1 (prospective, preapproval)
Tetrabenazine and 2D6 dosing (prospective, preapproval)
Trastuzumab and HER2+ Br Ca (“prospective”, preapproval)
Nilotinib and UGT hyperbilirubin (retrospective, preapproval)
Abacavir and HLAB*5701 HAS (prospective, post-approval)
Clopidegrel and 2C19 “resistance” (prospective, post-approval)
Cetuximab / Panitumamab and KRAS (retrospective, post-approval)
Carbamazepine and HLAB*1502 SJS (retrospective, post-approval)
Warfarin and 2C9/VKORC1 dosing (retrospective, post-approval)
L. Lesko, FDA
11
Test Validation
Patient Stratification
Clinical Validation
Clinical Utility
Marketing Authorization
--- Dx DEVELOPMENT---
Co-Development: Drug and PDx Ideal Paradigm
--- MARKER DISCOVERY---
Identify Stratification Markers
Assay Development
Test Development
Ph I
Exploratory discovery
Early discovery
Full discovery Exploratory Development
Full development, Regulatory Approval
Commercial Prep
Launch and LCM
Target ID Lead discovery Pre-clin Ph IIa Ph IIb Ph III File Phase IV
Scientific K
nowledge Timed to
Enable Prospectiv
e & Paralle
l
Drug-D
iagnostic C
o-Development
is th
e
Exception – N
ot the R
ule
12
PharmacodiagnosticsThe Hype Surrounding Personalized Medicine Needs to
be Balanced Against Many Challenges Research & Development
– Establishing molecular mechanism and biomarkers– Selecting and optimizing diagnostic platforms– Clinical specimen acquisition– Clinical validation– Potential decrease in therapeutic development productivity– Relevant biomarker science is often out of step with drug development timing
Regulatory– Integrated regulatory requirements (e.g., evidentiary standard)
are not established and currently inconsistent– Regulatory and reimbursement standards within and across
major markets (US, EU, and JP) are not harmonized
13
Classified by Risk:I Low RiskII Med Risk 510KIII High Risk PMA
• Analytical Validation• System Quality• Clinical Validation not
required
14
Regulatory Considerations for Drug/Diagnostic Development
Integrated regulatory requirements (e.g., evidentiary standard) are not established and currently inconsistent
Regulatory and reimbursement standards within and across major markets (US, EU, and JP) are not harmonized
US: both drugs and diagnostics are regulated by FDA– drugs under CDER or CBER
– IVDs under CDRH PMAs and 510Ks
– LDTs under CMS (CLIA)
EU: – centralized drug approval
– devices are certified (CE mark) via conformity assessment
15
PharmacodiagnosticsThe Hype Surrounding Personalized Medicine Needs to
be Balanced Against Many Challenges Research & Development
– Establishing molecular mechanism and biomarkers– Selecting and optimizing diagnostic platforms– Clinical specimen acquisition– Clinical validation– Potential decrease in therapeutic development productivity– Relevant biomarker science is often out of step with drug development timing
Regulatory– Integrated regulatory requirements (e.g., evidentiary standard) are not established and currently
inconsistent– Regulatory and reimbursement standards within and across major markets (US, EU, and JP) are not
harmonized
Commercial / Economics– Incentives poorly aligned between stakeholders– Liability and IP issues– Market access for the diagnostic and for therapeutic
Physician Education Laboratory Testing Infrastructure, Distribution and Reimbursement
– Market share and pricing for the therapeutic– Diagnostic value and the diagnostic company return on investment
16
Diagnostic Company (Diag, Inc.) Business Model
Diag, Inc. sell diagnostic products, the pharmaceutical company sell drugs
– Diag, Inc. provides the tools for patients, providers, payers, regulators and pharmaceutical company
Constraints to viability of the diagnostic business:– A) need for clinical trial as stated by FDA– B) cost of clinical trial for clinical validation of a companion
pharmacodiagnostic– C) relatively low price of reimbursement– D) no protection from LDT’s, homebrews– E) Diag, Inc. can only survive with Rx support so lack of
intrinsic value limits innovation
P. Collins, Qiagen
17
Pharmacodiagnostic Case Studies
Clopidogrel
Lung Cancer
Abacavir
Cetuximab
18
Polymorphisms: Potential Factors Contributing to Variability of Response to Clopidogrel
Clopidogrel has to be converted to an active metabolite (bioactivation)
Bioactivation is achieved via P450 enzyme(s)-mediated metabolism
CYP2C19, CYP3A4, CYP1A2 and CYP2B6 are involved in bioactivation,
Other CYP enzymes are being studied
Active metabolite generation may vary through: Drug-drug interaction (e.g. potentially
Omeprazole)
Polymorphism of CYP 450 enzymes
Hirota T, et al. Clin Pharmacol Ther 1999;65:148Plavix Package Insert October 2007Herbert JM, et al. Semin Vasc Med 2003;2:113-21
UM (31%) Ultra-Metabolizers*1*17*17/*17
EM (39%) Extensive Metabolizers
*1/*1
IM (21 %) Intermediate Metabolizers
*1/*2, *1/*3
PM (2.4 %) Poor Metabolizers*2/*2, *2/*3 and *3/*3
Unknown (6.8 %) *2/*17
2C19 Metabolizer phenotypes*
* Frequencies observed in CHARISMA
19
Mega Study CYP2C19*2 predicts worse outcome
– 1 or 2 copies of variant
No data for other CYP2C19 alleles– Gain of function: *17
*1/*1 ~ 40% Caucasian
*1/*17 or *17/*17 ~ 35% Caucasian
*2/*17 ~ 5% Caucasian
– Loss of function: *3, *4, *5 All rare in Caucasian
*3: 6 % - Chinese
*3/ 26% - Japanese
CYP2C19*1/*2 ~27% of CaucasiansCYP2C19 *2/*2 ~3% of Caucasians
CYP2C19*1/*1 ~70% of Caucasians
12.1 %
Prim
ary
Eff
icac
y O
utco
me
(%)
Days since Randomization
P = 0.018.0 %
Mega et al, N Engl J Med 2009; 360:354-62
20
Simon Study Registry analysis( n=2208)
CYP2C19*2*2, not CYP2C19 *1*2 were at risk for a MACE
Simon et al, N Engl J Med 2009; 360:363-75
21
October, 2006Hulot et al identify CYP2C19 polymorphisms as major determinant of variability in platelet aggregation in healthy subjects; additional publications later confirm this finding
2006 2007 2008
May, 2008Trenk et al find CYP2C19 polymorphismis associated with adverse outcomes forpatients on clopidogrel followed for one year
2009
December, 2008Three additional outcome studies, including TRITON-TIMI 38, demonstrate a higher risk of CV events for CYP2C19 poor metabolizers on clopidogrel
May, 2009FDA revises clopidogrel label to include descriptiveInformation about individuals with geneticallyreduced CYP2C19 activity
Emerging information established a role for CYP2C19 in clopidogrel response
Oct, 2009 Press Release:Quest Diagnostics Brings Genetic Testing for
Plavix(R) Response to Coronary Stent Patients at Scripps Health; First saliva-based
cardiovascular disease test from Quest Diagnostics identifies gene variants implicated in potentially lethal reaction to popular anti-clotting
drug
2010
October, 2009 Press Release: MEDCO announces the
“Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study” to enroll >
14,000 patients with ACS
22
Does Variability of Platelet Response correlate to Variability of Clinical Outcomes?
Adapted from: Serebruany V, et al. J Am Coll Cardiol 2005;45:246-51
To date, no definitive correlation has been established between the level of platelet response and clinical outcomes
23
Outstanding Questions for Genomic Testing for Clopidogrel Therapy
Quest Diagnostics Press Release (Oct, 2009)– “Patients who test positive for the mutated alleles
may receive alternative treatments based on a variety of factors. These treatments may include”
increased monitoring increased dosage of clopidogrel the use of alternative therapies
24
Outstanding Questions for Genomic Testing for Clopidogrel Therapy
Quest Diagnostics Press Release (Oct, 2009)– “Patients who test positive for the mutated alleles
may receive alternative treatments based on a variety of factors. These treatments may include”
increased monitoring increased dosage of clopidogrel the use of alternative therapies
More Evidence-based Medicine Required Challenging Landscape with Multiple
Stakeholders–Regulatory–Providers–Payors
25
Results of PREDICT-I (Mallal et al, New Eng J Results of PREDICT-I (Mallal et al, New Eng J Med, 2008)Med, 2008)
0
1
2
3
4
5
6
7
8
9
Inci
den
ce (
%)
3.4%(27/803)
7.8%(66/847)
2.7%(23/842)
OR 0.40P < 0.0001
OR 0.03P < 0.0001
Control arm
Prospective HLA-B*5701 screening arm
Clinically SuspectedHSR
Immunologically ConfirmedHSR
0.0%(0/802)
(0.25, 0.62)
(0, 0.18)
Patch Test
PPV = 48%
NPV = 100%
26
HLA-B*5701 association in two
independent groups
2002 2004 2006
Discovery
2008
From Research to Clinical Practice:The Abacavir Paradigm*
2010
* Adapted from Phillips & Mallal, Personalized Med. 6:393, 2009
Clinical Evidence(High Level) Clinical Application
(Depends on Lab Test) Clinical Adoption &Performance Evaluation
Genetic & Cellular Studies
PREDICT-1, SHAPE, &
observational studies
HIV Treatment Guidelines &
Labeling Change
PCR-based techniques
Ongoing studies & QA
27
Introduction of HLA-B*5701
Testing
Pharmacodiagnostic Case Study: Abacavir HypersensitivityIncreased Value with Introduction of PDx – Giving the Right Drug to the Right Patient
28
Companion Pharmacodiagnostics: individualized medicine in cancer
PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromelysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBeta-actinGAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0 -100)
Low risk RS <18
Int risk RS 18 - 30
High risk RS ≥ 31
Paik et al. N Engl J Med. 2004;351:2817-2826.
RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score + 0.05 x CD68- 0.08 x GSTM1- 0.07 x BAG1
Oncotype DX® 21-Gene Recurrence Score (RS) Assay
BATTLE I
I-SPY 2
TailorRx
BATTLE II
BATTLE III
29
Companion Pharmacodiagnostics: individualized medicine in cancer
30
Companion Pharmacodiagnostics: individualized medicine in cancer
"Here's my
sequence..."
31
ErbituxErbitux®® (Cetuximab) FDA Approved (Cetuximab) FDA Approved IndicationsIndications
Clinical SettingClinical SettingTumor SelectionTumor Selection
CriteriaCriteria
Colorectal CancerColorectal Cancer
Erbitux with IrinotecanErbitux with Irinotecan
20042004
Patients refractory to irinotecan Patients refractory to irinotecan containing therapycontaining therapy
EGFR-expressingEGFR-expressing
Erbitux as Single agentErbitux as Single agent
20042004
Patients intolerant of irinotecan Patients intolerant of irinotecan containing therapycontaining therapy
EGFR-expressingEGFR-expressing
Erbitux as Single agentErbitux as Single agent
20072007
After failure of both irinotecan and After failure of both irinotecan and oxaliplatin containing therapyoxaliplatin containing therapy
EGFR-expressingEGFR-expressing
Head & Neck CancerHead & Neck Cancer
Erbitux with Radiation Erbitux with Radiation Therapy 2006Therapy 2006
Locally or regionally advancedLocally or regionally advancedSCCHNSCCHN
NoneNone
Erbitux as Single agentErbitux as Single agent20062006
Recurrent / metastatic SCCHN after Recurrent / metastatic SCCHN after failure of platinum based therapyfailure of platinum based therapy
NoneNone
32
History of Companion Drug-Diagnostic Considerations for Cetuximab (2002 - 2007)
Early clinical development assumed EGFR expression would be predictive of benefit
– Specificity of cetuximab for its target
– Precedent for other targeted mAbs (e.g. trastuzumab, rituxumab)
Continuous and dedicated effort by academic and industry scientists to validate EGFR expression as a predictive marker and to further improve patient selection criteria for improved therapeutic index
– Preclinical models and biomarker discovery
– Exploratory prospective pharmacogenomic trial
Insufficient scientific foundation for prospectively incorporating other predictive markers (e.g. K-ras) at the time that 4 large randomized clinical trials were initiated in 1st, 2nd, & 3rd line treatment for CRC
33
Key K-Ras Events: April 2008 – July 2009
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug
VGDS to FDA
ASCO & World GI
K-Ras presentations
NCI / CTEP Action Letter
K-Ras in ERBITUX European
label
NCIC CO.17 K-Ras NEJM publication
NCCN changes
guidelines
FDA ODAC Meeting
Class Label Change in
US
20092008
•New class label for “lack of benefit in K-ras mutants”
•FDA PMA approved diagnostic required before labeling can describe benefit in K-Ras WT
ASCOProvisional
Clinical opinion
34
KRAS Testing and Regulation
EU Vectibix and Erbitux are indicated for KRAS WT CRC
– Approval supported by retrospective data– EMEA required a CE marked test
Not considered a high risk device by EU directive
USA Vectibix and Erbitux label update in 2009 based on safety information
– no treatment benefit for patients with KRAS mutations. Treatment not recommended for patients with KRAS mutations
Since treatment decisions will be based on test results, a PMA approved kit is required before a efficacy claim on benefit for KRAS WT
– Considered Class III high risk device
– FDA approved KRAS test under development
35
Predictive Biomarkers:Predictive Biomarkers:Lessons LearnedLessons Learned
Subgroup analyses – either prospective or retrospective - have Subgroup analyses – either prospective or retrospective - have become routinebecome routine
– Often exploratory but may influence labeling/approvalOften exploratory but may influence labeling/approval
– Recent examples of analyses showing associations between biomarker Recent examples of analyses showing associations between biomarker and outcomes have rapidly influenced medical practiceand outcomes have rapidly influenced medical practice
Clinical utility of a diagnostic test and level of evidence may be Clinical utility of a diagnostic test and level of evidence may be elusive elusive
– Impact of false + or false – in the context of useImpact of false + or false – in the context of use
– How will individualized therapy (e.g., in cancer) be generalized to How will individualized therapy (e.g., in cancer) be generalized to populations for evidence based medicinepopulations for evidence based medicine
Diagnostic ConsiderationsDiagnostic Considerations
– Diagnostic company development – technical and commercialDiagnostic company development – technical and commercial
– Regulatory approval and oversightRegulatory approval and oversight
– Access to the testAccess to the test
36
Companion Drug-Diagnostic Medicine in the Future
Expand and Accelerate the dialogue among stakeholders
– The macro-environment of companion drug-diagnostics
– The micro-environment of product development and labeling
Flexible process
– Not a “one size fits all approach”
– Weighing the evidence
Plausibility and relevance of biological underpinning
Replication of the observation
Provide incentives for the enterprise:
– Therapeutic and Diagnostic sponsors
– Patients, Physicians (especially specimen acquisition)
– Payors
Reimbursement for the value of the test-drug combination
37
Workshop on the Impact of Biomarkers on the Complexity of Drug Development
FDA, MIT Workshop: Impact of Biomarkers on Drug Development 21, 22 October 2009
Contributing organizations– Adaptive
Pharmacogenomics, LLC– Bristol-Myers Squibb– Eli Lilly and Company– FDA– Glaxo SmithKline– IMS Health– Merck– MIT– Roche– Van Andel Research
Institute
Functional specialties– Biomarker Development– Commercial Development– Economics– Finance & Planning– Regulatory– Statistics
38
Conclusions Many challenges remain for predictive medicine to
be realized in the future
The experiences in these case studies discussed here are likely to be repeated, i.e.,
–post approval scientific discovery leading to clinical application
An open dialogue and participation of a broad range of stakeholders is required to bring innovation to clinical and regulatory science to optimize patient selection for new and existing therapies