biomarkers lost in translation: a regulatory...
TRANSCRIPT
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Biomarkers – Lost in Translation:
A Regulatory Perspective
Rosa Giuliani, MD
Breast Unit, S. Camillo-Forlanini Hospital, Rome, IT
Scientific Advisory Group-Oncology-EMA
the views expressed are the personal views of the presenter and may not be understood or quoted as being made on behalf of or reflecting the position of EMA or its committees or working parties.
Current and Future Challenges for Innovative
Biomarker Development
Royal Society of Medicine, London
12 April 2017
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!the views expressed are the personal views of the presenter and may not
be understood or quoted as being made on behalf of or reflecting the
position of EMA or its committees or working parties
DISCLAIMERS and ACKNOWLEDGEMENTS
!EMA is not responsible for in vitro diagnostics (IVD) regulation/oversight in
the EU, nor does it currently evaluate their clinical utility in guiding the use of
drugs
Jorge Martinalbo @EMA (till February 2017)
Scientific officer, Scientific Advice, R&D Support
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-Regulatory initiatives/WP:
SA, Adaptive licensing
EMA-HTA, SAG-O
HPWP (collaboration with academia)
-EMA biomarkers and companion diagnostics related activities and procedures
-EMA activities and experience IVD/BM+ cancer drugs 1995-2014
-(some) regulatory issues and emerging challenges
Outline
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centralised (EMA) national
registrationprice & reimbursement
(access NHS, WTP)
guidelinesscientific advice (opt)
clinical trial approval
orphan drug designation paediatric studies
devices incl. IVDs, coDx
EU pharmacovigilance coordination
inspections
ACCESS
R&D
EMA structure & functions
decentralised body EU
- headquarters scientific secretariat, coordination (London > 1995)
- network of national agencies from 28 EU countries and > 5000 experts internal & external –
scientific committees (multidisciplinary) & working parties
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BENEFIT-RISK ASSESSMENT
Robustness of the whole lot of data:
biological plausibility, validity
RISK
BENEFIT
THE B/R is key and
It does not differ
for drugs based
on biomarkers
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Does a specific framework/
regulatory pathway for the development
of biomarker-driven drugs exist in EU?
NO
And yet….
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INDIVIDUALISEDSTRATIFIED
binary
EMPIRICAL
PARADIGM SHIFT Unselected/poorly
selected population,
huge numbers to
detect marginal differences
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EMA activities in the field of cancer BMs
Drug approval [IVDs, coDx: CE mark national]
BM-restricted indications (also post-A), cut-off?
R&D support
guidelines, scientific advice & qualification of novel methodologies (SAWP, PhGWP)
orphan drug designation in BM+ subsets
research consortia (Medicine Initiative_IMI OncoTrack, Cancer-ID)
Workshops
2016 CDDF immunotherapies; ESMO single-arm trials
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Under revision
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000406.jsp&mid=WC0b01ac0580034cf3
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EMA anticancer guideline
identify proper target population to optimize B/R
patient stratification, if convincing evidence of BM selectivity established early in non-
/clinical phases, confirmatory evidence in BM negative patients may not be required
tumor samples integral part; single biopsies may not be representative due to intra-
tumor heterogeneity; multi-sampling, liquid biopsies?
The development of biomarker diagnostic methods should be considered early in
clinical development, maximising the clinical application of the technology. A
diagnostic assay complying with the requirements laid down in IVD Directive
(98/79/EC), as appropriate, should be available at time of licensure
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For the use in confirmatory studies and e.g. as measures of efficacy, biomarkers must be carefully
and rigorously validated, ideally following systematic evaluation in well designed prospective
clinical trials (EMA/CHMP/446337/2011).
Of note, this guideline also opens for the possibility retrospective validation through replication of
findings.
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-Enrichment designs: only BM+ are included
Cons: no info on BM-ve pts
-Stratified designs: stratification by BM status
-Adaptive enrichment: BM+ and BM- pts are included option to restrict randomisation
To BM+ only, after interim analysis
Stratified and adaptive designs support the value of BM at predicting outcome (response),
but require large sample size
TAILORED TRIAL DESIGNs
In cases when info on BM-ve pts is insufficient, such studies may be requested after approval
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CT designs co-dev ‘simple’ coDx + BM-stratified drugs
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Ann Oncol,Nov 2016
accepted manuscript
Adapted phase II-III BELLE 4 study
1° line MBC
R 1:1, placebo controlled
Stratification: PI3Kactivation and HR status
207 pts
B+ pacli
416 pts
209 pts
P+ pacli
Interim analysis: no improvement of PFS in the full and in the PI3K pathway activated
population. Trial stopped for futility at the end of phase II
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PI3K activated tumors
in 35.3% pts,
Determined mainly
in archival tissues
PIK3CA 72.8%
PTEN gene mut 18.4%
Loss pf PTEN
expression 19%
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Cancer heterogeneity (populationsingle-cell level)
-93% oncology drugs fail the transition
from phase I to regulatory approval
-Success rate for drugs
with and without biomarker: 85% vs 51%
Heterogeneity has an impact on
biomarker validation
‘spatial’ temporal
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High rate
(>40%)
‘targeted’
but no BM
EU approvals 1995-2014: BM+ve vs not
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Drugs with BM+ indication EU
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‘CLUSTERS’
tandem BM/target-
histology
vs. expected
diversification
putative ‘drivers’
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TARGETED
Solidtumors
BM+ CYTOTOXIC
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Pignatti, CCR 2014
EMA activities in the field of cancer BMs
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Relevance of advice
DRUG DEVELOPMENT
UNMET
NEED
EARLY PHASE
PRECLINICAL
DEVELOPMENT
CLINICAL
DEVELOPMENT
SUBMISSION
for
APPROVAL
ADVANCED PHASE HTA/
Price&
reimbursement
Early dialogue is needed
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Multidisciplinary expert group of the CHMP 30 members (+ alternates) selected by expertise, not by EU MS, with complementary
scientific competence NCAs, academia, some co-members of COMP, CAT, PDCO, CHMP
monthly face-to-face (F2F) 4-day meetings, 11/year approx. 30-40 new products/each, 20 discussion meetings sponsors
interaction with other EMA WPs, WGs, committees letter peer-reviewed/adopted by CHMP, ad hoc discussions
Network external experts NCA, academia; CoI check
Patient involvement
Scientific Advice Working Party
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SA/PROTOCOL ASSISTANCE PROCEDURES 2001-2014
Total number of procedures Orphans
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EMA annual report 2013
by clinical development phase:
EMA SA/PA
EMA SA/PA requests by issues covered
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No access to raw data; ‘strategy’
Biomarker
scientific plausibility (target/related?)
non/clinical evidence for qualification
context of use: MoA, anatomical-histo tumour type…
Assay/test
establish analytical & clinical validity, cut-off
pre- (biospecimens) and post-analytical
platform, development and bridging
BM issues scientific advice
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EXPERTS selected according to their specific expertise
CORE GROUP (3-yrs)
CONTINUITY
CONSISTENCY
ADDITIONAL EXPERTS On a case by case basis
RELEVANT PROFESSIONAL
EDUCATION
TRAINING & EXPERIENCE eg patients & pts advocates
Inter-COMMITTEE SCIENTIFIC
ADVISORY GROUP (IC-SAG) for ONCOLOGY
SAGs are convened by CHMP to deliver answers, on a consultative basis, to specific questions, abt drugs at advanced stage of
development
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Biomarkers often used to “garnish”
Biomarkers as rescuers of drugs
on the verge of failure
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Pignatti, CCR 2014
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Encouraged parallel EMA & FDA application
(confidentiality agreement), communication
during assessment, joint meetings
BM Qualification Procedure in EU
A qualified BM can be used in drug development
without the confirmation of acceptance
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preclinical clinical drug use
EMA qualification novel methodologies
pharmacological screening
PK/PD modelling
toxicogenomics
dose-response
proof of concept
population selection
endpoints (MRD)
optimise population
guide treatment
regimen
in-depth assessment (raw data, protocols…), possible FDA parallel VXDS, platform for multi-
sponsor pre-competitive collaboration – outcomes:
0 requests for EMA qualification procedures BMs for cancer patient selection since 2008, all
SA on ‘approach’
Underused in oncology, missed opportunities (PD-L1?)
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CHMP Qualification Opinion (public document)
on the acceptability of a specific use of the proposed method (e.g. use of a biomarker in R&D non-/clinical studies), based on the assessment of submitted data, not product-specific
CHMP Qualification Advice (confidential document)
on future protocols and methods for further method development towards qualification, based on evaluation of scientific rationale and on preliminary data
Letter of support (public, subject to sponsor’s agreement)
when novel methodology under evaluation cannot yet be qualified but is shown to be promising based on preliminary data – to encourage data-sharing and facilitate eventual studies towards qualification
Qualification outcomes
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Current framework: IVD definition
Any medical device which is a reagent, reagent product, calibrator, control material,
kit, instrument, apparatus, equipment, or system
used alone or in combination
intended by the manufacturer to be used in vitro for the examination of
specimens, including blood and tissue donations, derived from the human
body, solely or principally for the purpose of providing information:
• concerning a physiological or pathological state
• concerning a congenital abnormality
• to determine the safety and compatibility with potential recipients
• to monitor therapeutic measures
Co-Dx are regulated within the medical devices legal framework (IVD Directive 98/79/EC)
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List categories according the Directive
NB: 3rd party independent certification organisation, on which regulatory national competent
authorities ‘delegate’ tasks of conformity assessment ‘Risk’
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Byron_CCR 2014
In EU the licenced indication of a
Pharmaceutical may require the use of a
Co-Dx, but the specific test is not normally
stipulated.
Range of proprietary and “in-house” tests
All consistent with the MA
-Vary levels of diagnostic accuracy:
Different subpopulations?
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Pignatti CCR 2014Proposed revision vs current status
Co-Dx will be required
to demonstrate
analytic performance
clinical performance
(Dx sensitivity,
specificity, PPV, NPV
Expected value in
normal or affected
Populations
Competent authorithy
Consulted
opinion in 60 days
Life-cycle of Co-DX: post
market surveillance plan
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-Timelines: final legal-linguistic review, planned formal adoption early 2017, 5-y transition
period, apply 2021/22
- All IVDs subject to demonstration of compliance with general safety and performance
evaluations
- Majority of IVD manufacturers engaging NBs as part of conformity assessment
procedures; responsible person for regulatory compliance appointed
CoDx definition: “essential to define patients’ eligibility to specific treatment” and
classified as 2nd highest risk category (class C) NB + EMA consultation (?)
• details on 60-day procedure and criteria to be outlined in a dedicated
guideline
New IVD regulation
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Drug/IVD evolution
tumor/BM drug IVD/coDxinitial
NSCLC
EGFRm
erlotinib
gefitinib
afatinib
RocheCobasEGFRMut
QiagentherascreenEGFRRGQ(RT-PCR)
NSCLC
ALK+
crizotinib AbbottVYSISALKBreakApart(FISH)
GIST
KIT+
imatinib Dakoc-KitpharmDx(IHC)
CRC
KRASwt
cetuximab
panitumumab
[EGFR+IHCDakoPharmDx-obsolete]
QiagentherascreenKRASRGQPCRKit
breast
HER2+
*gastric
trastuzumab*
pertuzumab
T-DM1
lapatinib
HercepTestDako(IHC,semiquant.)
melanoma
BRAFV600
vemurafenib
dabrafenib
RochecobasBRAFV600
BioMérieuxTHxIDBRAF
=NGS-basedmultiplexpanels,WES/WGS
move from coDx to multiplex?
IVDsalternatives+LDTs
QiagentherascreenEGFRRGQ
Plasma
IHCscreening->confirm
LDTs
Dako,Zymed,Invitrogen,DxS,
Qiagen,Transgenomic
IHC:LeicaBondOracle,
VentanaPATHWAY,BioGenex…
FISH:AbbottPathVysion,
VentanaINFORM
ISH:DakoHER2CISHPharmDx,
VentanaINFORMDualISH,etc.
LDTs?
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assaydivergences
drugnivolumab
BMSpembrolizumab
MSDdurvalumabAstraZeneca
atezolizumabRoche
avelumabMerck/Pfizer
target PD-1 PD-1 PD-L1 PD-L1 PD-L1
sample archival recentarchival/recent
archival/recentfreshcutslides
?
IHCassay
Dako28-8*COMPLEM
Dako22C3*coDX
VentanaSP263
VentanaSP142
Dako?
celltypes
TC TC TC IC&/orTC TC
cut-offsNSCLC
TC≥5%TC≥1%TC≥50%
TC≥25%TCorIC≥1%TCorIC≥5%
TC≥50%orIC≥10%TC≥1%
noharmonisedmeaningofPD-L1+,clinicalimplicationsindecisionmaking,orderingtestsandcomparingagents
→BluePrintPD-L1IHC
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ADAPTIVE PATHWAYS/MAPPs
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BREAKTHROUGHRARE MOLULTRA-RARE
R
prospectively identify when RCTs not strictly required for approval (e.g. unequivocal
equipoise loss) and/or feasible (ultra-rare entities or mol. subgroups in the context of
stratified medicine)
key elements: RCT feasibility, compelling efficacy thresholds on valid endpoints (ORR,
DoR, others?), adequate external controls, indirect comparisons, supportive &
confirmatory evidence…
screening IVD BM+
SAT framework – scenarios Courtesy of J. Martinalbo
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EU approvals on SATsS
OL
IDH
AE
MA
TO
LO
GIC
AL
201420132012201120102009200820072006
sunitinib (Sutent)RCC CMA
everolimus (Votubia)SEGA paed CMA
vismodegib (Erivedge) BCC CMA
clofarabine (Evoltra) ALL ped ExC
nelarabine (Atriance)ALL ExC
histamine HCl (Ceplene)AML ExC
ofatumumab (Arzerra) CLL CD20+ CMA
brentuximab vedotin (Adcetris) sALCL, HL CMA
pixantrone (Pixuvri) DLBCL CMA
bosutinib (Bosulif)CML CMA
imatinib (Glivec)DFSP ExCvar
2015
blinatumomab (Blincyto) ALL Ph- CMA
osimertinib (Tagrisso) NSCLC EGFRm T790M+ CMA
ceritinib (Zykadia) NSCLC ALK+ CMA
CMA
bortezomib (Velcade)MM ExC 2004
arsenic trioxide (Trisenox) APL ExC 2002
alemtuzumab (MabCampath) CLL ExC 2001
imatinib (Glivec)CML ExC 2001
Ph+ ALL, MDS/MSP, CEL/HES
docetaxel (Taxotere) breast ExC 1995
imatinib (Glivec)GIST ExC 2002
trastuzumab (Herceptin) breast HER2+ mono 3L+ ExC 2000
ponatinib (Iclusig)CML, Ph+ ALL CMA
nilotinib (Tasigna) CML
paclitaxel (Taxol) Kaposi ExC 1999
cladribine (Litak)HCL 2004
dasatinib (Sprycel) ALL Ph+
idelalisib (Zydelig)NHL-FL
ibrutinib (Imbruvica)CLL 1L del17p, MCL
EU approvals on SATs Courtesy of J. Martinalbo
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BM-stratified trials
Basket
Umbrella
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Challenges
- Rare mol. subsets, SATs, ‘novel’ designs (basket)
- Move from coDx to multiplex panels, WES/WGS
- Combinations?
- Divergences in IVDs for same BM in a drug class, data-sharing & cross-
validation
- Intra-tumor heterogeneity implications for registrational CTs,
multiregion/mets sampling, subclonal %, ‘liquid biopsies’…
- Drug label: BM+, uncertainty cut-offs – evolution during lifecycle
- P&R national – IVD ‘gatekeeper’ - informational needs patients, clinicians,
HTAs/payers - differential C/E by BM thresholds?
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CHALLENGES in DRUG DEVELOPMENT
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MarketaccessEUquality,
safety,efficacy
B/R
clinicalevidenceE&S
assoc.uncertainty
singleEUframeworkbudgetimpact,C/E,REA
nationalframeworks
P&R V
14
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RATIONAL DRUG DEVELOPMENT
STUDY DESIGNPATIENTS SELECTIONCANCER TYPE
TARGETS
DRIVERS
vs
PASSENGERS
CLINICAL
VS
STATISTICAL
RELEVANCE
1) DISEASE
2) MECHANISMS
ACTION/
RESISTANCE
3) TIME
BIOMARKERS INNOVATIVE TRIALSPATHWAYS
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RATIONALE DRUG
DEVELOPMENT
Clear and in depth knowledge of the druggable
disease
Selection of population
Mechanisms of action/resistance
The variable time taken on board (evolution
of the disease under treatment)
Innovative studies
VALUE and COST-
EFFECTIVENESS
- Approval granted first for patients who could
benefit more (“superlative” B/R)
-Extended observation (RDW)
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The biomarkers
novel
Patients
selection
Anticipation
of
resistance Avoid
unnecessar
y toxicity
Rational
allocation of
resources
GLOBAL collaboration
Academia/Regulators:
generation & validation of data
HTA/payers ‘clinical utility’
Pharma & Dx –
pre-competitive, data sharing?
NCI, ASCO, EORTC/
Academic networks‘broker’ biobanks?
…….