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Rosa Giuliani, MD
Breast Unit, S. Camillo-Forlanini Hospital, Rome, IT
Scientific Advisory Group-Oncology_EMA
SESSION 5: OPPORTUNITIES AND CHALLENGES WHEN IMPLEMENTING
PHC CONCEPTS INTO CLINICAL TRIAL DESIGNS
A CLINICAL / REGULATORY PERSPECTIVE ON EXPERIENCE
SO FAR WITH BIOMARKERS IN EU APPROVALS
OUTLOOK AND CHALLENGES
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.
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Presented By Brian Druker recipient of the Science Oncology Award at 2017 ASCO Annual Meeting
At the right time (editor’s noteme)
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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, validityRISK
BENEFIT
THE B/R is key concept
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
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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Data + biological noise
Exogenous selective pressure
How do we integrate these two key points?
What do we expect from biopsies?
cfDNA
Biologically relevant?
Biologically neutral?
Presented By Barry Taylor at 2017 ASCO Annual Meeting
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Molecular imaging
to investigate heterogeneity
Gebhart G et al,
Ann Oncol 2016
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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
….till the new
era of the tumor-
agnostic drug
development???
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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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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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Therapeutic areas
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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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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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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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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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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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BREAKTHROUGHRAREMOLULTRA-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…
screeningIVDBM+
SAT framework – scenarios Courtesy of J. Martinalbo
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NOT ALL DRUGS ARE CREATED EQUAL
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Timely (early) access to
innovative agents
Flexibility
Foster progress & health
Robust evidence
Quality of data
Miss the “magic moment”
for OS
RISKBENEFIT
EARLY ACCESS vs COMPLETE INFORMATION
EARLY
REGULATORY
APPROVAL
EARLY ACCESS
for PATIENTS
MAJOR CHALLENGE
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MarketaccessEUquality,
safety,efficacy
B/R
clinicalevidenceE&S
assoc.uncertainty
singleEUframeworkbudgetimpact,C/E,REA
nationalframeworks
P&R V
14Courtesy of J.Martinalbo
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The “FUNNEL effect”
(Too) Many variables at each stage
Some more transparent,
other less
REGULATORS
HTA
PAYERS
HOSPITALS
R&D
I am (stuck) here
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/03/news_detail_002722.jsp&mid=WC0b01ac058004d5c1
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First ever trial of penicillin at the Radcliffe Infirmary in Oxford
RANDOMIZED TRIAL12 PTS…Penicillin enough for 6!
BIOLOGIC EXPLOSION IN THE MIDST OF ECONOMIC CRISIS
PHASE TWO TRIAL CAN BE MISLEADING, PHASE III ARE
ENOURMOUSLY EXPENSIVE FOR VIRTUALLY EVERYONE
COOPERATION IS NOT AN OPTION ANYMORE, IT’S a NEED
RATIONAL DESIGN IMPLEMENTED WITH BIOMARKERS
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In the bookshopironically
on the same shelf
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Ann Oncol, 2015
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CHALLENGES in DRUG DEVELOPMENT
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V 1.1 exp Sept 2017SAT
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Sept 2016
The concept of personalized medicine is so appealing that seemingly only curmudgeons could criticize it.