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RSNA’s QIBA Volumetric

CT:
Progress and Plans
Andrew J. Buckler, MS
Principal, Buckler Biomedical
LLC
Background: Anecdotal
Evidence

-30% Δ
from BL =
RECIST
threshold
for PR

May 2010 Buckler Biomedical LLC 2


Target Lesion Measurement

Progressive
Disease
RECIST: Sum of LD

Disease
4cm lesion Unaided 1D

Stable
Interpretation

Response
Partial
∆ t

Response
Time Complete

Early Detection Figure courtesy Rick


& Nodule Sizing ? Avila, Kitware Inc.

May 2010 Buckler Biomedical LLC 3


Volumetric Image Analysis
with CT Seeks to Increase
Sensitivity vs. SLD
Target Lesion Measurement

Progressive
Disease
RECIST: Sum of LD

Disease
4cm lesion

Stable
Aided 3D
Interpretation

Response
Partial
Shorter ∆ t

Response
Time Complete

Early Detection
& Nodule Sizing ?
May 2010 Buckler Biomedical LLC 4
Key Questions that Need
Answers
What is the potential to
decrease time needed on
trial (or enable more
adaptive designs)?

What is the technical


variability in the
measurements?
What is the potential to
increase statistical
power (or decrease
…not to mention, does enrollment for same
it correlate to clinical power)?
outcomes?

May 2010 Buckler Biomedical LLC 5


The QIBA Process Draws
from Precedent but is
Based on Science
Clinica
l
Conte
xt
Profil
e
Claim
s With an IHE-like
certification
reputation
Groun Profile
d work Details

May 2010 Buckler Biomedical LLC 6


Clinica Decide what Needs to
l
Conte
xt
be Done by Starting
with the Disease
• Evaluate needs for the disease area:
– Link to relevant research programs for QIB development
– Define outcome measurements and surrogate endpoints
– Identify, research, validate, and quantify measures as necessary
• Based on the needs, identify and prioritize what
biomarkers to pursue, and for each biomarker,
what Profiles to compose

May 2010 Buckler Biomedical LLC 7


Profil State Functional
e
Claim
Profile Requirements
Claims andto Clinical
(what users are able achieve
s
with thisPerformance
Profile) as “Claims”
Claim #1: Can create, store, retrieve images of lung tumors
Claim #2: Can create, store, retrieve linear, area and volume measurements made on lung tumor
images
Claim #3: Can create, store, and retrieve mark ups of lung tumors, i.e., region of interest (ROI)
boundaries
Precursor: Need Sample Implementation Chest CAD polylines or New DICOM Segmentation objects (by pixel) are likely sufficient,
but should try out a sample implementation to confirm (and identify key Details to require in the Profile). Possibilities for data
storage include polylines, voxels, and polygons/triangles. See also Segmentation and Markup Formats
Claim #4: Can measure lung tumor volume with repeatability of 18% for tumors greater than 10mm in
Longest Diameter.
Rationale: For uniformly expanding cubes and solid spheres, an increase in the RECIST defined uni-
dimensional Longest Diameter of a Measurable Lesion corresponds to an increase in volume of about 72%. To
diagnose Progressive Disease at a change of about one half that volume, 36%, the noise needs to be less than about
18%. The claim is thus set to be "twice as sensitive as RECIST". <What do we mean by repeatability> How should the repeatability be
expressed? It's easier to meet % targets for larger tumors. Should we use mm3 instead? Or should we state % for a certain sized tumor? There is
a description in Jim Mulshines work that we can copy here? Precursor: Demonstrate this accuracy and repeatability is easily achievable
Groundwork: Test-Retest measurements of FDA phantoms i.e., very-best-case-scenario, with variability one order of magnitude less than
variability in "real life", i.e., algorithm returns variability of less than 1.5% <Relevant Groundwork Link 2:> Test-Retest measurements of small
sample of NIST cases, i.e., nearly-best-case-clinical-scenario, with variability for measurement of isolated, simple lung tumors of less than 3% (up
to 4 times the noise in phantoms and less than one fifth the noise expected in real life scenarios). <Relevant Groundwork Link 3:> Test-Retest
measurements of a few well behaved masses in the MSKCC coffee break study of less than 10% between Image Set 1 and Image Set 2 of each
patient studied twice in succession. This 10% threshold is somewhat capriciously based on the assumption that the precision of measurement in
selected MSKCC coffee break tumors will be twice as good as that which can be achieved in most clinical trial scenarios. Precursor: Should
thought be given to revising the RECIST definitions?
Claim #5: Can retrieve and/or contribute images, measurements and markups from/to caBIG. Are we and
caBIG ready to get into this now or is it OK to leave this until our next profile, e.g. volume change, when our ideas and caBIGs
infrastructure are more mature/stable?

May 2010 Buckler Biomedical LLC 8


Use Imaging Science
Groun
d work Approach to Modeling
Quantitative Accuracy Bio m a rke r
parenchym al m as s (lung nodule) res pons e ass es sm ent:
> ac quire CT im ages ; determ ine boundary of n odule(s ); m eas ure siz e/volum e of nodule(s );
> as ses s nodu le resp onse to treatm ent by c om paring c orrespon ding m eas urem ents over m ultiple-tim e points .

Description o f Issu e
Des crib e the nature of the iss ue(s )
Sig nificance
Is this Challenge really an iss ue?
Ra te (and explain if you lik e) How m uch
im pact this is s ue will have on prac tic al

Calibration us e of the b iom ark er?


No ne - No im pac t;
Low/Medium /High - S om e im pact;
Cha lle ng e Critic al - S how s toppe r

Sourceof Processing& V a ria tio n in dos e, injection effectivenes s, tim ing… infus ion protoc ols ) HIG H

SENSOR Decision P ha rm a ce u tica l / s td volum e vs volum e per unit body m as s for lesions near c ertain structures ,

Illumination Info.Extraction Con tra st Ag e n t segm e ntation m ay not be po ss ible


without c ontras t.

V a ria tio n in P a tie nt /(e.g., biology , tem perature, wak efulnes s, m otion, res piration… ) LO W -M E D
Bio ch e m istry infrequent fac tor and m os tly affects
Large patient weight chan ge could affect atten uation/s catter noise?
Transmission Cardiac output will affect c ontras t c irculation

Medium V a ria tio n in P a tie nt Different staff, different s ites prepare and pos ition the patient diffe rently
Ha n dling P roto col Lung tum or volum e m ight vary with res piration
M E. D-HIG H
im portant but reas ona bly eas y to c ontrol
(patien t positioning)
Anatomical Les ion loc ation in FO V m ay vary

Region Data Joint V a ria tio n d ue to (e.g., atte nuation, phys ic al im aging proc es s… P E T colinearity reduces
LO W
Specific M od a lity P h ysics res olution but not s pa tial integrity)

Target Association Decision S tra ight line trajectories

V a ria tio n in S ca nn e rS patial S am pling (e.g., finite s ys tem P S F , detector c hara cteristic s, table
HIG H
De sign s des ign … ) # detector rows are a big is sue relating to
Different # of rows c an affect s peed of volum e c overage single breathhold span
Les s than 4 s lic e results in breathing artifac ts 10-20% varianc es
S c atter, differenc es in energy
Different vendo rs use different s ys

V a ria tio n in Ind ividu aMl anufac turing variation, aging, P M , etc LO W

Inconsistency of measurements
S ca n ne rs Pretty stab le/c onsis tent and ea sily
calibrated for

Sourceof Processing& V a ria tio n in CT Low k V c an inc reas e noise to the point that nodule boundaries becom HIGeH

SENSOR Decision
Acqu isition P ro toco l unc lea r… (m ay relate to whether quant is vis ual/m anual or autom aticm) any attributes im pac t the results

Illumination Info.Extraction mAs

Collim ation used during ac quis ition affec ts the fund amental res olution

F O V selec tion changes m eas urem ent res ol


Calibration

Systems Engineering of sources of


variability and their effect strength
on outcome

May 2010 Buckler Biomedical LLC 9


Literature Review to
Groun
d work Establish Where we
1. Technical Feasibility
Are
2. Accuracy: Phantom Studies
3. Accuracy: Clinical Studies
4. Physiological Factors
5. Technical Factors
6. Sensitivity as a Function of Precision
7. Risks of Misleading Results
8. Thresholds for Classifying Changes
9. Medical and Clinical Significance
May 2010 Buckler Biomedical LLC 10
Groun
d work
Group “1A” Phantom
Study
The relative biases (SD) of the
1D, 2D and 3D methods were
-14.6 (20.4), -18.8 (28.3) and -1.3
(21.9) percentage points
averaged across all subgroups,
respectively.

The relative biases of 1D, 2D, and


3D were significantly different (all
three pairings with p<0.001).

Nodule shape, density, and slice


thickness were found to be
significant effects (p<0.001,
p=0.007, and p=0.008,
respectively).

May 2010 Buckler Biomedical LLC 11


Groun
d work
Groups 1B and 1C
1B: Patient datasets for comparing nodule sizing methods
Aims
(1) Investigate the min detectable
level of change in patient datasets
under a “No Change” condition 5 readers, 3
(2) Investigate both bias and variance
of both readers and algorithm- reads each
assisted readers in measuring
volumes, diameters and bi-
directional diameters of lesions
from Patient datasets

1C: Cross-scanner imaging of anthropomorphic phantom


Aims
Two Branches of 1-C Protocol
(1)Determine the effect of CT manufacturer on reader measurement of
1.“Current-clinical” branch specifies
volume under conventional cross-manufacturer protocol.
narrow range of parameters for each
manufacturer’s devices, akin to ACRIN
(2)Develop cross-manufacturer quality measures and determine the
6678.
impact of leveling quality on uncertainty in nodule sizing.
2.“Performance” branch specifies easily
(3)Study protocol is to implement Volume CT Profile for nodules and
implemented performance metrics of
collection parameters appropriate for late-stage lung cancer.
resolution and noise
(4)Study is to achieve specified quality using ACR phantom imagery
5 sites: Duke, UCLA, UMD, FDA, JHU
and to read lesion sizing on anthropomorphic phantom imagery.

May 2010 Buckler Biomedical LLC 12


Conduct Studies to
Groun
d work Characterize Aspects of
Marker
Assay
Performance
Diagnostic/ Effect on
validation predictive clinical
Reliability/ accuracy outcomes
Reproducibil
ity
For clinical X x x
practice
Technical Clinical
Clinical
Characteristi Efficacy
For Phase Xcs x
Performance x
Meta
II endpoint Studies
Experiments Analysis

C. Gatsonis (Brown University), ACRIN EISC 2008


Underlay courtesy C. Gatsonis (Brown University), ACRIN EISC 2008

May 2010 Buckler Biomedical LLC 13


Throughout Roadmap,
Profile
Details Define and Refine
Profile Details
To include explicit
coverage of:
• Covariates rationale
• Quality control metrics
• Acquisition protocols
• ROI definition
• Quantification computation
• Data transfer and storage issues
• Longitudinal measurements

May 2010 Buckler Biomedical LLC 14


Imaging Biomarker Qualification Process
Sponsoring Collaborative National Regulatory Agencies
A) Declaratory information from imaging test Request 1) Informal discussion of a potential biomarker sponsor
technical validation sources. Letter with the Biomarker Qualification Coordinator (BQC).

CONSULTATION AND ADVICE PROCESS


2) Biomarker Sponsor submits to BQC a written
B) Phantom and other controlled condition request for qualification of an exploratory biomarker.
support material for “stand-alone” assessment
and required initial and ongoing quality control 3) BQC evaluates qualification request.
specifics.
C) Implement and refine protocols for the 4) Biomarker Qualification Management Team
intended use (BQMT) accepts or declines the sponsor’s request to
D) Process map detailing steps contemplated proceed with qualification process.
to support qualification of the biomarker
5) Biomarker Qualification Review Team (BQRT)
E) Clinical performance groundwork to requests briefing document from biomarker sponsor.
characterize sensitivity and specificity for Briefing
readers using the imaging test when Docume 6) BQ Project Manger schedules face-to-face meeting
interpreted as a biomarker under specified nt between the sponsor and the BQRT.
conditions.
7) BQRT evaluates the briefing document and prepares
for the Biomarker Qualification face-to-face meeting.
8) BQRT and Sponsor BQDS Meeting.
F) Clinical efficacy groundwork to qualify
biomarker for its intended use in the 9) BQRT identifies and requests additional data from
appropriate "real world" imaging conditions. sponsor.
Full
G) Draft advice guidance on incorporation of 10) BQRT receives full data package and review period
Data
imaging biomarker into clinical trials. begins
Package
11) BQRT writes draft biomarker qualification review.
12) BQC routes the draft biomarker qualification

REVIEW PROCESS
reviews to all Offices
13) BQ Project Manager schedules the BQ review for
presentation at a CDER Regulatory Briefing.
14) CDER Regulatory Briefing presentation and
discussion is held.
15) CDER Office Directors make decisions to accept or
reject the BQRT recommendations.

H) Promote use of the imaging biomarker Signoff 16) BQC drafts letter for sign-off by the Director of
through education. Letter CDER communicating to the sponsor the results of the
biomarker qualification.

May 2010 Buckler Biomedical LLC 15


ID T a s k N a m e
Q 1 '1 0 Q 2 '1 0 Q 3 '1 0 Q 4 '1 0 Q 1 '1 1 Q 2 '1 1 Q 3 '1 1 Q 4 '1 1 Q 1 '1 2 Q 2 '1 2
F e b M a rA p r M a yJ u n J u l A u g S e p O c t N o vD e c J a n F e b M a rA p r M a yJ u n J u l A u g S e p O c t N o vD e c J a n F e b M a rA p r M a yJ u n
1 1 ) In fo r m a l d i s c u s s io n o f a p o te n ti a l b i o m a r k e r s p o n s o r w i th th e B i o m Qa IB
r k eAr ,AQ gu ea nli fic
c y a ti o n C o o r d i n a to r ( B Q C ) .
2 R e q u e s t le t t e r
3 A ) D e c l a r a to r y i n fo r m a ti o n a b o u t th e c l a s s o f te s ts d r a w n fr o m te s t v Qa lIB
id aA ti o n s o u r c e s .
4 C o m p o s e l e tte r Q IB A
5 R e v i e w w i th i n Q IB A Q IB A
6 2 ) B i o m a r k e r S p o n s o r s u b m i ts to B Q C a w r itte n r e q u e s t fo r q u a l i fic a ti o n o f aAn gee xnpcl oy r a to r y b i o m a r k e r .
7 3 ) B Q C e v a l u a te s q u a l i fi c a ti o n r e q u e s t. A gency
8 4 ) B i o m a r k e r Q u a l i fi c a ti o n M a n a g e m e n t T e a m ( B Q M T ) a c c e p ts o r d e c l i n e s th e s p oAn gs eo nr ’ cs yr e q u e s t to p r o c e e d w i th q u a l i fi c a ti o n p r o c e s s .
9 5 ) B i o m a r k e r Q u a l i fi c a ti o n R e v i e w T e a m ( B Q R T ) r e q u e s ts b r i e fi n g d o c u m e n t fr o m b i o Am ga er knec ry s p o n s o r .
1 0 B r ie f in g D o c u m e n t
11 B ) P h a n to m a n d o th e r c o n tr o l l e d c o n d i ti o n s u p p o r t m a te r i a l fo r “ s taQ nIBd A- a ,Sl o on ce ie” at ys s e s s m e n t.
12 C ) Im p le m e n t a n d r e fi n e p r o to c o l s fo r th e i n te n d e d u s e Q IB A ,S o c ie t y ,U P IC T
13 D ) P r o c e s s m a p d e ta i l i n g s te p s c o n te m p l a te d to s u p p o r t q u a l i fi c a tio Q IB
n oAf ,Sth oe cbiei ot ym a r k e r
14 E ) C li n i c a l P e r fo r m a n c e G r o u n d w o r k to c h a r a c te r i z e s e n s i ti v i ty a n d s pAe ,S
Q IB c ifio cci ie
ty tfoy ,A
r r Ce aRdINe r s u s in g th e i m a g in g te s t w h e n i n te r p r e te d a s a b i o m a r k e r u n d e r l im i te d c o n d i ti o n s .
15 C o m p o s e B r i e fi n g D o c u m e n t Q IB A
16 R e v i e w w i th i n Q IB A Q IB A
17 6 ) B Q P r o j e c t M a n g e r s c h e d u l e s fa c e - to - fa c e m e e tin g b e tw e e n th e s p o n s o r a n d th e B Q R AT .g e n c y
18 A g- fae nc ec ym e e ti n g .
7 ) B Q R T e v a l u a te s th e b r i e fi n g d o c u m e n t a n d p r e p a r e s fo r th e B i o m a r k e r Q u a l i fi c a ti o n fa c e - to
19 8 ) B Q R T a n d S p o n s o r B Q D S M e e ti n g . Q IB A ,A g e n c y
20 9 ) B Q R T id e n ti fi e s a n d r e q u e s ts a d d itio n a l d a ta fr o m s p o n s o r . A gency
21 Ite r a te d o c u m e n t Q IB A
22 R e - r e v i e w w i th B Q R T Q IB A ,A g e n c y
2 3 F u ll D a t a P a c k a g e
24 F ) C l i n ic a l E ffi c a c y G r o u n d w o r k to q u a l i fy b io m a r k e r a s a s u r r o g a teQ IB
e nAd ,A
p oCi nRt IN
i n ,Sr eoacl iew toyr l d i m a g i n g c o n d i ti o n s
25 G ) D r a ft a d v ic e g u i d a n c e o n i n c o r p o r a ti o n o f im a g i n g b i o m a r k e r i n to c l i n ic a l tr ti ay l,U
Q IB A ,S o c ie s . P IC T
26 C o m p o s e F u l l D a ta P a c k a g e Q IB A
27 R e v i e w w i th i n Q IB A Q IB A
28 1 0 ) B Q R T r e c e i v e s fu l l d a ta p a c k a g e a n d r e v ie w p e r i o d b e g i n s A gency
29 1 1 ) B Q R T w r i te s d r a ft b io m a r k e r q u a l i fi c a ti o n r e v i e w . A gency
30 1 2 ) B Q C r o u te s th e d r a ft b io m a r k e r q u a l i fi c a ti o n r e v i e w s to a l l O ffic e s A gency
31 1 3 ) B Q P r o j e c t M a n a g e r s c h e d u l e s th e B Q r e v i e w fo r p r e s e n ta ti o n a t a C D E R R e g u l a to r y B r ie fi n g . A gency
32 1 4 ) C D E R R e g u l a to r y B r i e fin g p r e s e n ta tio n a n d d i s c u s s i o n i s h e ld . A gency
33 1 5 ) C D E R O ffi c e D i r e c to r s m a k e d e c i s i o n s to a c c e p t o r r e j e c t th e B Q R T r e c o m m e n d a ti o n s . A gency
3 4 S ig n o f f L e t t e r a n d D e p lo y m e n t
35 1 6 ) B Q C d r a fts l e tte r fo r s i g n - o ff b y th e D ir e c to r o f C D E R c o m m u n i c a ti n g to th e s p o n s o r th e r e s u l ts o f th e b i o m a r k e r q u a l i fi c a ti o n . A ge nc y
36 H ) P r o m o te u s e o f th e i m a g i n g b i o m a r k e r th r o u g h e d u c a ti o n . Q IB A
Thanks, Andy. I would like to get this underway now. Merck would like to get
this underway now. I doubt that any objections will emerge from pharma. The
worst I've heard is that some companies will proceed with their own plans to
qualify v-CT independently of what we do. Best. Moz

Thanks Andy, we (Pfizer) agree with the position from Dave Mozely and would
support the letter. -Tim.

Dear Andy, I am totally in support of sending this Request Letter to the Agency.
Also I see no reason why there would be any objection to the Request Letter
from Novartis. As I mentioned before, I am working on getting a firmer
commitment from Senior Management. Best regards, Haren

Hi Andy, Definiens is very eager to support, both the request letter but
especially some of the tasks of the project plan. More concrete, we feel
in the postion to support the following tasks: 11, 12, 13, 14, 15, 24, 25,
26, 27, 36
Dr. Maria Athelogou will be the principal representative of Definiens in
this regard.
Best, Frank
May 2010 Buckler Biomedical LLC 17
Short Term Action Plan
Complete Consultative Phase leading to Scope Confiden Other group Overlap Ower/ Target Action/Comm
Qualification of VIA with chest CT for Lung of Work ce of alredy doing of worh Driver date/Stat ents
Cancer Clinical Trials Achiving it other us
group
  Compose letter and review Low High   0% Paul Q2-10  
Send letter              
Follow-up through BQRT meeting Medium High   40% Paul    
A Assemble Declaratory information High Low UPICT, CTN 30% Andy Q4-10  
Write Clinical Context section in Briefing Document              
Write literature review sections in Briefing Document              
Write QIBA process section in Briefing Document  
B <phantom task 1> Low High   0% Paul Q2-10  
…              
<phantom task n, e.g., write section in Briefing Medium High   40% Paul    
Document>
C <Profile task 1, e.g., UPICT consensus protocol> Low            
… (e.g., create non-protocol portions of Profile) Low            
… (e.g., add QIBA subcommittee findings)              
<Profile task n, e.g., write section in Briefing High High   100%      
Document>
D <process map task 1, e.g., determine what steps are Medium Low   60%      
needed>
…              
<process map task n, e.g., write section in Briefing Low Med   40%      
Document>
E <clinical performance task 1, e.g., summary of what's Medium Low   60%      
ongoing>
… (e.g., compile performance evaluation figures of              
merit)
<clinical performance task n> Low Med   40%      
  Write Results section of Briefing Document Medium Low   60%      
  Write Completing the Full Data Package section              
  Review Briefing Document              
  Send to agency              
  Participate in BQRT              
  Iterate with BQRT Low Med   40%      

May 2010 Buckler Biomedical LLC 18


Result: Qualified Marker for Pharma,
Profitable Products for Suppliers
Quantitative Imaging Test Discovery,
Development, and Validation
1[Private & Academic Sectors]
Path when clinical use is pursued Path when use is
first (though can proceed to established in clinical
qualification later)
Quantitative Imaging Test Approval trials first (though
5 regulatory agencies, e.g.,
[National feedback path would
allow its use in clinic
FDA CDRH] 2 Feedback
path to
later)

Intended use (usually initially having no


claim of surrogacy but which could be
4 provide
evidence to
extended if further clinical data could be extend initial
collected) intended use
for new,
Evidentiary stronger,
clinical claim
Studies for Quantitative Imaging
Coverage Test Qualification
Decisions [National regulatory
6[Payer 3 agencies,
organizations, e.g., FDA CDER]
e.g.,Reimbursable
CMS] Initial intended use now extended
based on to stronger association with
accumulated mechanism-of-action or surrogacy
evidence of
necessary and
reasonable use
Use in Routine Use in Clinical
Clinical Care Research

May 2010 Buckler Biomedical LLC 19


Summary and
Conclusions
• Volumetric image analysis (VIA) with CT seeks to increase
sensitivity vs. SLD
• Hypothesis: VIA performance can be linked to RECIST and
further to clinical
• Problems include paucity of evidence and need for
collaboration
• Quantitative Imaging Biomarker Alliance is working to satisfy
• Our driving hypotheses include:
these needs
• VIA in clinical trials:
• Early− accomplishments
will reduce numberare in publication
of subjects enrolledand additional
articlesper
aretrial
in process
− will
• We are decrease
actively time onwith
engaged study per CDER
both subjectand CDRH pathways
− will speed the delivery of new
treatments to patients with unmet
medical needs
• VIA in clinical practice:
− should influence patient management
May 2010 − should be extremely valuable
Buckler for all
Biomedical LLC 20
Acknowledgements
QIBA Groundwork Project Team
Mozley PD. Merck Research Laboratories, West Point, PA USA
Bendtsen C. Merck Research Laboratories, Rome, Italy
Schwartz LH. Memorial Sloan Kettering Cancer Center, New York, NY
Zhao B. Memorial Sloan Kettering Cancer Center, New York, NY
Thorne M. Siemens AG, Forchheim, Germany
Korne R. Definiens, AG. Munich, Germany
Rong Y. Perceptive Informatics, Inc. Belarica, MA USA
Peronne A. BioClinica, Inc., Newtown, PA USA
Gustafson D. Intio, Inc. Denver, CO USA
Buckler AJ. QIBA volumetric CT chair
Many other valuable contributors on the Quantitative CT Technical Committee
Teams, Sponsors, and Partners for Buckler Biomedical
caBIG team, RSNA, Kitware Inc., C. S. Draper Laboratory, Philips Research,
Perceptive Informatics

May 2010 Buckler Biomedical LLC 21

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