A Complex ADaM dataset? Three different ways to

Report
Accenture Life Sciences
Rethink Reshape Restructure…
for better patient outcomes
CDISC Journey in Lymphoma
using Cheson 2007
Kevin Lee
CDISC NJ meeting
April 17th, 2014
Disclaimer
Any views or opinions presented in this
presentation are solely those of the author
and do not necessarily represent those of
the company.
2
Agenda
1. Introduction of Oncology
2. Introduction of Lymphoma Studies
3. Introduction of Cheson
4. CDISC SDTM
5. CDISC ADaM
6. Conclusion
7. Questions
3
Cancer Trivia
• The word ‘cancer’ is related to the Greek word “crab” because
its finger-like projections were similar to the shape of the crab
• In 2010, the economic cost of the disease worldwide was
estimated at $1.16 trillion.
• One in eight deaths in the world are due to cancer.
• Cancer is the leading cause of death in developed countries.
• WHO predicts new cancer cases of 14 million in 2012 to 22
million in 2030 and cancer deaths from 8.2 million a year to 13
million annually.
• There are 28 million cancer survivors worldwide.
• Men who have never married are up to 35% more likely to die
from cancer than those who are married.
4
FDA New Drug Approval
• 2012
–37 Approval
–12 Oncology (32 %)
• 2013
–27 Approval
–8 Oncology (30 %)
5
Oncology Study
• How are the oncology studies different from other
studies?
–Tumor measurements and their response to
drug
–Toxicity (Lab and AE)
–Time to Event Analysis
• What tumor studies and response guidelines?
–Solid Tumor : RECIST 1.1
–Lymphoma : Cheson 2007
–Leukemia : IWCLL 2008
6
What is Lymphoma
• Cancer that starts in lymph nodes
• Type of Lymphoma
–Hodgkin lymphoma (HL) : lymphoma in the
presence of a specific type of abnormal cell
called a Reed-Sternberg cell
–Non-Hodgkin lymphoma (NHL) : lymphoma not
in the presence of a specific type of abnormal
cell called a Reed-Sternberg cell
• Guidelines for response : Cheson 2007
7
Cheson 2007
• History
–IWG (International Working Group) 1999 and
Cheson 2007
• Lesions (tumors)
–Type :
• Enlarged Lymph Nodes (long axis > 15 mm or its
greatest perpendicular axis > 10 mm by CT scan)
• Nodal Masses
• Extra Nodal Masses (> 10 mm )
8
Lymphatic System
A Nodal Mass is
the conglomerate
of several
enlarged nodes
touching one
another which
are not
distinguished
from individual
nodes any more.
9
Extra Nodal Site
Extra nodal – a
lymphoma that is
detected outside
of lymphatic
system.
10
Cheson 2007
• Two-dimensional measurement - product of longest
diameter and its greatest perpendicular axis (e.g., 40
mm * 15 mm = 600 mm^2)
11
What is to measure in Lymphoma
according to Cheson 2007
• Tumor measurements in CT / MRI
–Lymph Node, Nodal Masses and Extra Nodal
Masses
• PET scan on lesions (to distinguish viable
tumor from fibrosis)
• Bone Marrow Assessment
• Spleen and Liver Enlargement Assessment
12
Target Lesions according to Cheson
2007
• Normally 6 lesions
– lymph nodes or nodal masses
–Two perpendicular diameters should be clearly
measurable
• Quantitative measurements
–Longest diameter and its greatest transverse
perpendicular diameter
–Products of the diameters
–Sum of the products of the diameters (SPD) up
to 6 target lesions
13
Non-Target Lesions according to
Cheson 2007
• All other lesions beside target lesions
• Extra nodal (i.e., Liver, Spleen)
• Quantitative measurements
–Longest diameter and its greatest transverse
perpendicular diameter
–Products of the diameters
• Qualitative measurements – present,
absent, increased or decreased.
14
New Lesions according to Cheson
2007
• Any lesions that are newly found at postbaseline
• Either quantitative or qualitative
measurements
15
Lesions at baseline
Lesions
Measurable Lymph
Node or Nodal Masses
Targets
Non-Measurable or
Extra Nodal Masses
Non-Targets
16
Response Criteria
• Complete Response(CR) : Disappearance
of all evidence of disease
• Partial Response(PR) : Regression of
measurable disease and no new sites
• Progressive Diseases (PD) : Any new
lesions or any increase by 50% from nadir
in SPD
• Stable Disease (SD) : Fail to CR/PR or PD
• Not Evaluable (NE)
17
Complete Response (CR)
• Nodal Masses
• Typically FDG-avid lymphoma - if PET is positive in
screening, PET is negative for all lesions.
• Variably FDG-avid lymphoma - all the lymph
nodes/nodal masses regress to normal size (<= 15 mm
in their greatest transverse diameter or < 10 mm in
short axis if their greatest transverse diameter is
between 10 and 15)
• Spleen and Liver – Not palpable, nodules disappeared
• Bone Marrow – Infiltrate cleared; if indeterminate by
morphology, immunohistochemistry should be negative
18
Partial Response (PR)
• Nodal Masses
• A 50% decrease in the sum of the product of diameters
(SPD) of six target lesions
• No increase in any lesions
• Typically FDG-avid lymphoma - if PET is positive in
screening, PET is positive at least one lesion.
• Variably FDG-avid lymphoma - all the lymph
nodes/nodal masses regress.
• Spleen and Liver – Not palpable, nodules regressed
by 50 % in SPD.
• Bone Marrow – Irrelevant
19
Progressive Disease (PD)
• Nodal Masses
• Any new lesions (more than 15 mm in any axis)
• An increase by 50% in SPD from nadir of any
involved lesions
• An increase by 50% in the longest diameter from
nadir of any involved lesions
• Positive PET.
• Spleen and Liver – nodules increase by 50 % in
SPD.
• Bone Marrow – New or recurrent involvement
20
CDISC Domains or Datasets for
Lymphoma Studies
• SDTM
–TU : Tumor Identification
–TR : Tumor Results
–RS : Response
–LB / FA : Bone Marrow
–PE : Liver and Spleen Palpable assessment
• ADaM
–-TTE : Time to Event Analysis Datasets
21
Efficacy Evaluation in Lymphoma
• Primary
– Overall Survival : Death as event.
– Progression-free survival : Disease Progression or
death as a event. preferred end point in Lymphoma
studies.
• Secondary
– Event-free survival
– Overall Response Rate : Phase II trials of novel new
agents
– Time to Progression
– Disease Free Survival
22
Example
• Randomized and open label Phase II Study
• Lymphoma following Cheson 2007
• 5 cycles
• 3 target and 2 non-target lesions at
screening
• Primary Efficacy – Overall Survival and
Progression Free Survival
23
SDTM TU (Tumor Identification)
USUBJI
D
TULIN
KID
TUTESTC
D
TUTEST
TUORRES
TULOC
TUMETHO
D
001-01001
T01
TUMIDENT
Tumor
Identification
TARGET
NODAL
PELVIC
LYMPH NODE
CT SCAN
001-01001
T02
TUMIDENT
Tumor
Identification
TARGET
NODAL
AXILARY
LYMPH NODE
CT SCAN
001-01001
T03
TUMIDENT
Tumor
Identification
TARGET
NODAL
CERVICAL
LYMPH NODE
CT SCAN
001-01001
NT01
TUMIDENT
Tumor
Identification
NON-TARGET
EXTRA NODAL
LIVER
CT SCAN
001-01001
NT02
TUMIDENT
Tumor
Identification
NON-TARGET
EXTRA NODAL
SPLEEN
CT SCAN
001-01001
T01
TUMIDENT
Tumor
Identification
TARGET
NODAL
PELVIC
LYMPH NODE
FDGPET
001-01001
T02
TUMIDENT
Tumor
Identification
TARGET
NODAL
AXILARY
LYMPH NODE
FDGPET
001-01001
T03
TUMIDENT
Tumor
Identification
TARGET
NODAL
CERVICAL
LYMPH NODE
FDGPET
Key points to note:
• Subject 001 has 3 target and 2 non-targets
• TU.TULINKID is connected TR.TRLINKID using RELREC.
24
SDTM TR at Screening
USUBJ
ID
TRGRI
D
TRLIN
KID
TRTE
STCD
TRTEST
TRCAT
TROR
RES
TROR
RESU
VISIT
TRME
THOD
001-01001
Target
T01
LDIAM
Longest
Diameter
Measure
ment
20
mm
Screening
CT
SCAN
001-01001
Target
T01
LPERP
Longest
Perpendicular
Measure
ment
15
mm
Screening
CT
SCAN
001-01001
Target
T01
AREA
Area
Measure
ment
300
mm^2
Screening
CT
SCAN
001-01001
Target
T01
TUMST
ATE
Tumor State
Qualitati
ve
POSITI
VE
Screening
FDGP
ET
001-01001
Target
SUMAR
EA
Sum of
Products of
Perpendicular
Diameters
Qualitati
ve
2560
001-01001
NonTarget
NT01
TUMST
ATE
Tumor State
Qualitati
ve
PRESE
NT
Screening
CT
SCAN
001-01001
NonTarget
NT02
TUMST
ATE
Tumor State
Qualitati
ve
PRESE
NT
Screening
CT
SCAN
Key points to note:
• Area and Sum of Area were collected
• SPD at screening for 001 is 2,560 mm^2
mm^2
Screening
25
SDTMTR at Cycle 1
USUBJ
ID
TRGRI
D
TRLIN
KID
TRTE
STCD
TRTEST
TRCAT
TROR
RES
TROR
RESU
VISIT
TRME
THOD
001-01001
Target
T01
LDIAM
Longest
Diameter
Measure
ment
15
mm
Visit 1
CT
SCAN
001-01001
Target
T01
LPERP
Longest
Perpendicular
Measure
ment
10
mm
Visit 1
CT
SCAN
001-01001
Target
T01
AREA
Area
Measure
ment
150
mm
Visit 1
CT
SCAN
001-01001
Target
T01
TUMST
ATE
Tumor State
Qualitati
ve
NEGATI
VE
Visit 1
FDGP
ET
001-01001
Target
SUMAR
EA
Sum of
Products of
Perpendicular
Diameters
Qualitati
ve
1200
001-01001
NonTarget
NT01
TUMST
ATE
Tumor State
Qualitati
ve
PRESE
NT
Visit 1
CT
SCAN
001-01001
NonTarget
NT02
TUMST
ATE
Tumor State
Qualitati
ve
PRESE
NT
Visit 1
CT
SCAN
mm
Visit 1
Key points to note:
• SPD at visit 1 for 001 is 1,200, more than 50 % decrease.
• FDGPET is “negative” from “positive”.
26
Bone Marrow - SDTM LB and FA
USUBJI
D
LBCAT
LBSPEC
LBSPID
LBTEST
LBORR
ES
LBOR
RESU
VISIT
001-01001
HEMATO
LOGY
BONE
MARROW
BR01
Bone Marrow
Infiltrate
35
%
Screening
001-01001
HEMATO
LOGY
BONE
MARROW
BR01
Bone Marrow
Infiltrate
9
%
Visit 1
USUBJID
FACAT
FASP FATEST
ID
FAORRES
VISIT
001-01-001
BONE MARROW
BIOPSY
BR01
Bone Marrow Biopsy Results
POSITIVE
Screening
001-01-001
BONE MARROW
BIOPSY
BR01
Bone Marrow Biopsy Results
POSITIVE
Visit 1
Key points to note:
• LB.LBSPID is connected to FA.FASPID
• We can also use BR (Biopsy) domain following SDTM terminology
• Row 1: Bone Marrow Infiltration (i.e., 35%) and its result (i.e., POSITIVE) are
collected, so the example has infiltration number in LB and results in FA.
27
Liver and Spleen Palpable
Assessment - SDTM PE
USUBJI
D
PECAT
PEMETHOD
PETESTCD
PETEST
PEOR
RES
VISIT
001-01001
PHYSICAL
EXAMINATION
PALPATION
SPLEENEN
Spleen
Enlargement
YES
Screening
001-01001
PHYSICAL
EXAMINATION
PALPATION
SPLEENEN
Spleen
Enlargement
NO
Visit 1
001-01001
PHYSICAL
EXAMINATION
PALPATION
LIVEREN
Liver
Enlargement
YES
Screening
001-01001
PHYSICAL
EXAMINATION
PALPATION
LIVEREN
Liver
Enlargement
NO
Visit 1
Key points to note:
• Subject 001 was palpable at Screening, but not palpable at
Visit 1
28
SDTM RS (Response)
USUBJI
D
RSTESTC
D
RSTEST
RSCAT
RSORRES
VISIT
RSDTC
RSSE
Q
001-01001
OVRLRESP
Overall Response
CHESON
2007
PR
Cycle
1
2011-0301
1
001-01001
OVRLRESP
Overall Response
CHESON
2007
SD
Cycle
2
2011-0601
2
001-01001
OVRLRESP
Overall Response
CHESON
2007
PR
Cycle
3
2011-0901
3
001-01001
OVRLRESP
Overall Response
CHESON
2007
PD
Cycle
4
2011-1201
4
001-01001
OVRLRESP
Overall Response
CHESON
2007
PD
Cycle
5
2012-0301
5
Key points to note:
• Overall Response for each visit was collected.
29
Response Assessment at given visit
Tumor
Assessment
by PET (TU)
Tumor
measurement
in SPD by CT
SCAN (TU)
Bone Marrow
Infiltrate (LB,
FA)
Response
(RS)
Spleen and
Liver
Enlargement
(PE)
30
ADaM : Overall Survival (OS)
USUBJI
D
TRTP
PARAM
AVA
L
STARTDT
ADT
CNSR EVNTDESC
001-01001
Study
Drug 1
Overall Survival
(Days)
452
2011-01-01
2012-03-01
1
PROGRESSION
DISEASE
001-01002
Control
Overall Survival
(Days)
338
2011-02-01
2012-01-05
1
LOST TO
FOLLOW-UP
001-01003
Control
Overall Survival
(Days)
212
2011-02-05
2011-09-05
0
DEATH
001-01004
Study
Drug 1
Overall Survival
(Days)
463
2011-03-20
2012-06-25
1
COMPLETED
STUDY
001-01005
Study
Drug 1
Overall Survival
(Days)
67
2011-03-26
2011-06-01
1
PROGRESSION
DISEASE
Key points to note:
• DEATH is NOT censored.
31
ADaM : Progression Free Survival (PFS)
USUBJID
TRTP
PARAM
AVAL
STARTDT
ADT
CNSR EVNTDESC
001-01-001
Study
Drug 1
Progression
Free Survival
(Days)
452
2011-01-01
2012-03-01
0
PROGRESSION
DISEASE
001-01-002
Control
Progression
Free Survival
(Days)
338
2011-02-01
2012-01-05
1
LOST TO
FOLLOW-UP
001-01-003
Control
Progression
Free Survival
(Days)
212
2011-02-05
2011-09-05
0
DEATH
001-01-004
Study
Drug 1
Progression
Free Survival
(Days)
463
2011-03-20
2012-06-25
1
COMPLETED
STUDY
001-01-005
Study
Drug 1
Progression
Free Survival
(Days)
67
2011-03-26
2011-06-01
0
PROGRESSION
DISEASE
Key points to note:
• In PFS, DEATH and PD are NOT censored.
32
Conclusion
• Standard for Lymphoma Studies
1. Cheson 2007 : Tumor Measurements and
Responses
2. CDISC SDTM : submission data
3. CDISC ADaM : analysis data
33
2014 Summer Preview
• Blockbuster Movies
• Webinar : FDA Electronic submission Guidance
• PharmaSUG (June 1st to 4th)
–CDISC Electronic Submission
34
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Email address : [email protected]
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35
Questions and Discussion
© 2014 Accenture All Rights Reserved.
36

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