a working proposal for immunogenicity in cdisc · would still need additional flexibility in...
TRANSCRIPT
Only to be used in USA & Canada, never outside these two countries
Joleen White, PhD
Head of NBE Drug Disposition Project Support
EMD Serono current practice
plus current working proposal (in progress) from PhUSE
A Working Proposal for
Immunogenicity in CDISC
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Perspective of an immunogenicity expert
Excited to work with PhUSE and CDISC to integrate the scientific and operational aspects
Current EMD Serono SDTM for one compound in the portfolio
Current working proposal from PhUSE/FDA Computational Sciences Collaboration
Using IS domain
Alternate using LB domain for SEND 3.0
Rationale for use of ISSCAT* rather than ISTEST and ISTESTCD for uniqueness
Flexibility of proposal to accommodate multiple testing and reporting algorithms
Examples A-J included for detailed future reference
Will discuss selected examples during call
* Original proposal was to use ISSCAT, however now considering a separate or non-standard variable in supplemental qualifier, so final proposal may look slightly different
Outline
Analyte Endpoint description
ISTESTCD ISSCAT ISTEST
Binding antibodies
Screening for binding antidrug antibodies
ADABAB Screening Antidrug binding
antibodies
Confirmation of detection of binding antidrug antibodies
ADABAB Confirmation Antidrug binding
antibodies
Quasi-quantification of binding antidrug antibodies
ADABAB Titer Antidrug binding
antibodies
Neutralizing antibodies
Screening for neutralising antidrug antibodies
ADANAB Screening Antidrug
antibodies
Confirmation of neutralising antidrug antibodies
ADANAB Confirmation Antidrug
antibodies
Quasi-quantification of neutralising antidrug antibodies
ADANAB Titer Antidrug
antibodies
Current EMD Serono (Merck KGaA, Darmstadt, Germany) approach (under revision)
Missing a way to distinguish when multiple IMPs in same study
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Analyte Endpoint description
ISTESTCD ISTEST ISTSTDTL* ISCAT ISSCAT**
Binding antibodies
Screening for binding antidrug antibodies
ADA_BAB Binding antidrug
antibodies Screening
Antidrug antibodies
Free text description of test article (specific epitopes optional)
Confirmation of detection of binding antidrug antibodies
ADA_BAB Binding antidrug
antibodies Confirmation
Antidrug antibodies
Free text description of test article (specific epitopes optional)
Quasi-quantification of binding antidrug antibodies
ADA_BAB Binding antidrug
antibodies
Quasi-quantification
Antidrug antibodies
Free text description of test article (specific epitopes optional)
Neutralising antibodies
Screening for neutralising antidrug antibodies
ADA_NAB Neutralizing
antidrug antibodies
Screening Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Confirmation of neutralising antidrug antibodies
ADA_NAB Neutralizing
antidrug antibodies
Confirmation Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Quasi-quantification of neutralising antidrug antibodies
ADA_NAB Neutralizing
antidrug antibodies
Quasi-quantification
Antidrug antibodies
Free text description of test article (specific epitopes optional)
Page 1 of 3: Preferred option for antibodies against the test article
Working Proposal from PhUSE/FDA Computational Sciences Collaboration
* Need to check to see if this is in published standard or if in a proposed standard. Propose this to be expected but
not required field. Left blank in cases where granularity is not required
** Original proposal was to use ISSCAT, however now considering a separate or non-standard variable in
supplemental qualifier, so final proposal may look slightly different
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Analyte Endpoint description
ISTESTCD ISTEST ISTSTDTL* ISCAT ISSCAT**
Binding antibodies
Screening for cross-reactive binding antidrug antibodies
ADA_X Binding antidrug
antibodies Screening
Antidrug antibodies
Free text description of endogenous molecule (specific epitopes optional)
Confirmation of detection of cross-reactive binding antidrug antibodies
ADA_X Binding antidrug
antibodies Confirmation
Antidrug antibodies
Free text description of endogenous molecule (specific epitopes optional)
Quasi-quantification of cross-reactive binding antidrug antibodies
ADA_X Binding antidrug
antibodies
Quasi-quantification
Antidrug antibodies
Free text description of endogenous molecule (specific epitopes optional)
Neutralising antibodies
Screening for cross-reactive neutralising antidrug antibodies
ADA_XN Neutralizing
antidrug antibodies
Screening Antidrug
antibodies
Free text description of endogenous molecule (specific epitopes optional)
Confirmation of cross-reactive neutralising antidrug antibodies
ADA_XN Neutralizing
antidrug antibodies
Confirmation Antidrug
antibodies
Free text description of endogenous molecule (specific epitopes optional)
Quasi-quantification of cross-reactive neutralising antidrug antibodies
ADA_XN Neutralizing
antidrug antibodies
Quasi-quantification
Antidrug antibodies
Free text description of endogenous molecule (specific epitopes optional)
Page 2 of 3: Preferred option for antibodies cross-reactive against endogenous molecules
Working Proposal from PhUSE/FDA Computational Sciences Collaboration
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Analyte Endpoint description
LBTESTCD LBTEST LBCAT LBSCAT
Binding antibodies
Screening for binding antidrug antibodies
ADA_BABS Binding antidrug antibodies
Screening Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Confirmation of detection of binding antidrug antibodies
ADA_BABC Binding antidrug antibodies
Confirmation Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Quasi-quantification of binding antidrug antibodies
ADA_BABQ Binding antidrug antibodies
Quasi-quantification Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Neutralising antibodies
Screening for neutralising antidrug antibodies
ADA_NABS Neutralizing antidrug antibodies
Screening Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Confirmation of neutralising antidrug antibodies
ADA_NABC Neutralizing antidrug antibodies
Confirmation Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Quasi-quantification of neutralising antidrug antibodies
ADA_NABQ Neutralizing antidrug antibodies
Quasi-quantification Antidrug
antibodies
Free text description of test article (specific epitopes optional)
Page 3 of 3: SEND 3.0 option for antibodies against the test article (cross-reactive analogous)
Working Proposal from PhUSE/FDA Computational Sciences Collaboration
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Field Screening and Confirmatory Quasi-quantitation
ISMETHOD From method library (one example: IMMUNOCHEMILUMINOMETRIC ASSAY)
ISSPEC From sample type (usually SERUM)
ISORRES/ISSTRESC Positive or Negative (if NR, see below) Number (if NR, see below)
ISORRESU/ISSTRESU Blank Titer
ISSTRESN Blank Number (same as ISORRES)
ISREFID From case report form, link to result from testing laboratory
ISNAM Testing laboratory name, free text
ISLLOQ Blank
Additional Fields
STUDYID, DOMAIN, USUBJID, ISSEQ, VISITNUM, VISIT, VISITDY, ISDTC, ISDY, ISSTAT, ISREASND
ISBLFL: Flag for baseline visit coded from VISIT, VISITDY, and protocol SoA
ISSPCCND: Use comments from testing laboratory
NR: no result to be modeled therefore leave blank and use REASND
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Majority of ISTESTCD would be company-specific
Significant overlap between companies
Would require reuse of codes within a company due to limited character count
(only 1 additional character so 36 unique codes per company)
No additional characters remaining for the SEND 3.0 backup option
ISSCAT* allows construction of company-specific library across all studies
Do recommend separating out cross-reactive to endogenous analytes
Allows recognition of subcategory of particular interest in safety evaluation
Theoretically possible to further define ADA_X and ADA_XN for common endogenous
analytes in CDISC standards
Would still need additional flexibility in ISSCAT* if specific epitopes of endogenous analyte
are evaluated
Recognized disadvantage that ISTESTCD does not describe a unique analyte
Selected reasons to use ISSCAT* for analyte rather than ISTEST and ISTESTCD
* Original proposal was to use ISSCAT, however now considering a separate or non-standard variable in
supplemental qualifier, so final proposal may look slightly different
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Mix and match the 12 main categories plus ISSCAT* to work with any testing schematic
BAB vs NAB for therapeutic proteins
X vs XN for endogenous proteins
ISSCAT for specific analyte (and epitope as needed)
Program the ADaM to integrate entries across the rows/subjects for immunogenicity TLFs
* Original proposal was to use ISSCAT, however now considering a separate or non-standard variable in supplemental qualifier, so final proposal may look slightly different
Flexibility in Use of the CDISC terms
HAHA Assay 10
Example A: One analyte through all three tiers (most common for clinical)
ADA_BAB Screening
Assay ADA_BAB Confirmatory
Assay ADA_BAB Quasi-
Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
ISTESTCD: ADA_BAB ISTSTDTL:
Quasi-quantification
HAHA Assay 11
Example B: Consolidated reporting for screening and confirmatory
ADA_BAB Screening
Assay ADA_BAB Confirmatory
Assay ADA_BAB Quasi-
Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
ISTESTCD: ADA_BAB ISTSTDTL:
Quasi-quantification
HAHA Assay 12
Example C: Consolidated reporting for screening and confirmatory, no titer (Christy example?)
ADA_BAB Screening
Assay ADA_BAB Confirmatory
Assay
NEG
NEG
POS
POS
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
or (Blank)
HAHA Assay 13
Example D: Screening only (most common for nonclinical and nAb) (Christy example?)
ADA_BAB Screening
Assay
NEG
POS
ISTESTCD: ADA_BAB ISTSTDTL:
Screening or (Blank)
HAHA Assay 14
Example E: No confirmatory assay (also common for nAb) (Leslie example 1?)
ADA_BAB Screening
Assay
ADA_BAB Quasi-
Quantitation
NEG
POS
ADA_BAB Titer
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISTESTCD: ADA_BAB ISTSTDTL:
Quasi-quantification
HAHA Assay 15
Example F: Cross-reacting antibodies important for one endogenous protein (Thomas 1)
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ADA_X Screening Assay
ADA_X Confirmatory Assay
ADA_X Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_X ISTSTDTL: Screening
ISSCAT: Endogenous Protein
ISTESTCD: ADA_X ISTSTDTL: Confirmatory
ISSCAT: Endogenous Protein
ISTESTCD: ADA_X ISTSTDTL: Quasi-quantification ISSCAT: Endogenous Protein
HAHA Assay 16
Example G: Cross-reacting antibodies important for n endogenous proteins (Thomas 3)
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ADA_X Screening Assay
ADA_X Confirmatory Assay
ADA_X Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_X ISTSTDTL: Screening
ISSCAT: Endogenous Protein n
ISTESTCD: ADA_X ISTSTDTL: Confirmatory
ISSCAT: Endogenous Protein n
ISTESTCD: ADA_X ISTSTDTL: Quasi-quantification ISSCAT: Endogenous Protein n
n *
HAHA Assay 17
Example H: Additional testing for n specific epitopes
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic X
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic X
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic X
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic X Epitope n
ISTESTCD: ADA_BAB ISTSTTTL: Confirmatory
ISSCAT: Therapeutic X Epitope n
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic X Epitope n
n *
HAHA Assay 18
Example I: Screen whole molecule, primary testing for n specific epitopes (Thomas 2)
ADA_BAB Screening Assay
NEG
POS
ISTESTCD: ADA_BAB ISTSTDTL: Screening or (Blank)
ISSCAT: Therapeutic X
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic X Epitope n
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory
ISSCAT: Therapeutic X Epitope n
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic X Epitope n
n *
HAHA Assay 19
Example I: Screen/confirm/titer whole molecule, confirm for n specific epitopes
ADA_BAB Screening Assay
NEG
POS
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic X
ADA_BAB Confirmatory Assay
NEG
POS
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory or (Blank) ISSCAT: Therapeutic X Epitope n
n *
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic X
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic X
HAHA Assay 20
Example J: Testing required for additional n therapeutic proteins in combination (Leslie example 2)
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic X
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic X
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic X
ADA_BAB Screening Assay
ADA_BAB Confirmatory Assay
ADA_BAB Quasi-Quantitation
NEG
NEG
POS
POS ADA_BAB
Titer
No further data
No further data
ISTESTCD: ADA_BAB ISTSTDTL: Screening
ISSCAT: Therapeutic n
ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic n
ISTESTCD: ADA_BAB ISTSTDTL: Quasi-quantification
ISSCAT: Therapeutic n
n *