a working proposal for immunogenicity in cdisc · would still need additional flexibility in...

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

1 Title of Presentation | DD.MM.YYYY


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



ISTESTCD ISTEST ISTSTDTL* ISCAT ISSCAT**

Binding antibodies


ADA_BAB Binding antidrug

antibodies Screening

Antidrug antibodies

Free text description of test article (specific epitopes optional)



antibodies Confirmation

Antidrug antibodies




antibodies

Quasi-quantification

Antidrug antibodies


Neutralising antibodies


ADA_NAB Neutralizing

antidrug antibodies

Screening Antidrug

antibodies




antidrug antibodies

Confirmation Antidrug

antibodies




antidrug antibodies


Antidrug antibodies


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



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


antibodies Confirmation

Antidrug antibodies


Quasi-quantification of cross-reactive binding antidrug antibodies


antibodies


Antidrug antibodies



Screening for cross-reactive neutralising antidrug antibodies

ADA_XN Neutralizing

antidrug antibodies

Screening Antidrug

antibodies


Confirmation of cross-reactive neutralising antidrug antibodies

ADA_XN Neutralizing

antidrug antibodies


antibodies


Quasi-quantification of cross-reactive neutralising antidrug antibodies

ADA_XN Neutralizing

antidrug antibodies


Antidrug antibodies


Page 2 of 3: Preferred option for antibodies cross-reactive against endogenous molecules




LBTESTCD LBTEST LBCAT LBSCAT

Binding antibodies


ADA_BABS Binding antidrug antibodies

Screening Antidrug

antibodies



ADA_BABC Binding antidrug antibodies


antibodies



ADA_BABQ Binding antidrug antibodies

Quasi-quantification Antidrug

antibodies




ADA_NABS Neutralizing antidrug antibodies

Screening Antidrug

antibodies



ADA_NABC Neutralizing antidrug antibodies


antibodies



ADA_NABQ Neutralizing antidrug antibodies

Quasi-quantification Antidrug

antibodies


Page 3 of 3: SEND 3.0 option for antibodies against the test article (cross-reactive analogous)



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


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


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:


HAHA Assay 11

Example B: Consolidated reporting for screening and confirmatory

ADA_BAB Screening


Assay ADA_BAB Quasi-

Quantitation

NEG

NEG

POS

POS ADA_BAB

Titer

No further data




HAHA Assay 12

Example C: Consolidated reporting for screening and confirmatory, no titer (Christy example?)

ADA_BAB Screening


Assay

NEG

NEG

POS

POS


or (Blank)

HAHA Assay 13

Example D: Screening only (most common for nonclinical and nAb) (Christy example?)

ADA_BAB Screening

Assay

NEG

POS


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




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: 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)




NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data




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




NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data


ISSCAT: Therapeutic X

ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic X






NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data


ISSCAT: Therapeutic X Epitope n

ISTESTCD: ADA_BAB ISTSTTTL: Confirmatory




n *

HAHA Assay 18

Example I: Screen whole molecule, primary testing for n specific epitopes (Thomas 2)


NEG

POS

ISTESTCD: ADA_BAB ISTSTDTL: Screening or (Blank)





NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data







n *

HAHA Assay 19

Example I: Screen/confirm/titer whole molecule, confirm for n specific epitopes


NEG

POS




NEG

POS

ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory or (Blank) ISSCAT: Therapeutic X Epitope n

n *



NEG

POS ADA_BAB

Titer

No further data

No further data




HAHA Assay 20

Example J: Testing required for additional n therapeutic proteins in combination (Leslie example 2)




NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data









NEG

NEG

POS

POS ADA_BAB

Titer

No further data

No further data


ISSCAT: Therapeutic n

ISTESTCD: ADA_BAB ISTSTDTL: Confirmatory ISSCAT: Therapeutic n


ISSCAT: Therapeutic n

n *

a working proposal for immunogenicity in cdisc · would still need additional flexibility in...

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