IS Domain Scope Update for the SDTMIG v3.4: A Development History and the Difficulties of Standardizing Complicated Biological Processes

Section 1: An expanded scope and new definition for the IS domain in the SDTMIG v3.4

The current Immunogenicity Specimen Assessments (IS) domain in the SDTMIG v3.4 is designed to represent data pertaining to specimen-based assessments that measure the “presence, magnitude and scale of the immune response upon an antigen stimulation or encounter.” Not only does the new domain definition better align with the scientific definition of “immunogenicity”, but it also expands the scope of the IS domain from the previous versions of SDTMIG (i.e., v3.2 and v3.3), where the IS domain was defined to represent data pertaining to “assessments that describe whether a therapy provoked/caused/induced an immune response”.

The “antigen” (of interest) in the updated IS domain definition is any entity capable of inducing a host immune response, and may be (but is not limited to), drug/test article (i.e., study/non-study therapy), allergen, microorganism (e.g., bacteria, virus, fungi, parasite, etc.), self-antigen (i.e., autoantigen), and others.

The assessments that “detect the presence of, and quantify the magnitude and scale of the immune response upon an antigen stimulation or encounter”, and are in scope for inclusion in the IS domain per the SDTMIG v3.4, are the following:

1. Activated immune cells, specifically and mainly (but are not limited to) those measured via ELISPOT:

a. Cytokine-secreting cells

b. Antibody-secreting cells

2. Activated immune cell products: antibody (i.e., humoral immune response)

a. Antidrug antibody.

b. Anti-microbial antibody for both microbiology and vaccine studies.

c. Anti-allergen antibody, for allergy studies.

d. Anti-autoantigen antibody (also called autoantibody), for autoimmune disease studies.

e. Others, such as alloantibody for transplantation, transfusion studies.

3. Other currently unclassified specimen-based, immune response tests.

More details and description of the changes and updates made to the IS domain in the SDTMIG v3.4 can be found in section 6.3.5.5 Immunogenicity Specimen Assessments (IS), specifically, assumptions 2 and 3.
 

Section 2: Problems that led to, and rationales behind, the IS domain scope update for the SDTMIG v3.4

Domain and variable level limitations

Prior to the release of the SDTMIG v3.4, most specimen-based immunogenicity assessment data had been mapped to the Microbiology Specimen (MB) and Laboratory Test Results (LB) domains, which do not have the sufficient structure and standard variables to support the meaningful representation of such data. As a result, various supplemental qualifiers had to be created to map key immunogenicity testing information in both LB and MB.

• Note: The IS domain in the SDTMIG v3.4 has new standard variables for the stable and consistent representation of the key information.

The MB and LB domains also employ a pre-coordinated TEST/TESTCD values modeling approach, and there is a lack of clear definition and boundaries on what is considered as the “analyte” under assessment, which is typically mapped to the --TEST/--TESTCD variables. Consequently, too much information is pre-coordinated into the TEST/TESTCD values, overloading the --TEST/--TESTCD variables. In addition, CDISC Conformance Rules dictate that <=8-character TESTCD/PARMCD and <=40-character TEST/PARM values be available for data submission to regulators. Because of the 8- and 40-character limit, LB and MB TEST/TESTCD values are heavily abbreviated, and in some instances, TESTCD values are replaced with the NCI C-codes to ensure uniqueness (see Appendix, Example 2) which significantly undermine their meaningfulness and clarity, and further make data/dictionary management of the TEST/TESTCD values difficult.

• Note: the updated IS domain in the SDTMIG v3.4 takes a post-coordination modeling approach, with the introduction of several new variable qualifier standard variables to help to resolve the overloading of the --TEST/--TESTCD variables issue.

Multiple SDTM Findings domains were utilized to represent data of a common topic, due to changes in SDTMIG versioning and the limited IS domain scope

The specimen-based assessments that measured the presence of and/or quantify the magnitude and scale of the immune responses, and are in scope for the IS domain in the SDTMIG v3.4, had historically been mapped to various specimen-based domains, such as LB, MB and/or IS. More specifically:

Activated immune cells (section 1, bullet 1) after study therapeutic exposure has been in IS.

Anti-drug antibody (section 1, bullet 2a) should be modeled in IS. Previously there had been discussions on representing this data in LB.

Anti-microbial antibody (section 1, bullet 2b) could be mapped to multiple domains:

• When collected prior to study treatment exposure:
  • Use the LB domain, if submitting data under the SDTMIG v3.2 or SENDIG v3.0 and v3.1.
  • Use the MB domain, if submitting data under the SDTMIG v3.3.
• When collected after study treatment exposure: use the IS domain.

 Anti-allergen antibody (section 1, bullet 2c) could be mapped to multiple domains

• Use LB, if it is due to natural, or previous exposure to allergens or treatments.
• Use IS, if it is measured after administration of a study immunotherapy (e.g., increased/decreased anti-allergen IgE antibody titers in response to, for example, allergy shots).

Autoantibody and alloantibody (section 1, bullets 2d-2e) are still mapped to LB per the SDTMIG v3.2/3.3.

• There is a similar confusion/lack of clarity with alloantibodies in organ transplantation studies. If the organ recipient has certain anti-doner alloantibodies due to previous exposure (e.g., from blood transfusion, pregnancy, or prior transplant), this data belongs in LB. If the alloantibody levels change after receiving organ transplantation, then they belong in IS.

In summary, the “baseline” immune response testing data prior to study treatment exposure would most likely end up in a different domain. The section below describes and discusses the SDTM modeling of a specific use-case, which models Respiratory Syncytial Virus (RSV) vaccine-induced humoral protective immune response via the quantification of RSV antibody production. In this example, when one measures “TEST = RSV IgG Antibody”, this piece of data can mean two things:

• It is an anti-microbial antibody, produced in response to the RSV natural infection, and can be used to detect prior or current RSV infection, therefore it should be mapped to the MB domain (note the MB domain is used to store data pertaining to detection, identification, and characterization of non-host microorganisms), as per the SDTMIG v3.2/v3.3.
• It can also be a vaccine-induced antibody. If it is produced in response to the RSV study vaccine, it should be mapped to IS, per the SDTMIG v3.2/v3.3.

The data collected in the form of controlled terminology is the same for the above two scenarios (e.g., MB/ISTEST = RSV IgG Antibody, per the SDTMIG v3.2/v3.3). This then raises the question: for a RSV vaccine trial, when baseline measurement is performed, and there is RSV IgG antibody presence (and a titer is also frequently collected at this time) - this is prior to RSV study vaccine administration. Should users map the baseline data to MB or IS or both? In this case, users are required to perform the following mental process:

First, there is a presence/quantity of RSV IgG antibody at baseline, this could be due to a prior or ongoing natural infection, therefore could be mapped to MB.

• Note: MB is used to model non-host microorganism detection, identification and quantification type of data. In this specific scenario, the RSV antibody levels at baseline are collected to compare with the RSV vaccine-induced protective antibody levels after study vaccine administration – the baseline measurement is not meant for microbial identification/detection purpose, consequently, using MB is a stretch on its domain scope.
• Note: A separate, but closely related argument has also been made about whether anti-microbial antibody tests should be modeled in MB in the first place. The MB domain is used for the direct assessments of the non-host microorganism of interest itself that indicates a presence (or absence) of the microorganism at the time of specimen testing. The presence of the anti-microbial antibody is the host’s immune response toward a pathogen, and is a surrogate measure for prior or current infection. If a particular anti-microbial antibody is present, it doesn’t necessarily signal a current and ongoing infection, nor the presence of the microorganism at the time of specimen testing.

Second, the presence of the RSV antibody at baseline could be the result of a prior vaccine exposure (or from both prior infection and vaccination). Because it is not induced by the “study” vaccine, it does not belong in IS. Where would one map it? Using MB would be technically incorrect.

 Lastly, the version of the SDTMIG also affects the domain used for mapping this baseline record – it should go into LB if submitted under the SDTMIG v3.2, and MB if submitted under the SDTMIG v3.3.

Following the above process, the SDTM modeling for “RSV IgG antibody quantification” test, based on the SDTMIG v3.2/v3.3, would look like Mock 1 or 2 examples (note variables have been omitted from the tables for simplicity):