Examples for SDTMIG v3.4

New IS domain-specific variables

Illustration of variables: 

Example 1: Tiered Testing of ADA

This example shows the tiered testing of antidrug antibody (ADA). Typical tiered testing scheme for ADA evaluation includes the following steps: screening, confirmatory, and "characterization". In the first tier, all evaluable samples are run in the screen assay. Samples that score positive in the screen assay are then analyzed in a confirmatory assay (tier 2). Samples that are positive for ADA in the screen and confirmatory tiers are reported as positive, while samples that are negative in either tier are reported as negative. Further tiered testing of positive samples frequently includes analysis of antibody titer and neutralizing activity. The variable "TSTOPO" has the following controlled values: SCREEN, CONFIRM and QUANTIFY to describe the operational objective or the reason behind each testing step, and also to provide uniqueness to each row of record. ISGRPID is used in this example to show that the records are related to each other, and in this case, tests are done in a tiered, sequential manner.

Example 2: Consolidated Reporting of ADA

The example below shows how to represent the various types of antidrug antibody tests (ADA). Of note, while most ADAs do not inhibit the pharmacodynamic activity of the drug, neutralizing antidrug antibodies (NAbs) can inhibit drug activity soon after the drug is administered. However, most ADAs, or rather, the non-NAbs can lower the drug's systemic exposure just as well by increasing the rate of drug clearance, resulting in a clinically similar outcome to that of Nabs – reduced clinical efficacy.

Rows 1-4 in this example show binding antidrug antibody reaction against the administered analogue drug, whereas rows 5-8 show cross-reactive antidrug antibody reaction against the endogenous protein that's structurally similar to the analogue study drug. Both the study drug and the endogenous protein are represented by the IS domain-specific variable "ISBDAGNT", which only qualifies the ISTEST variable. The variable, "ISTSTOPO", is also used in this dataset to describe the purpose of each testing step, and provides uniqueness to each record. ISGRPID is used to show which records are related.

Example 3 - ADA Reaction Against Drug Components - Breakdown Product

This example shows the production of antidrug antibody in response to both the prodrug and its active metabolite. A prodrug is a compound that, after administration, is metabolized into a pharmacologically active drug. Please note in this example, even though only confirmatory records are reported and shown, it is assumed that the screening step has also been performed.

Example 4 - ADA Reaction Against Drug Components: Multiple Epitopes per Molecule

The example below shows the production of antidrug antibody in response to both the study biologic drug and also to different immunogenic epitopes of the biologic drug. This also captures an example for when the tier stops at screening (interferon beta1a assay) and goes straight into NAB from there. While unusual, it reflects the flexibility of these fields to incorporate multiple options.

A biologic drug may be biotechnology-derived therapeutic proteins (including mAbs) and peptides, some plasma-derived products (e.g., coagulation factor replacement products), and naturally derived proteins (e.g. therapeutic enzymes and toxins).

Example 5 - Autoimmune Disease Diagnosis

The example below shows how to represent autoantibody data.

Example 6 - Vaccine Studies

The example below shows how to represent data about vaccine-induced immunological responses, as well immunological data collected during the trial but are not germane to the study vaccine.

Example 7: Testing of Antibody-secreting Cells

Traditional methods such as ELISA that monitor humoral immune responses after immunization or infection typically only quantify specific antibody titers in serum. These methods do not provide any information about the actual number and location of the immune cells that secrete antibodies or cytokines.

The Enzyme-Linked ImmunoSpot (ELISpot) assay is a method to detect and quantify analyte-secreting T or B cells. Generally during Elispot testing, a colored precipitate forms and appears as spots at the sites of analyte localization (analytes typically are cytokines or antibodies), with each individual spot representing an individual analyte-secreting cell. The spots can be counted with an automated ELISpot reader system or manually, using a stereomicroscope. The example below shows how to represent the quantification of antibody-secreting cells (ASCs) as the number of spots per million peripheral blood mononuclear cells (PBMC) as determined by B-cell ELISpot from a vaccine trial.

The IS domain-specific variable, Secreted Molecule by Cells/SCMBCL, is introduced in the example below to allow flexibility in data representation and post-coordination of the various secreted antibody types and their respective ASCs. This approach liberates the ISTEST variable from having to house pre-coordinated and thus hyper-specific values crafted based on secretion and cell types.

Example 9 - Microneutralization Assay

In vaccine studies, microneutralization assays are commonly used in vitro assays to quantify viral-specific neutralizing antibodies in the subject’s specimen that can block viral infection in vitro, and so provide output of vaccine efficacy.  

Typically, a subject's serum and the virus of interest are added to in vitro cell cultures. If neutralizing antibodies are present in the serum, those antibodies will bind to the virus and thereby "blocking" and preventing the virus from infecting the cells in the culture plates. By vaccination with a vaccine that induces antibody response, one thus assumes that the quantity of viral-specific antibodies that are able to block viral infection are increased. The neutralization titer is the antiviral antibody titer that blocks viral infection of the cells. The NEUTRALIZING TITER 50% (also known as NT50) in the context of microneutralization assays is defined as the antiviral antibody titer that blocks 50% of viral infection of the cells. Please note that some users may also represent "Neutralizing Titer 50%" as "IC50 titer" or other test descriptors. CDISC recommends housing values such as NT50, IC50 neutralizing titer, etc. in the ISTSTDTL variable.

The example below shows data from the same Respiratory Syncytial Virus (RSV) vaccine study where the subject is being vaccinated with a viral vector containing RSV Epitope B. The subject is tested before (baseline) and after vaccination (visits 1 and 2) whether the anti-RSV binding antibodies present in the subject’s serum also have the functionality to neutralize RSV infection in vitro.

*A Neutralizing antibody is defined as antibodies that bind to, block and prevent non-self agents from infecting cells.

Example 10 - Opsonophagocytic Killing Assay

In vaccine trials, the opsonophagocytic killing (OPK) assay is used as a correlate for protection to measure the "functional capacities" of vaccine-induced antibodies. This in vitro assay aids selecting promising vaccines by demonstrating whether the vaccine-induced antibodies drive efficient complement deposition and subsequent opsonophagocytic killing. 

Typically this test is performed by incubating post-immunization sera of a subject with the bacterial strain of interest, phagocytes and complement proteins. If anti-bacterial antibodies are present in the subject's serum, those antibodies will bind to the bacteria together with complement proteins, this subsequently targets the bacteria for opsonization, which is the ingestion and destruction of invading non-self agents by phagocytes. By vaccination, one thus assumes that the quantity of bacterial-specific antibodies are increased, leading to a decreased number of viable bacterial cells in the presence of phagocytes, functional antibodies and complement. The assay read-out is expressed in Opsonization Index (OI) which is calculated using linear interpolation of the serum dilution containing functional antibody killing the desired percentage (usually 50%) of the bacteria, using a pre-specified algorithm.

The example below shows data from a vaccine study for Escherichia Coli (E.Coli) where the subject is being vaccinated with a vector containing E.Coli epitope X. The subject is tested before (baseline, row1) and after vaccination (rows 2-3) whether the vaccine-induced antibodies drive efficient complement deposition and subsequent opsonophagocytic killing of the E.Coli in vitro. The assay read-out is expressed in Opsonization Index (ISTSTDTL), which is a unit-less test.

A functional antibody is defined as antibodies that bind to non-self agents and initiate opsonization (destruction by complement and phagocytes) or active killing of the said non-self agent by other types of cells. Being able to recruit and activate the complement system is the key and definitive nature of a functional antibody.