Modeling in vitro Test Agent Name, Dosing Concentration and Units: Control/Study Drugs, Therapeutics and other Agents

Stefan's use-case:

In a new trial, the secretion of cytokines by immune cells is measured in a mixture of likely serum and culture medium. The procedure is like this: Blood is drawn and is then incubated for 24 hours in that medium. Substances that are supposed to provoke an immune reaction are added, such as specific antibodies or the study drug. After 24 hours, the cells are removed and the supernatant is collected and analyzed for cytokines such as Interferon gamma and Interleukins.

The secretion is provoked by a Stimulating Agent (Test Condition) and we know what substance was used (Test Condition Agent). However, now comes the tricky part: the study drug should be added to that test tube in different concentrations in order to assess if there are differences in the reaction of the immune cells (T cells and NK cells) secreting Interferon and Interleukins.

So the question is: How would you capture these different concentrations of the Test Condition Agent? Would you recommend to have separate codes in the Test Condition Agent for, let’s say, “Study drug, concentration A”, “Study drug, concentration B”, … and then set up different analytes, one per concentration? Would you use a supplemental qualifier? Or would there be a further option you would recommend we have not yet considered?

Background Information:

1. This was sent to the lab team for discussion and we decided that the INF-y response tests should be modeled in IS.
2. Craig said there are NO other variables to capture the units and dosing concentrations for the test agents that are added to the samples. In fact, this is a gap in the CDISC model that we lack variables (or a domain) to help mapping in vitro drug/non-drug exposure data. The EX/EC and AG domains are used for mapping in vivo drug and non-drug agents exposure data (respectively). These domains have variables for mapping dosing concentrations and units, but we can't use them for in vitro exposure data. Craig said he would pre-coordinate the concentrations and units of the agents added into the ISCNAGT (test condition agent) variable, see the texts in red in the above example.
   • this is a problem because a single CDISC domain variable should be designed for a single meaning and a single purpose. The Test Condition Agent variable is used for the name/identity of the agent. I think we would be breaking rules to also include the concentration and unit of the agent in this variable as well.
3. While brain storming Stefan's use-case, I remembered that in the MS domain, there are MSAGENT (Agent Name), MSCONC (Agent Concentration), MSCONCU (Agent Concentration Units) variables that were developed back in SDTMIG v3.2 to represent the study and control drugs used for microbial resistance testing. Basically, for these MS tests, you dump antibiotics on a plate to see if the bacteria would be resistant or susceptible for the drug by measuring a few outputs, at differing drug concentrations.

Questions/Discussion Needed:

I want to run this by the team to see if we actually have a "duplicated purpose variable" issue here.

1. Is the Test Condition Agent (ISCNDAGT) variable the same as the Agent Name (MSAGENT)?
2. Do we use them for the same purpose? - they both are used to map the name of the thing/entity (e.g. study/control drug, stimulating test materials like TB antigens) you add to a sample to induce a response.
3. If yes, do we need to merge these two variables? Seeing as we are making changes for IG4.0, this might be worth considering, and will need multiple team's approval.
4. Can we also then extend the use of the standard variables --CONC (Agent Concentration), --CONCU (Agent Concentration Units) to the other specimen-based domains for mapping concentration and unit of the in vitro test agent? There are now use-cases needing these variables in IS, MS and CP.
5. Other concerns....

Here is an MS example from IG3.4:

After E. faecalis was identified in the subject sample, drug susceptibility testing was performed at each of the labs using both the sponsor's investigational drug and amoxicillin. Because an identified organism is the subject of the test, the NHOID variable is populated with "ENTEROCOCCUS FAECALIS". Between the 2 labs (MSNAM), a total of 3 susceptibility testing methods were used: epsilometer, disk diffusion, and macro broth dilution (MSMETHOD). Epsilometer and disk diffusion both use agar diffusion methods, in which an agar plate is inoculated with the microorganism of interest and either a strip (epsilometer) or discs (disk diffusion) containing various concentrations of the drug are placed on the agar plate. The epsilometer test method provides both a  minimum inhibitory concentration (MSTESTCD = "MIC"), the  lowest concentration of a drug  that inhibits the growth of a microorganism, and a qualitative interpretation (MSTESTCD = "MICROSUS") such as susceptible, intermediate, or resistant. The disk diffusion test method provides the diameter of the zone of inhibition (MSTESTCD = "DIAZOINH") and a qualitative interpretation such as susceptible, intermediate, or resistant (MSTESTCD = " MICROSUS" ). The quantitative and qualitative results are grouped together using MSGRPID.

The third method, macro broth dilution, was used to test the specimen at a predefined drug concentration of each of the drugs. When the drug and amount are a predefined part of the test, the variable MSAGENT is populated with the name of the drug being used in the susceptibility test. The variables MSCONC and MSCONCU represent the concentration and units of the drug being used.