Exposure in ADaM

Most pharmaceutical companies adhere to the ICH E3 guideline “Structure and Content of Clinical Study Reports” when creating a clinical study report (CSR). For exposure analysis , the ICH guideline recommend that the investigational products should be characterized by:

. The number of patients exposed

. The duration of exposure

. The dose to which they were exposed.

Therefore, the following items could be needed in your TFL:

. Duration of treatment

. Number of cycles received 

. Number of patients with dose adjustments 

. Reasons for dose adjustments 

. Dose intensity as a percentage of dose received relative to the planned dose

. Dose compliance as a percentage of dose received relative to the prescribed dose.

This of course is not an exhaustive list.

Some considerations to take into account when programming ADEX

When calculating some of the variables such as the dose intensity, careful attention needs to be placed on the unit that is required.

For example if the unit is mg/m2 then the body surface area (BSA) of the subject may need to be used in the derivation. BSA is often used in clinical purposes over body weight because it is a more accurate indicator of metabolic mass. The metabolic mass can be estimated as fat-free mass because body fat is not metabolically active.

Let’s take another example. Let’s say that the unit is mg/kg then the weight of the subject in kg may need to be used in the derivation.

It is also important to pay attention to the scheduling that is mentioned in the SAP and in the protocol. There are times when the dose scheduling in the EX domain is not as expected and it has be corrected.

There could be difference between the dose scheduling in the protocol and in the EX domain because the EX domain should contain one record per constant-dosing interval per subject. “Constant-dosing interval” is sponsor defined, and may include any period of time that can be described in terms of a known treatment given at a consistent dose, frequency, infusion rate.

Let’s see that through an example for calculating the cumulative dose.

The code below will calculate the cumulative dose for each subject, per treatment and visit when each visit is not in the dataset.

proc sql noprint;
create table CUMDOS as select USUBJID, EXTRT, VISIT,
sum(EXDOSE) as EXCUMUDOS
from EX (where=(EXDOSE > 0))
group by USUBJID, EXTRT, VISITNUM;
quit;

The code below will calculate the cumulative dose for each subject, per treatment and visit when each visit is in the dataset. In other words this is when there is one record per cycle in the dataset.

data CUMUDOS;
set EX (where=(EXDOSE > 0));
EXCUUMDOS = (EXENDY — EXSTDY + 1) * EXDOSE;
run;

Relative Dose Intensity (%)

The relative dose intensity is the percentage of the drug a subject has taken compared to the amount of drug the subject was meant to take. That means that if the relative dose intensity is 100% then the subject took all the drug that they were planned to take. Dose omissions and dose reductions contributes to the decrease of the relative dose intensity percentage.

The formula to calculate the relative dose intensity is as follows:

(actual cumulative dose / planned cumulative dose) * 100

The problem with the above formula is that we can have erroneous result if the actual cumulative dose and the planned cumulative dose are not in the same unit.

In order to prevent this you can use the following formula :

(actual dose intensity / planned dose intensity) * 100

This formula will ensure that the same units are used and also divide the actual and planned cumulative dose by the respective Body Surface Area (BSA).

Also, please note that if your calculation of cumulative dose is not correct then the relative dose will not be correct either.