Many date variables are collected in the clinical trial database. The date variables include date of birth, date of disease diagnosis, date of medical history onset, start and stop date of adverse events, start / stop date of concomitant medications, ......
It is not uncommon that the partial dates may be collected where the partial dates mean that at least one of the components (day, month, or year) is missing.
Partial date for date of birth is not because the subjects don't remember their birth date, is because the data security law prevents the sponsors from collecting the date of birth information in certain countries (especially in Germany).
In statistical analyses, the partial dates need to be handled or imputed for the purpose of allocating the event (adverse events, concomitant medication) into the appropriate categories (treatment-emergent adverse events, prior medications, concomitant medications added during the study,...) or calculating the duration of the events (duration from the disease diagnosis to the study start).
For clarity, the algorithm and rules for imputing the partial dates need to be specified in the statistical analysis plan (SAP). There is no regulatory guidance about which algorithm and rules will be appropriate when imputing the partial dates. Different companies may have different rules when imputing partial dates. In general, the rules will be adequate as long as it is on the conservative side, for example, if an adverse event has a partial or missing start date and can't be determined if it occurs before the first dose of the study drug, the adverse event will be classified as 'treatment-emergent adverse event'.
Partial date imputation is always a single imputation - the missing day or missing month will be replaced with a fixed day or month based on the imputation algorithm. The candidates for replacing the missing day could be: the first day of the month, the last day of the month, the day of the first dose of the study drug. The candidates for replacing the missing day and month could be Jun 30 of the year or July 1 of the year.
Usually, if all day, month, and year are missing, the missing date will not be imputed. The adverse events with missing onset date will be classified as 'treatment-emergent AEs' and the concomitant medication will be classified as 'on treatment medications' (i.e., to be included in summaries of concomitant medications during the study).
Below are a list of algorithm and rules for imputing the partial dates for adverse events and concomitant medications:
In an SAP for a Pfizer phase I study, if the day of the month is missing, the 1st day of the month is used.
In
a Novartis study SAP, the rather complicated algorithm was proposed for imputing the partial dates for adverse events and concomitant medications:
In a study by Johnson & Johnson, the appended SAP specified the rules for imputing the partial dates for adverse events, concomitant medications, and for disease diagnosis as the following:
In a study by
ChemoCentryx in NEJM,
the appended SAP described the imputation rules for partial dates for adverse events and concomitant medications as the following:
In the paper "Partial Dates; decisions and implications of handling partially missing dates" by Bowman, the following rules were stated for imputing the partial dates for adverse events and concomitant medications.
Missing Adverse Event Start and Stop Dates date:
There are two options available. The partial start date may be set to the first of the month or to equal the study medication start date. As previously discussed, the first option would indicate the adverse event began prior to the study medication. However, the second option, setting the start date of AE1 to the study medication start date will suggest the adverse event had a short duration, as the adverse event end date is also defined as June 2006, but began during the treatment period of the study drug. Although the second option is not ideal, as AE1 may have had a longer duration, it is more conservative to associate the adverse event start with a date during study medication. Another solution to consider is not to impute a date at all but merely to assign a study phase to the start of the adverse event. In this example, a phase of "treatment" could be allocated to the start of teh adverse event, which would ensure it was classed most conservatively, without defining an actual date to the start of the adverse event.
Concomitant Medications:
Subject has a partial concomitant medication
start date of “--Apr2006” (see figure 1). As discussed above, missing start
dates may be set to the first of the month, which is shown under option 1.
However, this then pushes the concomitant medication to starting before the
first dose of the Study Medication (15Apr2006) and would suggest that the Study
Medication had no involvement with the concomitant medication being taken. Is
this really the most conservative approach? If not is there an alternative? The missing concomitant medication start date could be set to equal the first dose of Study Medication, options 2. This option allows the concomitant medication to be classed as an on-treatment medication, and is therefore the most conservative.
