Counting the study day

For every clinical trial, we need to count the study day for calculating the follow-up visits and for assessing the temporal relationship between events. The study day starts with the day that the subject is randomized and receives the first dose of the study medication. Usually, the randomization date and the first dose of the study medication date are the same. In clinical study protocol, there should always be a ‘schedule of events’ or ‘schedule of evaluations’ table which defines the study procedures and the study visits. This table should include the study day.

There is one critical difference in counting the study days. The protocol could count the day of subject receiving the first dose of the study medication as “day 0” or “day 1”.

If the first dose date is counted as day 0, the day immediately after the first dose date will be counted as day 1 and the date immediately before will be counted as day -1. Therefore, the study day is counted continuously as … day -7, day -6, day -5, day -4, day -3, day -2, day -1, day 0, day 1, day 2,… In this case, for programming, the study day variable can be created using the formula:

          The event/visit date – first dose date  

The problem with this counting is in 'day 0'. People are used to calling the first day of the study medication as the 'day 1'.

If the first dose date is counted as day 1, the day immediately after the first dose date will be counted as day 2 and the date immediately before will be counted as day 0 – which is confusing. In practice, if the first dose date is counted as day 1, the day 0 will not be used in the study day counting. The date immediately before will be counted as day -1 (skipped day 0). Therefore, the study day is counted as: day -7, day -6, day -5, day -4, day -3, day -2, day -1, day 1, day 2,… For programming, the study day variable would be created using two separate formulas for predose and postdose visits.

For pre-dose:

           the event/visit date – first dose date

For post-dose:

           the event/visit date – first dose date + 1

Both of these approaches (counting including study day 0 or not including study day 0) are not wrong, but sometimes confusions can arise when we calculate the study day variable. Even for CDISC, there are disagreements in handling this between Submission Data Set Tabulation Model (SDTM) (not allowing study day 0) and Analysis Data Set  Model (ADaM) (allowing study day 0).

The following clinical trial protocol templates indicate that the study day counting starts with day 0:

• http://www.nia.nih.gov/NR/rdonlyres/57864169-734F-4B05-9DC0-A7B2E38C5A55/0/ProtocolTemplate_11_12_2007_Final.doc
• http://www.nidcr.nih.gov/ClinicalTrials/ToolkitClinicalResearchers/ClinicalTrialsProtocolTemplate/InterventionProtocolTemplate.htm
• http://www.niaid.nih.gov/LabsAndResources/resources/toolkit/Documents/CTTemplate_SL2.dot

The following clinical trials indicate that the study day counting starts with day 1. There are more industry trials like this.

• http://www.rochetrials.com/studyResultGet.action?studyResultNumber=WV15730&productName=Tamiflu&genericName=Oseltamivir
•  http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/8610405

The unit used in counting the study day depends on the length of the clinical trials. For a trial with months and years in duration, instead of counting by day, it is more practical to count by week, month, or year. For example, for a clinical trial with three years treatment duration, the last treatment date would be three years away. If we count by day, it will be something like day 1095. Even worse, some people may apply the time window to this date to have the last treatment date 1095 +/- 7 days. Sound stupid, isn’t it?

Counting the study day correctly is important for study investigators/coordinators to avoid the protocol deviation. The Barnettinternational actually developed a tool to facilitate the study day /visit scheduling.