Calculation of length of the study drug exposure

We have been using the following formula in calculating the length of the study drug exposure in many studies:

# of days of drug exposure = the last dose date - the first dose date + 1

However, this seems to be correct only if the subject receive daily dose of the study medication. We have many studies where the subject receive weekly infusion or every three weeks infusion of the study medication. In this situation, the above formula will underestimate the length of the study drug exposure.

The correct formula should be tied up with the dose interval.

If a subject receive weekly dose, the formula would be:
# of days of drug exposure = the last infusion date - the first infusion date + 7
or
# of weeks of drug exposure = (the last infusion date - the first infusion date + 7)/7

If a subject receive study drug every three weeks, the formula would be:
# of days of drug exposure = the last infusion date - the first infusion date + 21
or
# of weeks of drug exposure = (the last infusion date - the first infusion date + 21)/7

An early clinical trial with N=2

In the late 18th century, King Gustav III of Sweden decided that coffee was poison and ordered a clinical trial.

• The King condemned a convicted murderer to drink coffee every day.
• The control was another murderer who was condemned to drink tea daily.
• The outcome measure is 'death'.
• Two physicians were appointed to determine the outcome.

Results:

• The two doctors died first
• The king was murdered
• Both convicts enjoyed long life until the tea drinker died at age 83. (no age was given for the coffee drinker)

J Int Med. Oct 1991:289 - introduction to editorial from Nordic School of Public Health, Goteborg Sweden

Reprinted in Annal of Internal Medicine 1992: 117:30

Lack of clinical equipoise

Clinical equipoise provides the ethical basis for conduct of randomized clinical trials. This principal states that a clinical trial is acceptable only insofar as there is professional disagreement between researchers concerning uncertainty regarding the outcome of the study.1and thus even if a clinician prefers one arm over another, randomization is still sound when there are others who believe the other way around.

However, there are often different opinions between regulatory and investigator regarding the interpretation of equipoise and biases generated from publications suggestive of the efficacy of one product over another may cause lack of equipoise. Lack of clinical equipoise causes unwillingness at the investigator level to enroll patients because of strong belief by the majority of physicians in one treatment being superior over another. This results in difficultly in designing studies to support licensing a product such that physicians are unwilling to participate in a study that is necessary to satisfy regulatory agency(s) requirements for trial data demonstrating efficacy and safety.


References:
Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 317: 141-145, 1987
Lilford RJ Declaratio of Helsinki should be strengthened. BMJ 322(7281) 299
Ashcroft R: Equipoise, knowledge and ethics in clinical research and practice. Bioethics 13 (3/4):314-326, 1999
Royall RM: Ethic and Statistics in Randomized Clinical trials. Statistical science 6(1): 52-66 1991