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It might seem easy to define the intervention you want to study, but it rarely is. Although you know what the intervention will be, such as a specific drug, device, or therapy, you must also specify how it will be used. Often you need to consider how the intervention is actually used in practice so that you can specify how it is to be administered within your protocol.
19.1 Problems in Describing an Intervention
There are often complexities in taking a medication. A medication may require that it be taken in the morning after getting out of bed, or at night just before going to bed. Some medications must be given with meals, and others must be taken at least two hours after (or before) meals. Some must be taken with other medications, and others cannot be taken with specific other medications or with specific foods. Some medications are titrated to individual responses, so they are increased if a participant does not respond. Other medications are reduced (but not eliminated) if there are side effects. We are unaware of any medications that must be taken on a specific calendar day or date, but are aware that some medications are prescribed that way (always take on Sunday, or take once a month on the first day of the month) to help patients remember to take their medicine.
When providing the details of the intervention for your study, you need at least to think about the following items, and to specify all relevant ones in your clinical protocol:
when the medication is taken;
how the medication is taken;
what the medication is taken with;
what must be avoided with the medication;
how the dose or dose schedule is adjusted for toxicity;
how the dose or dose schedule is changed for inadequate efficacy; and
what should be done when a dose is missed.
This needs to be done for every treatment involved in the intervention. If your intervention is being added to a standard of care, then you need to give all the information necessary to describe the use of the standard of care as well.
A new drug is found to be excreted renally. Thus, dosage of the agent is defined based on a participant’s creatinine clearance assessed using a procedure specified in the study protocol or the more detailed Manual of Procedures (MOP; Section 29.3).
A new drug is being tested, which is titrated to the individual participant’s response, like insulin is adjusted in diabetics. The protocol or MOP needs to specify when dose adjustment is considered, how the decision to adjust doses is made, how the new dose is determined, and how frequently it may be changed. This includes what measurements are made to decide whether the dose needs to be adjusted and how these measurements are interpreted to determine what the next dose should be.
A new drug is taken once a week. If a participant misses a dose and remembers later, the participant is instructed to take it within three days of the day it was due. Otherwise, the participant is instructed not to take a dose until the next scheduled treatment day, to avoid taking two doses too close together.
A drug is known to have certain side effects in some participants. For some of the side effects (such as rash), if the side effect is mild or moderate, participants should continue taking the drug as scheduled, at the regular dose. Although the participant may continue taking the drug if a rash is mild or moderate, the drug must be held back if the rash is severe. Thus, there need to be rules defining what a severe rash is. If the drug could be restarted later, there would need to be rules about when the drug could be restarted, and how the dose would be adjusted for the participant. For another potential side effect (change in liver enzymes), even if the side effect is mild, the participant needs to discontinue the drug because the side effect may rapidly become more serious.
In many oncology studies, multiple medications are taken. The protocol must specify for each medication the dose used, any pretreatment needed for a medicine (e.g., to minimize allergic reactions, fluid loading, etc.), and what needs to be done for adverse reactions. In addition, when more than one medication is being given, the order of the medications needs to be specified if they are taken on the same day. There must also be rules about side effects, including rules for deciding which drug should be considered the cause for different specific toxicities and thus needs its dose adjusted. As in Example 19D, rules for dose holding, adjustment, and restarting are also needed.
Some interventional studies assess the additional benefit of the new intervention when added to the standard intervention. One example would be assessing the effect of a new chemotherapy agent being added to a standard regimen for a specific cancer. As in Example 19E, dosing information is needed for each of the drugs in the regimen, not just the experimental intervention.
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