Open Science
Introduction
Methods
Results
Discussion
Implementation
Item 19: Whether the personnel who enrolled and those who assigned participants to the interventions had access to the random allocation sequence
Examples
“Sequential randomisation codes were computer generated using permuted blocks . . . An independent study statistician generated the randomisation codes . . . Good Clinical Practice (GCP) trained research nurses or First Nations health practitioners allocate the study medicine to each mother–infant pair by selecting the next sequentially labelled (prerandomised) study medication from the appropriate stratification group. The allocation sequence number is recorded by the research team on the data collection form (DCF), the database and in the participant’s medical record [316]."
“LabCorp Drug Development (a subcontractor to the IWRS [interactive web response system] vendor) generated the live randomisation schedules. Site personnel enrolled participants in the IWRS. The IWRS assigned participants to the trial groups per live randomisation schedules. LabCorp Drug Development didn’t have any involvement in the rest of the trial . . . Site personnel were involved in participant care and performing trial procedures throughout the trial; however, they were masked to treatment assignment [297]."
“All participants were screened by a masked trial doctor who also obtained informed consent . . . The masked trial doctor then provided all participants with guideline-recommended care and a prescription for the trial medicine kit . . . The randomisation sequence was created using randomly permuted blocks by an independent statistician (who had no involvement in the rest of the trial) [317]."
“The details of sequence generation and group allocation were unavailable to research team members bar one unblinded research assistant. The unblinded research team member that created the randomisation sequence had no contact with participants and was not involved with data collection or analysis [318]."
“Block randomisation was by a computer generated random number list prepared by an investigator with no clinical involvement in the trial . . . After the research nurse had obtained the patient’s consent, she telephoned a contact who was independent of the recruitment process for allocation consignment [319]."
Explanation
As noted in item 18, concealment of the allocated intervention at the time of enrolment is especially important. Thus, in addition to knowing the methods used, it is also important to understand how the random sequence was implemented; specifically, whether the personnel who enrolled and those who assigned participants to the interventions had access to the random allocation sequence.
In practice, the process of randomising participants into a trial has three different steps: sequence generation, allocation concealment mechanism, and implementation (table 6). Although the same individuals may carry out more than one process under each heading, investigators should strive for complete separation of the people involved with generation and allocation concealment from the people who implement assignments. Thus, if someone is involved in the sequence generation or allocation concealment steps, ideally, they should not be involved in the implementation step. When this separation is not possible, importantly the investigators should ensure that the assignment schedule is unpredictable and locked away from even the person who generated it.
Even with flawless sequence generation and allocation concealment, failure to separate creation and concealment of the allocation sequence from assignment to trial group may introduce bias. For example, the person who was enrolling and assigning participants and who also generated an allocation sequence would likely have access to the sequence list and could consult it when interviewing potential participants for a trial. Thus, that person could bias the enrolment or assignment process, regardless of the unpredictability of the assignment sequence and the impenetrability of the allocation concealment mechanism. Investigators must therefore ensure that the assignment schedule is unpredictable and locked away (eg, in a safe deposit box in a building inaccessible to the enrolment location) from even the person who generated it. In that instance, the report of the trial should specify where the investigators stored the allocation list.
Thus, for full assessment of randomisation in a trial report, authors should confirm that personnel who enrolled and those who assigned participants to the interventions did not have access to the random allocation sequence. At minimum, authors should confirm complete separation of the people involved with generation and allocation concealment from the people involved in the implementation of assignments. If complete separation did not occur, then authors should describe how the people involved in the implementation were prevented from accessing the sequence (eg, specifying that the allocation sequence was locked in a secure location).
Sometimes those who enrol and those who assign are different people, but frequently the same individuals do both. These individuals may be termed differently by authors (eg, recruiters), but the functions remain the same.
Full assessment of implementation is not always possible from trial reports. In a sample of 199 medical journals, 63% of trial reports did not provide sufficient information to assess whether the person who generated the allocation sequence was not also the person who allocated participants to treatment groups [306]. Only 31% of trial reports provided sufficient details on who recruited participants and who generated the allocation sequence [306].