Open Science
Introduction
Methods
Results
Discussion
Randomisation: Sequence generation
Item 17a: Who generated the random allocation sequence and the method used
Examples
“Randomization was done using computer-generated random numbers (Stat Trek software) by trained staff at the Soltan Mirahmad Clinic (Kashan, Iran) [261]."
“The randomization was conducted by two independent researchers who were not involved in the study using a computer random sequence generator [262]."
Explanation
Randomisation eliminates selection bias at trial entry and is the crucial component of high quality randomised trials (box 5) [271]. Successful randomisation hinges on two steps: generation of an unpredictable allocation sequence and concealment of this sequence from the investigators enrolling participants (item 18) [268, 269].
Box start
Box 5: Treatment allocation in trials
The method used to assign interventions to trial participants is a crucial aspect of clinical trial design. Random assignment is the preferred method; it has been successfully used regularly in trials for more than 75 years [263]. Randomisation has three major advantages [264]. Firstly, when properly implemented, it eliminates selection bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Without randomisation, treatment comparisons may be prejudiced, whether consciously or not, by selection of participants of a particular kind to receive a particular treatment. Secondly, random assignment permits the use of probability theory to express the likelihood that any difference in outcome between intervention groups reflects mere chance [265]. Thirdly, random allocation, in some situations, facilitates blinding the identity of treatments to the investigators, participants, and evaluators, possibly by use of a placebo, which reduces bias after assignment of treatments [266]. Of these three advantages, reducing selection bias at trial entry is usually the most important [267].
Successful randomisation in practice depends on two inter-related aspects: adequate generation of an unpredictable allocation sequence and concealment of that sequence until assignment occurs [268, 269]. A key issue is whether the sequence is known or predictable by the people involved in allocating participants to the comparison groups [270]. The treatment allocation system should thus be set up so that the person enrolling participants does not know in advance which treatment the next person will get, a process termed allocation concealment [268, 269]. Proper allocation concealment shields knowledge of forthcoming assignments, whereas proper random sequences prevent correct anticipation of future assignments based on knowledge of past assignments.
Box end
Who generated the random allocation sequence is important mainly for two reasons. Firstly, someone, or some group, should take responsibility for this critical trial function. Secondly, providing information on the generator might help readers to evaluate whether anyone had access to the allocation sequence during implementation. Investigators should strive for complete separation, independence, between the trial staff involved with generation of the allocation sequence and those staff who implement assignments (see explanation for item 19).
Participants should be assigned to comparison groups in the trial on the basis of a chance (random) process characterised by unpredictability (box 5). Successful randomisation in practice depends on two inter-related aspects: adequate generation of an unpredictable allocation sequence and concealment of that sequence until assignment occurs. A key issue is whether the sequence is known or predictable by the people involved in allocating participants to the comparison groups. The treatment allocation system should thus be set up so that the person enrolling participants does not know in advance which treatment the next person will receive, a process termed allocation concealment (item 18). Proper allocation concealment shields knowledge of forthcoming assignments, whereas proper random sequences (item 17) prevent correct anticipation of future assignments based on knowledge of past assignments (box 5).
Authors should provide sufficient information such that the reader can assess the methods used to generate the random allocation sequence and the likelihood of bias in group assignment. Any software used for random sequence generation should also be reported. It is important that information on the process of randomisation is included in the body of the main article and not as a separate supplementary file, where it can be missed by the reader.
The term “random” has a precise technical meaning. With random allocation, each participant has a known probability of receiving each intervention before one is assigned, and the assigned intervention is determined by a chance process and cannot be predicted. However, “random” is sometimes used inappropriately in the literature to describe trials in which non-random, “deterministic” allocation methods were used, such as alternation, hospital numbers, or date of birth. When investigators use such non-random methods, they should describe them precisely and should not use the term “random” or any variation of it. Even the term “quasi-random” is unacceptable for describing such trials. Trials based on non-random methods generally yield biased results [4, 268, 272-277]; bias presumably arises from the inability to adequately conceal these more predictable, non-random sequence generation systems.
Many methods of sequence generation are adequate. However, readers cannot judge adequacy from such terms as “random allocation,” “randomisation,” or “random” without further elaboration. Authors should specify the method of sequence generation, such as a random-number table or a computerised random number generator. The sequence may be generated by the process of minimisation, a non-random but generally acceptable method.
In some trials, participants are intentionally allocated in unequal numbers to each intervention: for example, to gain more experience with a new procedure or to limit costs of the trial. In such cases, authors should report the randomisation ratio (eg, 2:1, or two treatment participants per control participant; item 9).
In a representative sample of PubMed indexed trials in 2000, only 21% reported an adequate approach to random sequence generation [220]; this increased to 34% for a similar cohort of PubMed indexed trials in 2006 [221]. Two more recent studies showed further small increases to about 40% [278, 279], but another reported a stubbornly similar level of 32% [277]. When authors report an adequate approach to random sequence generation, in over 90% of cases they report using a random number generator on a computer or a random number table [221, 279].