Examples

“Participants were centrally assigned to randomised study treatment using an interactive web response system (IWRS) . . . Block randomisation schedules were computer generated by a vendor with a block size of 6 in a randomisation ratio of 2:1 and distributed to the IWRS vendor (endpointClinical) for participant randomisation" [297]."

 

“For allocation concealment, numbered containers were used. The interventions were sealed in sequentially numbered identical opaque containers according to the allocation sequence" [298]."

 

“Furthermore, we employed syringes sequentially numbered and packaged in opaque and sealed containers. Specifically, syringes containing esmolol or placebo were centrally prepared, pre-coded based on the randomization list, and sent sequentially to the operating room immediately before administration" [299]."

 

“Allocation was concealed using sequentially numbered, opaque, sealed envelopes (SNOSE) prior to making the incision" [300]."

 

“Allocation concealment was done using sequentially numbered, sealed, opaque packages” [261]."

 

“The allocation sequence was concealed from the researcher (JR) enrolling and assessing participants in sequentially numbered, opaque, sealed and stapled envelopes. Aluminium foil inside the envelope was used to render the envelope impermeable to intense light. To prevent subversion of the allocation sequence, the name and date of birth of the participant was written on the envelope and a video tape made of the sealed envelope with participant details visible. Carbon paper inside the envelope transferred the information onto the allocation card inside the envelope and a second researcher (CC) later viewed video tapes to ensure envelopes were still sealed when participants' names were written on them. Corresponding envelopes were opened only after the enrolled participants completed all baseline assessments and it was time to allocate the intervention [301]."

 

Explanation

Item 17 discussed generation of an unpredictable sequence of assignments. Of considerable importance is how this sequence is applied when participants are enrolled into the trial (box 5). A generated allocation sequence should be implemented by using allocation concealment [269], a critical mechanism that prevents foreknowledge of treatment assignment and thus shields those who enrol participants from being influenced by this knowledge. The decision to accept or reject a participant should be made, and informed consent should be obtained from the participant, in ignorance of the next assignment in the sequence [302]. In summary, adequate allocation concealment safeguards knowledge of forthcoming assignments, whereas proper random sequences (item 17) prevent correct anticipation of future assignments based on knowledge of past assignments.

 

Allocation concealment should not be confused with blinding (item 20). Allocation concealment seeks to prevent selection bias (box 5), protects the assignment sequence before and until allocation, and can always be successfully implemented [268]. In contrast, blinding seeks to prevent ascertainment bias, protects the sequence after allocation, and cannot always be implemented [269]. Without adequate allocation concealment, however, even random, unpredictable assignment sequences can be subverted [268, 303].

 

Centralised or third party assignment is especially desirable. Many good allocation concealment mechanisms incorporate external involvement. Use of a pharmacy or central computer or telephone randomisation system are common techniques. Automated assignment systems are likely to become more common [221]. When external involvement is not feasible, an excellent method of allocation concealment is the use of numbered containers. The interventions (often medicines) are sealed in sequentially numbered identical containers according to the allocation sequence [304]. Enclosing assignments in sequentially numbered, opaque, sealed envelopes can be a good allocation concealment mechanism if it is developed and monitored diligently [288, 305]. This method can be corrupted, however, particularly if it is poorly executed. Investigators should ensure that the envelopes are opaque when held to the light, and are opened sequentially and only after the participant’s name and other details are written on the appropriate sequentially numbered sealed envelope [288, 305, 306].

 

A number of methodological studies provide empirical evidence to support these precautions [4, 268, 275-277, 307-309]. Trials in which the allocation sequence had been inadequately or unclearly concealed yielded larger estimates of treatment effects than did trials in which authors reported adequate allocation concealment. These findings provide strong empirical evidence that inadequate allocation concealment contributes to bias in estimating treatment effects.

 

Despite the importance of the mechanism of allocation concealment, published reports frequently omit such details. Among older studies, the mechanism used to allocate interventions was omitted in reports of 89% of trials on rheumatoid arthritis [310], 48% of trials in obstetrics and gynaecology journals [269], and 44% of trials in general medical journals [294]. In a more broadly representative sample of all PubMed indexed randomised trials, only 18% reported any allocation concealment mechanism and some of those reported mechanisms were inadequate [220]. At the same time, some trials where there is no reporting of allocation concealment may have been properly concealed, as demonstrated by inspection of their protocols [311].

 

Newer studies further illuminate poor reporting of allocation concealment. Unclear reporting (ie, the authors did not provide sufficient information in the paper to allow judgment to be made on the adequacy of method of allocation concealment) was found in 78% [312] and 85% [277] of trials. Moreover, those two studies determined that only 27% [312] and 14% [277] used an adequate allocation concealment mechanism, while another found a similar level of 12% [278]. A review of trials in journals of traditional Chinese medicine found that only 7% used adequate allocation concealment [313].

 

Fortunately, reporting and conduct may be improving in recent years, for example, after the CONSORT 2010 guidelines were published [314]. Another study found that reporting on allocation concealment and sequence generation was much better in journals that endorsed the CONSORT 2010 guidelines than in non-endorsing journals [305]. Moreover, that study found that 57% of trials in the sample had used an adequate allocation concealment mechanism [305]. However, other empirical studies show only modest improvements, for example, an evaluation of over 176 000 trials [315] found that allocation concealment reporting increased from 5.1% in 1966-90 to 19.3% in 2010-18. While any improvement is encouraging, more efforts to improve conduct and reporting remain necessary.