Allocation Concealment 154
Importance of Allocation Concealment 154
Personal Accounts of Deciphering 155
What to Look for With Allocation Concealment 156
Baseline Comparisons 159
What to Look for With Baseline Characteristics 160
Proper randomisation rests on adequate allocation concealment. An allocation concealment process keeps clinicians and participants unaware of upcoming assignments. Without it, even properly developed random allocation sequences can be subverted. Within this concealment process, the crucial unbiased nature of randomised controlled trials collides with their most vexing implementation problems. Proper allocation concealment frequently frustrates clinical inclinations, which annoys those who do the trials. Randomised controlled trials are anathema to clinicians. Many involved with trials will be tempted to decipher assignments, which subverts randomisation. For some implementing a trial, deciphering the allocation scheme might frequently become too great an intellectual challenge to resist. Whether their motives indicate innocent or pernicious intents, such tampering undermines the validity of a trial. Indeed, inadequate allocation concealment leads to exaggerated estimates of treatment effect, on average, but with scope for bias in either direction. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering. Investigators must effectively immunise trials against selection and confounding biases with proper allocation concealment. Furthermore, investigators should report baseline comparisons on important prognostic variables. Hypothesis tests of baseline characteristics, however, are superfluous and could be harmful if they lead investigators to suppress reporting any baseline imbalances.
The reason that the Medical Research Council’s controlled trial of streptomycin for pulmonary tuberculosis should be regarded as a landmark is thus not, as is often suggested, because random number tables were used to generate the allocation schedule… Rather it is because of the clearly described precautions that were taken to conceal the allocation schedule from those involved in entering patients.
Generation of an unpredictable randomised allocation sequence represents the first crucial element of randomisation in a randomised controlled trial. Implementation of the sequence, while concealing it at least until patients have been assigned to their groups (allocation concealment), is the important second element, without which randomisation collapses in a trial.
As a direct consequence of randomisation, the first table in most reports of randomised controlled trials describes the baseline characteristics of the comparison groups. Researchers should describe their trial population and provide baseline comparisons of their groups so that readers can assess their comparability. In this chapter we focus on proper approaches to allocation concealment and to reporting of baseline characteristics.
Researchers have many misconceptions with respect to allocation concealment. Proper allocation concealment secures strict implementation of a random allocation sequence without foreknowledge of treatment assignments. Allocation concealment refers to the technique used to implement the sequence, not to generate it. Nevertheless, some people discuss allocation concealment with digressions into flipping coins or use of random number tables. Those digressions amount to methodological non sequiturs ; allocation concealment is distinct from sequence generation. Furthermore, some investigators confuse allocation concealment with blinding of treatments.
Without adequate allocation concealment, even random, unpredictable assignment sequences can be undermined. Knowledge of the next assignment could lead to the exclusion of certain patients based on their prognosis because they would have been allocated to the perceived inappropriate group. Moreover, knowledge of the next assignment could lead to direction of some participants to perceived proper groups, which can easily be accomplished by delaying a participant’s entry into the trial until the next appropriate allocation appears. Avoidance of such bias depends on the prevention of foreknowledge of treatment assignment. Allocation concealment shields those who admit participants to a trial from knowing the upcoming assignments. The decision to accept or reject a participant should be made, and informed consent should be obtained, in ignorance of the upcoming assignment.
Importance of Allocation Concealment
Results of empirical investigations have shown that trials that used inadequate or unclear allocation concealment, compared with those that used adequate concealment, yielded up to 40% larger estimates of treatment effect. The badly done trials tended to exaggerate treatment effects, although the opposite can happen. Moreover, the worst concealed trials yielded greater heterogeneity in results (i.e., the results fluctuated extensively above and below the estimates from better studies). These findings provide empirical evidence that inadequate allocation concealment allows bias to seep into trials.
Indeed, having a randomised (unpredictable) sequence should make little difference without adequate allocation concealment. Assume that investigators generate an adequate allocation sequence with a random number table. They then, however, post that sequence on a bulletin board, so that anyone involved in the trial could see the upcoming assignments. Similarly, the allocation sequence could be implemented through placing method indicator cards in translucent envelopes. This inadequate allocation concealment process could be deciphered by simply holding the envelopes to a bright light ( Fig.14.1 ). With both the bulletin board and the envelopes, those responsible for admitting participants could detect the upcoming treatment assignments and then channel individuals with a better prognosis to the experimental group and those with a poorer prognosis to the control group or vice versa. Bias could easily be introduced, despite an adequate randomised sequence.
Researchers should, therefore, ensure both adequate sequence generation and adequate allocation concealment in randomisation schemes. A mistake in either could compromise randomisation, resulting in incorrect results. For example, results of a trial could reveal a large treatment effect that only reflects a biased allocation procedure, or they could reveal no effect when in reality a harmful one prevails. Moreover, the results of such a trial can be more damaging than similar results from an explicitly observational research study. Biases are usually assumed and acknowledged in observational studies, and the statistical analysis and eventual interpretation attempt to take those biases into account. Conversely, studies labelled as randomised are frequently assumed to be free of bias, and commonly inadequate reporting masks the deficiencies they might have.
Consequently, the credibility of randomised controlled trials lends support to faster and greater changes in clinical or preventive management, which, if based on a compromised study, squanders scarce health resources, or even worse, harms people’s health. Thus the well-deserved credibility of randomised controlled trials produces an indirect liability. Wrong judgements emanate easily from improperly randomised trials.
Personal Accounts of Deciphering
Findings of empirical investigations suggest that investigators sometimes undermine randomisation, though they rarely document such subversions. Nevertheless, when investigators responded anonymously to queries during epidemiological workshops, many did relate instances in which allocation schemes had been sabotaged.
The individual accounts of such instances describe a range of simple to intricate operations. Most allocation concealment schemes were deciphered by investigators simply because the methods were inadequate. Investigators admitted, for instance, altering enrolment or allocations to particular study groups after decoding future assignments, which were either posted on a bulletin board or visible through translucent envelopes held up to bright lights. Some also related opening unsealed assignment envelopes, sensing the differential weight of envelopes, or simply opening unnumbered envelopes until they found a desired treatment.
Investigators had a harder time deciphering the better allocation concealment schemes. Nevertheless, eventually someone described circumventing virtually every type of scheme. For example, some physicians took sequentially numbered, opaque, sealed envelopes to the hot light (an intense incandescent bulb) in the radiology department for deciphering of assignments. In studies using central randomisation, trial investigators related ringing the central number and asking for the next several assignments all at once; they received them in at least a couple of circumstances. In trials with sequentially numbered drug containers, someone described deciphering assignments based on the appearance of the container labels. Another had stopped trying to decipher a drug container scheme until she saw an attending physician, late at night, ransacking the office files of the principal investigator for the allocation list. Suggesting her methodological naivety and innocence, she first thought of the attending physician’s cleverness and not of the probability that such action would bias the trial.
Although investigators theoretically understand the need for unbiased research, they sometimes fail to maintain impartiality once they are involved in a trial. Researchers might want certain patients to benefit from one of the treatments or the trial results to confirm their beliefs. Thus certain trial procedures in properly done randomised controlled trials frustrate clinical inclinations, which annoys those doing the trial.
Some scientists aim to deliberately sabotage their results. However, many attempts at decoding the randomisation sequence simply indicate an absence of knowledge of the scientific ramifications of such actions. Furthermore, for some, the deciphering of the allocation scheme might frequently become too great an intellectual challenge to resist. As Oscar Wilde wrote, ‘The only way to get rid of temptation is to yield to it.’ Whether their motives are innocent or not, however, such tampering undermines the validity of a trial. Investigators must recognise the inquisitiveness of human nature and institute methodological safeguards. Proper allocation concealment will deter subversion, in effect, immunising trials against selection and confounding biases.
To develop a proper allocation scheme takes time, effort, and thought. Investigators cannot simply delegate this task without thoroughly examining the final product. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering.
What to Look for with Allocation Concealment
Researchers consider certain approaches to allocation concealment as adequate: sequentially numbered, opaque, sealed envelopes (SNOSE); pharmacy controlled; numbered or coded containers; central randomisation (e.g., by telephone to a trials office); or other method whose description contained elements convincing of concealment, such as a secure computer-assisted method. These criteria establish minimum methodological standards, yet they are met by only about a quarter of trials. Consequently, in assessment of allocation concealment from published reports, readers will be fortunate to find such standards reasonably met ( Panel 14.1 ). Realistically, however, those minimum standards should be exceeded. If researchers provide descriptions that incorporate not only the minimum standards, but also elements of more rigorous standards, readers can have more confidence that selection and confounding biases have been averted (see Panel 14.2 ).
Identical ampullas were prepared containing either 1 ml dexamethasone (Krka, Vital Pharma Nordic, Novo Mesto, Slovenia) 4 mg/ml or 1 ml placebo (0·9 per cent saline); the solutions were transparent and identical. According to a computer-generated block randomization list, 120 identical sequentially numbered containers were prepared containing either 2 × 1 ml 4 mg/ml dexamethasone or 2 × 1 ml placebo. The randomization code was kept separately at the Hospital Pharmacy of the Capital Region of Denmark.
Allocation concealment was ensured by keeping the randomization lists in the care of one of the investigators (TS) who was not involved in the clinical part of the study. Independent pharmacists dispensed the study medications into identical, sequentially numbered containers according to randomization lists.
Central randomisation (by telephone) was stratified by centre.
Patients were randomised centrally by the Centre for Digestive Diseases after screening in a 1:1 ratio to either faecal microbiota transplantation or placebo, using a preestablished computer-generated randomisation list…
Patients were centrally allocated (1:1) to azithromycin or identical-looking placebo using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Stenlake Compounding Pharmacy (Bondi Junction, Sydney, NSW, Australia) formulated the study drug and matching placebo tablets. Study packs were labelled with the allocated randomisation number and bottle numbers.
Immediately after randomization and for 14 days, the research pharmacists prepared reconstituted opaque bags of micafungin or placebo according to the randomization list and provided it to the site for infusion.
Pharmacy-controlled randomization was used to conceal the random allocation of treatment using random number tables. This was performed by different team participants (BA, BS), who were neither directly involved in patient registration nor in assessing the outcomes. The formulation codes were broken only after complete results were obtained from all the participating patients on completion of treatment period.
Allocation to treatment groups was… concealed using central randomisation generated by the clinical trials unit. The responsible senior statistician was not involved in study conduct or monitoring. Patients, investigators, and study personnel were masked to treatment assignments during the study; we used subsequently opened sealed, opaque, sequentially numbered envelopes containing the allocation information.
Randomisation was done using sequentially numbered, opaque sealed envelopes, to be opened in consecutive order.
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.