[ps2id id=’sequence-generation’ target=”/]16. ALLOCATION
16a. Sequence generation
Method of generating the allocation sequence (e.g., computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (e.g., blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions.
Example
“Participants will be randomly assigned to either control or experimental group with a 1:1 allocation as per a computer generated randomisation schedule stratified by site and the baseline score of the Action Arm Research Test (ARAT; <= 21 versus >21) using permuted blocks of random sizes. The block sizes will not be disclosed, to ensure concealment.” 224
Explanation
Participants in a randomised trial should be assigned to study groups using a random (chance) process characterised by unpredictability of assignments. Randomisation decreases selection bias in allocation; helps to facilitate blinding/masking after allocation; and enables the use of probability theory to test whether any difference in outcome between intervention groups reflects chance.17;225-227
Use of terms such as “randomisation” without further elaboration is not sufficient to describe the allocation process, as these terms have been used inappropriately to describe non-random, deterministic allocation methods such as alternation or allocation by date of birth.121 In general, these non-random allocation methods introduce selection bias and biased estimates of an intervention’s effect size,17;167;228;229 mainly due to the lack of allocation concealment (Item 16b). If non-random allocation is planned, then the specific method and rationale should be stated.
Box 1 outlines the key elements of the random sequence that should be detailed in the protocol. Three-quarters of randomised trial protocols approved by a research ethics committee in Denmark (1994-95) or conducted by a US cooperative cancer research group (1968-2006) did not describe the method of sequence generation.2;11
Box 1: Key elements of random sequence to specify in trial protocols
- Method of sequence generation (e.g., random number table or computerised random number generator)
- Allocation ratio (Item 8) (e.g., whether participants are allocated with equal or unequal probabilities to interventions)
- Type of randomisation (Box 2): simple versus restricted; fixed versus adaptive (e.g., minimisation); and, where relevant, the reasons for such choices
- If applicable, the factors (e.g., recruitment site, sex, disease stage) to be used for stratification (Box 2), including categories and relevant cut-off boundaries
Box 2 defines the various types of randomisation, including minimisation. When restricted randomisation is used, certain details should not appear in the protocol in order to reduce predictability of the random sequence (Box 3). The details should instead be described in a separate document that is unavailable to trial implementers. For blocked randomisation, this information would include details on how the blocks will be generated (e.g., permuted blocks by a computer random number generator), the block size(s), and whether the block size will be fixed or randomly varied. Specific block size was provided in 14/102 (14%) randomised trial protocols approved by a Danish research ethics committee in 1994-95, potentially compromising allocation concealment.2 For trials using minimisation, it is also important to state the details in a separate document, including whether random elements will be used.
Box 2: Randomisation and minimisation (adapted from CONSORT 2010 Explanation and Elaboration)17;230;231
Simple randomisation
Randomisation based solely on a single, constant allocation ratio is known as simple randomisation. Simple randomisation with a 1:1 allocation ratio is analogous to a coin toss, although tossing a coin is not recommended for sequence generation. No other allocation approach, regardless of its real or supposed sophistication, surpasses the bias prevention and unpredictability of simple randomisation.231
Restricted randomisation
Any randomised approach that is not simple randomisation is restricted. Blocked randomisation is the most common form. Other forms, used much less frequently, are methods such as replacement randomisation, biased coin, and urn randomisation.231
Blocked randomisation
Blocked randomisation (also called permuted block randomisation) assures that study groups of approximately the same size will be generated when an allocation ratio of 1:1 is used. Blocking can also ensure close balance of the numbers in each group at any time during the trial. After every block of eight participants, for example, four would have been allocated to each trial group.232 Improved balance comes at the cost of reducing the unpredictability of the sequence. Although the order of interventions varies randomly within each block, a person running the trial could deduce some of the next treatment allocations if they discovered the block size.233 Blinding the interventions, using larger block sizes, and randomly varying the block size will help to avoid this problem.
Biased coin and urn randomisation
Biased coin designs attain the similar objective as blocked designs without forcing strict equality. They therefore preserve much of the unpredictability associated with simple randomisation. Biased-coin designs alter the allocation ratio during the course of the trial to rectify imbalances that might be occurring.231 Adaptive biased-coin designs, such as the urn design, vary allocation ratios based on the magnitude of the imbalance. However, these approaches are used infrequently.
Stratified randomisation
Stratification is used to ensure good balance of participant characteristics in each group. Without stratification, study groups may not be well matched for baseline characteristics, such as age and stage of disease, especially in small trials. Such imbalances can be avoided without sacrificing the advantages of randomisation. Stratified randomisation is achieved by performing a separate randomisation procedure within each of two or more strata of participants (e.g., categories of age or baseline disease severity), ensuring that the numbers of participants receiving each intervention are closely balanced within each stratum. Stratification requires some form of restriction (e.g., blocking within strata) in order to be effective. The number of strata should be limited to avoid over-stratification.234 Stratification by centre is common in multicentre trials.
Minimisation
Minimisation assures similar distribution of selected participant factors between study groups.230;235 Randomisation lists are not set up in advance. The first participant is truly randomly allocated; for each subsequent participant, the treatment allocation that minimises the imbalance on the selected factors between groups at that time is identified. That allocation may then be used, or a choice may be made at random with a heavy weighting in favour of the intervention that would minimise imbalance (for example, with a probability of 0.8). The use of a random component is generally preferable.236 Minimisation has the advantage of making small groups closely similar in terms of participant characteristics at all stages of the trial.
Minimisation offers the only acceptable alternative to randomisation, and some have argued that it is superior.237 On the other hand, minimisation lacks the theoretical basis for eliminating bias on all known and unknown factors. Nevertheless, in general, trials that use minimisation are considered methodologically equivalent to randomised trials, even when a random element is not incorporated. For SPIRIT, minimisation is considered a restricted randomisation approach without any judgment as to whether it is superior or inferior compared to other restricted randomisation approaches.
Box 3: Need for a separate document to describe restricted randomisation
If some type of restricted randomisation approach is to be used, in particular blocked randomisation or minimisation, then the knowledge of the specific details could lead to bias.238;239 For example, if the trial protocol for a two arm, parallel group trial with a 1:1 allocation ratio states that blocked randomisation will be used and the block size will be six, then trial implementers know that the intervention assignments will balance every six participants. Thus, if intervention assignments become known after assignment, knowing the block size will allow trial implementers to predict when equality of the sample sizes will arise. A sequence can be discerned from the pattern of past assignments and then some future assignments could be accurately predicted. For example, if part of a sequence contained two “As” and three “Bs,” trial implementers would know the last assignment in the sequence would be an “A.” If the first three assignments in a sequence contained three “As,” trial implementers would know the last three assignments in that sequence would be three “Bs.” Selection bias could result, regardless of the effectiveness of allocation concealment (Item 16b).
Of course, this is mainly a problem in open label trials, where everyone becomes aware of the intervention after assignment. It can also be a problem in trials where everyone is supposedly blinded (masked), but the blinding is ineffective or the intervention harms provide clues such that treatments can be guessed.
We recommend that trial investigators do not provide full details of a restricted randomisation scheme (including minimisation) in the trial protocol. Knowledge of these details might undermine randomisation by facilitating deciphering of the allocation sequence. Instead, this specific information should be provided in a separate document with restricted access. However, simple randomisation procedures could be reported in detail in the protocol, because simple randomisation is totally unpredictable.
[ps2id id=’concealment-mechanism’ target=”/]
16b. Concealment mechanism
Mechanism of implementing the allocation sequence (e.g., central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned.
Example
“Participants will be randomised using TENALEA, which is an online, central randomisation service . . . Allocation concealment will be ensured, as the service will not release the randomisation code until the patient has been recruited into the trial, which takes place after all baseline measurements have been completed.” 240
Explanation
Successful randomisation in practice depends on two interrelated aspects: 1) generation of an unpredictable allocation sequence (Item 16a), and 2) concealment of that sequence until assignment irreversibly occurs.233;241 The allocation concealment mechanism aims to prevent participants and recruiters from knowing the study group to which the next participant will be assigned. Allocation concealment helps to ensure that a participant’s decision to provide informed consent, or a recruiter’s decision to enrol a participant, is not influenced by knowledge of the group to which they will be allocated if they join the trial.242 Allocation concealment should not be confused with blinding (masking) (Item 17) (Table 3).243
Table 3. Differences between allocation concealment and blinding (masking) for trials with individual randomisation.
[table nl=”~~” div style=”float:left” class=”table table-bordered” tablesorter=”0″ table delimiter=”|”]
[attr width=”50″]| Allocation concealment |Blinding (masking) [attr width=”175″]
Definition| Unawareness of the next study group assignment in the allocation sequence| Unawareness of the study group to which trial participants have already been assigned
Purpose| Prevent selection bias by facilitating enrolment of comparable participants in each study group| Prevent ascertainment, performance, and attrition biases by facilitating comparable concomitant care (aside from trial interventions) and evaluation of participants in each study group
Timing of implementation| Before study group assignment| Upon study group assignment and beyond
Who is kept unaware| Trial participants and individuals enrolling them| One or more of the following: Trial participants, investigators, care providers, outcome assessors.~~
Other groups: Endpoint adjudication committee, data handlers, data analysts
Always possible to implement?|Yes|No
[/table]
Without adequate allocation concealment, even random, unpredictable assignment sequences can be subverted.233;241 For example, a common practice is to enclose assignments in sequentially numbered, sealed envelopes. However, if the envelopes are not opaque and contents are visible when held up to a light source, or if the envelopes can be unsealed and resealed, then this method of allocation concealment can be corrupted.
Protocols should describe the planned allocation concealment mechanism in sufficient detail to enable assessment of its adequacy. In one study of randomised trial protocols in Denmark, over half did not adequately describe allocation concealment methods.2 In contrast, central randomisation was stated as the allocation concealment method in all phase 3 trial protocols initiated in 1968-2003 by a cooperative cancer research group that used extensive protocol review processes.11 Like sequence generation, inadequate reporting of allocation concealment in trial publications is common and has been associated with inflated effect size estimates[ps2id id=’implementation’ target=”/].167;244;245
16c. Implementation
Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions.
Example
“Randomization
All patients who give consent for participation and who fulfil the inclusion criteria will be randomized. Randomisation will be requested by the staff member responsible for recruitment and clinical interviews from CenTrial [Coordination Centre of Clinical Trials].
In return, CenTrial will send an answer form to the study therapist who is not involved in assessing outcome of the study. This form will include a randomisation number. In every centre closed envelopes with printed randomisation numbers on it are available. For every randomisation number the corresponding code for the therapy group of the randomisation list will be found inside the envelopes. The therapist will open the envelope and will find the treatment condition to be conducted in this patient. The therapist then gives the information about treatment allocation to the patient. Staff responsible for recruitment and symptom ratings is not allowed to receive information about the group allocation.
. . .
The allocation sequence will be generated by the Institute for Medical Biometry (IMB) applying a permuted block design with random blocks stratified by study centre and medication compliance (favourable vs. unfavourable) . . . The block size will be concealed until the primary endpoint will be analysed. Throughout the study, the randomisation will be conducted by CenTrial in order to keep the data management and the statistician blind against the study condition as long as the data bank is open. The randomisation list remains with CenTrial for the whole duration of the study. Thus, randomisation will be conducted without any influence of the principal investigators, raters or therapists.”246
Explanation
Based on the risk of bias associated with some methods of sequence generation and inadequate allocation concealment, trial investigators should strive for complete separation of the individuals involved in the steps before enrolment (sequence generation process and allocation concealment mechanism) from those involved in the implementation of study group assignments. When this separation is not possible, it is important for the investigators to ensure that the assignment schedule is unpredictable and locked away from even the person who generated it. The protocol should specify who will implement the various stages of the randomisation process, how and where the allocation list will be stored, and mechanisms employed to minimise the possibility that those enrolling and assigning participants will obtain access to the list.
[ps2id id=’blinding-masking’ target=”/]
17. BLINDING (MASKING)
17a. Blinding (Masking)
Who will be blinded after assignment to interventions (e.g., trial participants, care providers, outcome assessors, data analysts), and how.
Example
“Assessments regarding clinical recovery will be conducted by an assessor blind to treatment allocation. The assessor will go through a profound assessment training program . . . Due to the nature of the intervention neither participants nor staff can be blinded to allocation, but are strongly inculcated not to disclose the allocation status of the participant at the follow up assessments. An employee outside the research team will feed data into the computer in separate datasheets so that the researchers can analyse data without having access to information about the allocation.”247
Explanation
Blinding or masking (the process of keeping the study group assignment hidden after allocation) is commonly used to reduce the risk of bias in clinical trials with two or more study groups.166;248 Awareness of the intervention assigned to participants can introduce ascertainment bias in the measurement of outcomes, particularly subjective ones (e.g., quality of life)166;167; performance bias in the decision to discontinue or modify study interventions (e.g., dosing changes) (Item 11b), concomitant interventions, or other aspects of care (Item 11d)229; and exclusion/attrition bias in the decision to withdraw from the trial or to exclude a participant from the analysis.249;250 We have elected to use the term “blinding”, but acknowledge that others prefer the term “masking” because “blind” also relates to an ophthalmologic condition and health outcome.251;252
Many groups can be blinded: trial participants, care providers, data collectors, outcome assessors or committees (Item 5d), data analysts,253 and manuscript writers. Blinding of data monitoring committees is generally discouraged.254;255
When blinding of trial participants and care providers is not possible because of obvious differences between the interventions,256;257 blinding of the outcome assessors can often still be implemented.17 It may also be possible to blind participants or trial personnel to the study hypothesis in terms of which intervention is considered active. For example, in a trial evaluating light therapy for depression, participants were informed that the study involved testing two different forms of light therapy, whereas the true hypothesis was that bright blue light was considered potentially effective and that dim red light was considered placebo.258
Despite its importance, blinding is often poorly described in trial protocols.3 The protocol should explicitly state who will be blinded to intervention groups – at a minimum, the blinding status of trial participants, care providers, and outcome assessors. Such a description is much preferred over the use of ambiguous terminology such as ‘single blind’ or ‘double blind’.259;260 Protocols should also describe the comparability of blinded interventions (Item 11a)150—for example, similarities in appearance, use of specific flavours to mask a distinctive taste—and the timing of final unblinding of all trial participants (e.g., after the creation of a locked analysis data set).3
Furthermore, any strategies to reduce the potential for unblinding should be described in the protocol, such as pre-trial testing of blinding procedures.261 The use of a fixed code (versus a unique code for each participant) to denote each study group assignment (e.g., A = Group 1; B = Group 2) can be problematic, as the unblinding of one participant will result in the inadvertent loss of blinding for all trial participants.
Some have suggested that the success of blinding be formally tested by asking key trial persons to guess the study group assignment, and comparing these responses to what would be expected by chance.262 However, it is unclear how best to interpret the results of such tests.263;264 If done, the planned testing methods should be described in the trial protocol.[ps2id id=’emergency-unblinding’ target=”/]
17b. Emergency unblinding
If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial.
Example
“To maintain the overall quality and legitimacy of the clinical trial, code breaks should occur only in exceptional circumstances when knowledge of the actual treatment is absolutely essential for further management of the patient. Investigators are encouraged to discuss with the Medical Advisor or PHRI [Population Health Research Institute] physician if he/she believes that unblinding is necessary.
If unblinding is deemed to be necessary, the investigator should use the system for emergency unblinding through the PHRI toll-free help line as the main system or through the local emergency number as the back-up system.
The Investigator is encouraged to maintain the blind as far as possible. The actual allocation must NOT be disclosed to the patient and/or other study personnel including other site personnel, monitors, corporate sponsors or project office staff; nor should there be any written or verbal disclosure of the code in any of the corresponding patient documents.
The Investigator must report all code breaks (with reason) as they occur on the corresponding CRF [case report form] page.
Unblinding should not necessarily be a reason for study drug discontinuation.”265
Explanation
Among 58 blinded Danish trials approved in 1994-95, three-quarters of protocols described emergency unblinding procedures.3 Such procedures to reveal the assigned intervention in certain circumstances are intended to increase the safety of trial participants by informing the clinical management of harms or other relevant conditions that arise. A clear protocol description of the conditions and procedures for emergency unblinding helps to prevent unnecessary unblinding; facilitates implementation by trial personnel when indicated; and enables evaluation of the appropriateness of the planned procedures. In some cases (e.g., minor, reversible harms), stopping and then cautiously re-introducing the assigned intervention in the affected participant can avoid both unblinding and further harm.