Keele Clinical Trials Unit

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1 Keele Clinical Trials Unit Standard Operating Procedure (SOP) Summary Box Title Randomisation SOP Index Number SOP 32 Version 3.0 Approval Date 31-Jan-2017 Effective Date 14-Feb-2017 Review Date January 2019 Lead Author Martyn Lewis Reference KCTU/SOP32/v3.0/14-Feb-2017 DISCLAIMER This SOP is the property of Keele Clinical Trials Unit (Keele CTU), Faculty of Health, Keele University and the content cannot be reproduced without specific permission from the owner. All SOPs and associated documents must be accessed through the dedicated SOP area of the RI for Primary Care and Health Sciences (ipchs) Intranet to ensure the correct version is being used. If this document is being accessed through any other method, such as electronic copies saved onto a network drive or in printed form, it is only valid for use if the version number and effective date shown above is the same as that shown on the ipchs Intranet. Any superseded versions of this document need to be promptly withdrawn from use. All individuals undertaking functions outlined in this document are responsible for ensuring that they are trained in the procedures outlined in the correct version of this document. SOP Template v6.0 date 18 Aug 2016 Signature Box Role Print Name Signature Date Sponsor QA Tracy Nevatte Signed hard copy stored in 31-Jan-2017 Manager approved SOP file with QA office Head of Research Clark Crawford Signed hard copy stored in 31-Jan-2017 Integrity approved SOP file with QA office Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 1 of 10

2 Version History Log Version Date Reason(s) for Change Implementation Plan Approved Nov-2015 New SOP All RI staff will be notified of the revised SOP. Staff are expected to read the updated version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date. Once the SOP has been released implementation training will be organised for the Keele CTU IT Team Sept-2016 Added background info and clarity to procedures Producing & verifying Master Randomisation Schedule Emergency randomisation process & necessity to lockin to master schedule Sign-off of randomisation schedule Details on concealment Involvement of DMC Requirement to document reasons for selecting a system for randomisation & the processes followed (development, testing & audit trail of changes) All RI staff will be notified of the revised SOP. Staff are expected to read the updated version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date Jan-2017 Added information regarding blinding procedures notably extension of section 3.3 to clarify the procedure of generating a number of schedules for which one will be adopted for the trial (to support blinding). Reference to the newly drafted CHL14 Randomisation Schedule Sign-Off Checklist (v1.0) is included. All Keele Health and Social Care Research QMS users will be notified of the new SOP. Staff are expected to read the new version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 2 of 10

3 Table of Contents 1. Purpose Scope and Applicability Procedures Randomisation Schedule Randomisation Procedures Randomisation Specification Emergency Randomisation Unit of Randomisation Number to Randomise and Randomisation Ratio Allocation of the Randomisation Code Allocation Concealment Maintaining Balance Blocking Stratification Minimisation Key Personnel to whom this SOP Applies Study Statistician Database Developer Data Systems Manager Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 3 of 10

4 1. Purpose This SOP covers randomisation processes and considerations when developing computerised randomisation. Randomisation gives chance assignment of treatments to individuals in a clinical trial and produces treatment groups that are similar in respect of known and unknown other factors (covariates). It reduces the possibility of bias in the selection and allocation of treatment to subjects. 2. Scope and Applicability This SOP applies to all individuals undertaking functions outlined herein. This includes all core Keele CTU staff and all other academic, research, management or admin staff, or students working on Keele University sponsored/ Keele CTU managed clinical research projects through site agreements, service or other contractual arrangements. This SOP must be followed in line with the NHS Research Governance Framework, and the University, Research Institute and CTU policies. Where applicable to Clinical Trials of Investigational Medicinal Products (CTIMPs) this SOP must be followed in line with the UK Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments, and the EU Clinical Trials Directive. Where applicable to non-ctimp studies this SOP must be followed in line with the appropriate Good Clinical Practice guidance. 3. Procedures 3.1 Randomisation Schedule The randomisation schedule of a clinical trial documents the random allocation of treatments (or order of treatment in crossover studies) to individual patients or a group (cluster) of patients (e.g. patients within a general practice). It is a sequential list of treatments/treatment codes corresponding to subject number (usually dictated by schedule of entry). Different trial designs will require different procedures for generating randomisation schedules: the reasons for selecting a particular system for randomisation should be documented. CHL14 Randomisation Schedule Sign Off Checklist requires completion at different stages of the development process by the database developer, statistician and Quality Office. A single master randomisation schedule will be implemented within each trial after complete sign off of the checklist. To help safeguard against potential problems, the master randomisation schedule should be reproducible (if the need arises). In multicentre trials the randomisation procedures should be organised centrally (i.e. Keele CTU will implement the randomisation schedule if it is the one or designated lead CTU for the study). 3.2 Randomisation Procedures The Study Statistician needs to liaise with the Database Designer to ensure the method of randomisation is understood and all relevant information handed over to the designer. Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 4 of 10

5 Consideration needs to be given to: - Randomisation method. - Blinding issues (consideration and thought need to be given to the formation within tables to prevent unnecessary un-blinding). - Any validation, which must be set up appropriately, to ensure that the data entered is as accurate as possible (i.e. fields in the database must be correctly specified, e.g. appropriate age range, clinical codes etc.). Such validation may be applied to balancing factors/ strata and to appropriately ensure only relevant eligible/ consenting subjects are randomised. - Consent and continuation routes/ scenarios to be clearly defined and discussed. All randomisation procedures are to be developed by the Study Statistician in collaboration with the Database Designer with input from other members of the Study Team, as appropriate. Full details of the randomisation procedure should be included in the study protocol (with the exception of block sizes which would potentially lead to knowing the allocation of a participant), using the following sections: - Unit of randomisation (e.g. individual patient or cluster of patients) - Number to randomise and randomisation ratio - Allocation of the randomisation code - Allocation concealment - Maintaining balance (e.g. block permutations/ minimisation algorithms) The next unit to be randomised into a trial should receive the treatment corresponding to the next free number in the appropriate randomisation schedule (in the respective stratum, if randomisation is stratified (see section 3.11)). The appropriate number and associated treatment for the next unit should only be allocated when enrolment of that unit to the randomised part of the trial (i.e. relevant eligibility, consent and signatories) has been confirmed. Once randomisation is complete, confirmation of allocation should be notified and recorded as soon as possible. 3.3 Randomisation Specification A randomisation specification needs to be produced, developed and validated (with testing documentation available) to demonstrate that the system used will follow the intended randomisation sequence (as protocolised) Ten Randomisation Schedules will be produced by the database developer which will be reviewed and approved by the lead study statistician Following the approval of all ten randomisation schedules, one of these is required to be chosen at random (using a random number generator) by the database developer which will be used as the Master Randomisation Schedule The process for generating the 10 randomisation schedules and then the choosing of the Master Randomisation Schedule needs to be fully documented and give clear transparency for producing and verifying a Master Randomisation Schedule An audit trail needs to be retained in respect of this procedure to allow for reproducibility of the randomisation schedule; this will be done by keeping a log of secure seeds used in pre-testing and for the main schedule (the seed is a number used to initialise the random number generation process; if the same seed is used Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 5 of 10

6 again then the random sequence generated would remain the same, which is useful in reconstructing the randomisation list for auditing purposes) The seed used for the main schedule should be at the discretion of the database designer (and kept concealed from the Trial Statistician and other members of the Study Team) The procedure allows generation of a pre-sequence for the master randomisation schedule: the summary allocation balance (overall and by strata as required) can be checked by the database designer and the Statistician before final sign-off to ensure compliance with intended schedule or at least it should be made be available for checking if the need arises The size of the master randomisation schedule should tally with the sample size requirement in the protocol; and the simulations should mimic the intended size of the trial. All this is included in a Master Randomisation list, which is an essential document required to reconstruct trial activities and include full documentation of results of testing (including simulations) and an audit trail of development and changes to fulfil quality assurance requirements (to be signed off at each stage by the Database Developer and Trial Statistician). The Data Monitoring Committee will oversee the ongoing trial allocation and monitor whether this aligns to the intended schedule (refer to SOP 14: Monitoring and Audit) A 'Randomisation Schedule sign off checklist' (current, v0.1) {add online link here} must be signed off at different stages by the database developer, statistician and QA Office as relevant - and the final approved document subsequently stored within the Study Master File. 3.4 Emergency Randomisation The randomisation schedule may or may not allow for emergency cover; if this is to be included it is designed to integrate and lock into the master randomisation schedule (which may be at the point in the sequence in which the emergency list is triggered (ideal as it gives greatest likelihood of parity in numbers allocated per arm and balance of prognostic factors - but gives logistical challenges), or alternatively to take the reverse order of the sequence from the end of the master schedule (easier to manage but compromises a little on likelihood of exact balance). Keele CTU operates a web- and telephone-based randomisation service. In the event of not being able to access the sequence through the usual route (e.g. computer system or telephone network is down) a back-up system may be necessary to implement and lock into the sequence pathway for the main randomisation schedule (as described above); this would need to be operationalised whilst ensuring the retention of security and allocation concealment. For example, if access to the master randomisation schedule is via web-randomisation and to safeguard against web-/network failure a telephone-back up service possibly an offline solution (accessible during usual 9am-5pm working hours Monday-Friday) can be made available and utilised if access to the web / electrical faults limit accessibility. 3.5 Unit of Randomisation The unit of randomisation needs to be considered to balance the risk of contamination and bias. Where there is little or no possibility of contamination of treatments across the randomised groups, the unit of randomisation will be the individual patient, and the trial will likely be either parallel-group or factorial in design. However, where there is potential for contamination, the unit of randomisation will need to be at a higher level, such as the Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 6 of 10

7 general practice level, and the trial will be a cluster randomised trial. The method of statistical analysis should reflect the unit of randomisation. 3.6 Number to Randomise and Randomisation Ratio Information should be provided on the number of units to be randomised in order to satisfy the sample size calculation. Where over-sampling is to be carried out to allow for attrition during the follow-up period of the trial, details should be provided. The units recruited should be randomised to the treatment groups with a fixed ratio, e.g. in a 2-parallel arm trial the treatments may be allocated in a ratio of 1: Allocation of the Randomisation Code Details should be provided on who will select the final treatment group allocation (usually the Database Designer), and where this information is to be stored until the randomisation code is to be broken. 3.8 Allocation Concealment The randomisation schedule needs to be filed securely by the CTU. A clear, coherent approach to maintaining appropriate concealment of the randomisation code is required. Members of the Study Team that need to be aware of the randomisation code during the active phase of the trial, in order for them to be able to carry out their role, need to be identified. Processes should be put into place so that the randomisation code is concealed from all other members of the Study Team until the point when the main analysis has been completed. These processes need to include restrictions in: - Access to components of the management database and, - Involvement with treatment related issues generated by the treatment providers. In some cases, emergency unblinding may be called for in the event of a serious adverse reaction to treatment and maybe requested under certain circumstances from the external Data Monitoring Committee (e.g. as a result of interim evaluation). In these cases please follow the study specific process for unblinding: this should all be documented in the protocol/study master file. 3.9 Maintaining Balance Simple randomisation, or randomisation without restriction, is the most basic method of random treatment assignment and is usually achieved using a sequence of random numbers from a statistical textbook, or nowadays using a computer-generated sequence. Simple (unrestricted) randomisation is generally regarded as acceptable for large trials. However, there may be specific characteristics of the treatment process or the patients that need to be balanced across the treatment arms and the randomisation process can be enhanced to maintain this balance using (restriction) methods such as: - Blocking - Stratification - Minimisation As well as accounting for prognostic factors through such design approaches, it is also recommended that the ensuing statistical analysis also control for these same factors. Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 7 of 10

8 3.10 Blocking In individual randomised trials a blocking process can be used to maintain a certain ratio (usually 1:1) in treatment allocation; to ensure for example, equal numbers of patients are assigned to each of the treatment arms. Blocks may be of a designated fixed size (e.g. 2 or 4 or 6), or allowed to vary in size an approach often referred to as random permuted blocks (e.g. 2, 4 and 6). In this process, block sizes need to be specified, which are normally multiples of the number of treatments in the trial, in which the treatment groups are balanced e.g. in a 2-arm parallel trial the randomisation process may involve blocks of size 2, 4 and 6. It is recommended that block lengths should be sufficiently short to limit possible imbalance, but long enough to avoid predictability towards the end of the block sequence. Investigators and other relevant staff should be blind to the block length (this detail should not be included in the study protocol); the use of different block sizes, randomly selected for each block, can achieve the same purpose. It is advisable to use randomly changing block sizes in order to enhance allocation concealment. The Study Statistician needs to provide the Database Designer with the details of the block sizes required Stratification In some trials, it is important that a small number of specific patient characteristics are well-balanced across the treatment groups, and stratified randomisation with blocking (or minimisation (see section 3.12)) can be used to ensure this balance. Multi-centre trials should ideally be stratified on the basis of participating Centre. Stratified block randomisation is achieved by performing a separate block-randomisation procedure within each of two or more subsets of participants (for example, defined based on site/centre and/or age category and/or disease severity). Stratified block randomisation with random permuted blocks helps eliminate the issue of predictability while ensuring reasonable balance across potentially prognostic factors. Block and stratified-block randomisation are particularly relevant to small trials where there is greater risk from imbalance. Variables and cut-offs for stratification will be defined by the Study Statistician in collaboration with other members of the Study Team Minimisation Minimisation (dynamic allocation) is an alternative to stratified randomisation, particularly when there are many characteristics on which to balance (i.e. more than two or three). The first patient 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, usually incorporating a random component. Deterministic dynamic allocation approaches should be avoided and an appropriate element of randomisation should be incorporated for each treatment allocation. Minimisation ensures balance on a combination of prognostic variables, by allocating with high probability the next patient (or cluster) to enter the trial to whichever treatment would minimise the overall imbalance on the prognostic variables between the groups at that stage in the trial. Only those factors known to affect outcome should be considered: variables and cut-offs are to be selected by the Study Statistician in collaboration with other members of the Study Team Blinded trials Where a trial is blinded, the Master Randomisation Schedule will be used to inform the treatment allocation of each participant randomised and will be forwarded to the third party manufacturing facility to be used for labelling of the product(s) the affiliated steps of the process for corresponding sign off are within points 7 and 8 of CHL14 Randomisation Schedule Sign Off Checklist. Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 8 of 10

9 To ensure the study teams remain blind to treatment allocation, correspondence with the third party manufacturing facility will be performed by the QA office When the Master Randomisation Schedule is sent over to the third party manufacturing facility for blinded trials, the code-break will be sent over in a password protected document. However, the password to this document should be sent separately (i.e. the password should not be sent in the same correspondence as the document outlining the code break) For blinded trials, the code break will be held within the database (only accessible to the database developer team hidden from others who have access to this database) with a paper copy being stored in the QA office in a locked tambour unit with restricted access Un-blinding / Code break There should be a particular element of the database to manage the processing of un-blinding / code breaking Un-blinding / code breaking would usually be performed by the site undertaking the study activity. In the instance where this is a multi-centre trial, a lead site/pharmacy would be delegated these duties If a participant presented with a medical emergency, and the treating clinician felt it was clinically indicted to know the IMP that the participant had received, the treating clinician should telephone the telephone number presented on the participant card (given to the participant following randomisation to enable un-blinding / code breaking of treatment allocation to take place). The telephone number for unblinding / code breaking should be available 24 hours a day Working instructions for trial specific processes for un-blinding are required to be in place prior to the trial going live. This should include processes to consider if the website is unavailable Access to the un-blinding/code breaking website will be outlined in the training manual / working instruction for the CTIMP being conducted. Access will only be given following appropriate training and delegation of duties to perform this duty A copy of the trial protocol, and the relevant summary of product characteristics / IMPD documents should be available on the un-blinding / code breaking website for reference Keele CTU are responsible for checking the secure fax account and secure account linked to the CTIMP for emergency un-blinding / code breaking notifications on a daily basis (working days) to ensure that these are dealt with appropriately according to SOP 20: Safety Reporting and Pharmacovigilance. Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 9 of 10

10 4. Key Personnel to whom this SOP Applies 4.1 Study Statistician - Develop the randomisation algorithm - Test the computerised randomisation - Sign off the computerised randomisation 4.2 Database Developer - Work with the study statistician to develop the computerised randomisation - Write a test plan 4.3 Data Systems Manager - Review randomisation process with Study Statistician and Database Developer to adhere to data management plans for validation The final version of the randomisation schedule will be version controlled and approved (signed and dated see CHL14 Randomisation Schedule Sign Off Checklist) by the Database Developer, Study Statistician(s) and Data Systems Manager prior to the start of recruitment for a trial (as per requirement of SOP 2: Document Control). Ref: KCTU/SOP32/v3.0/14-Feb-2017 Page 10 of 10