SOP24: Standard Operating Procedure for Randomisation

Transcription

1 SOP24: Standard Operating Procedure for Randomisation Authorship Team: Alan Watkins for Joint SOP Group on Trial Techniques (viz Bridget Wells, Kerina Jones, Moira Morgan, Sian Davies, Sinead Brophy, Steve Allen) Approved by WWORTH JEG (Ian Russell in chair) Signature Date 07 May Version Record Version Number Effective Date Reason for Change 0 31 Dec 2008 SOP approved by NWORTH Jan 2009 Adapted to WWORTH needs Mar 2009 Reviewed by JSOPG Jun 2009 Reviewed by JSOPG Aug 2009 Reviewed by COnStRUCT team Sept 2009 Approved in principle at JMG May 2010 Minor amendments Feb 2012 Prepare SOP for JSOPG. Trials in practice EPO, WWADR, REFRAMED Mar 2012 Minor amendments following JSOPG Apr 2012 Authorised for use Jun 2013 Update header and formatting amendments May 2014 Remove training log post JSOPG discussion - MS & CS WWORTH-SOP24RandomisationV Page 1 of 13 Not guaranteed if printed

2 1 Table of Contents 0 Version Record Table of Contents Glossary Introduction Purpose Roles and Responsibilities Procedure Procedure Flow Chart Type of Randomisation Participant registration Recording eligibility information on potential participants Recording pre-specified information on actual participants Recording consent and treatment allocation Principles and considerations when choosing or designing randomisation systems Predictability or balance? Method of access Method of generating allocations Emergency randomisation Preparation System testing For systems requiring live randomisation: For randomisation schemes not requiring live randomisation: Implementation of systems Randomisation Phase End of trial Staff training Training staff providing randomisation Training of centre and site staff in use of the systems Quality assurance Training Plan References Related SOPs...13 WWORTH-SOP24RandomisationV Page 2 of 13 Not guaranteed if printed

3 2 Glossary The full Glossary is in Swansea University H drive/documents/526- WWORTH/Development Group/Glossary. 3 Introduction Standard Operating Procedures (SOPs) are succinct formal documents designed to achieve consistency in specified trial functions by specifying standard practice in performing those functions (GCP 1.55 & EMeA, 2002). While SOPs should cite relevant legislation & regulations, and key references & evidence, they need not expound theory. WWORTH SOPs should accord with all relevant regulations, including the European Union Clinical Trial Directive, ICH Good Clinical Practice (GCP) and the current NHS Research Governance Framework. They will seek to distinguish between regulations for CTIMPs and for other research. This document is the Standard Operating Procedure of the West Wales Organisation for Rigorous Trials in Health (WWORTH). It describes the roles, responsibilities and actions of individuals developing, testing and implementing randomisation for trials. 4 Purpose The purpose of this SOP is to define all the stages in the registration of potential trial participants and the provision and use of a randomisation service. Stages identified include: a. Participant registration i. Recording eligibility information on potential participants ii. Recording pre-specified information on actual participants iii. Recording consent and treatment allocation b. Preparing for Randomisation i. Defining randomisation requirements for the trial ii. Selecting appropriate types of randomisation iii. Commissioning of a randomisation service if necessary iv. Designing the randomisation system v. Testing the randomisation system c. Implementing randomisation i. Training the staff and initial implementation ii. Day to day management during recruitment and randomisation WWORTH-SOP24RandomisationV Page 3 of 13 Not guaranteed if printed

4 d. After recruitment i. Unblinding procedures if required ii. Checking integrity of randomisation process and records iii. Archiving randomisation records and databases e. Quality assurance 5 Roles and Responsibilities The people responsible for the randomisation service are the WWORTH manager and statistical team, the trial statistician and trial manager or data manager CI responsible for liaising with the trial statistician to define requirements for the trial. Overall responsibility for the recruitment, randomisation and safety of participants, although this is usually delegated to other members of the trial team. PI responsible for randomisations taking place at a site, for implementing the allocated treaments, and for initiating unblinding requests based on clinical need. Some of these responsibilities may be delegated to other site staff. Statistical team responsible for the mathematical integrity of the randomisation systems written or commissioned, and quality assurance for the algorithms of WWORTH trials. Responsible, in consultation with the IT team, for developing and documenting of generic systems and procedures to build up expertise. Database and IT specialists (IT team) responsible for the writing, testing and implementation of databases, web interfaces and other associated IT systems. Responsible, in consultation with the statistical team, for developing and documenting of generic systems and procedures. Trial Statistician responsible for ensuring there is adequate and appropriate recording of registration and randomisation processes. Responsible for the choice of an appropriate randomisation scheme, training other members of the trial team, and provision of specific training materials, troubleshooting problems as they happen and providing accrual figures to the WWORTH meetings (if not provided by trial managers or data managers). Responsible for input of emergency randomisation information and trouble shooting, in consultation with the IT specialist, for the system. Responsible for ensuring a trial specific emergency randomisation SOP exists where necessary. Responsible for ensuring the randomisation process is compatible with adequately blinding the trial. Some practical and operational responsibility may be delegated to the trial manager or data manager, or another statistician. WWORTH-SOP24RandomisationV Page 4 of 13 Not guaranteed if printed

5 WWORTH Manager - responsible for overseeing the general functioning of the randomisation services provided within WWORTH, negotiating, where appropriate, and in consultation with other members of the team, the costings for the service and other management issues. Ensuring there is emergency randomisation cover in accordance with the needs of the trial. Trial manager responsible for setting up systems to register participants, commissioning a randomisation service if necessary, developing, in consultation with a statistician and other appropriate specialists, the details of the specification and testing the face validity of the product. Responsible for overseeing the day-to-day implementation of registration and randomisation requests. May be responsible for providing accrual figures to the trial team and WWORTH meetings 6 Procedure 6.1 Procedure Flow Chart Trial design phase: specify allocation ratio, type of randomisation, delivery system, blinding policy, stratification variables, et cetera Randomisation specifications Design and internal testing of systems Training, implementation and external testing of process Randomisation and recruitment End of recruitment: checks and comparisons End of trial: archiving WWORTH-SOP24RandomisationV Page 5 of 13 Not guaranteed if printed

6 6.1.1 Type of Randomisation Two main types of randomisation are typically used in trials. The first is cluster randomisation, in which participants can be linked to units (such as hospitals or ambulance stations), and the units are randomised, so that all participants associated with the unit then receive the treatment assigned to that unit. Cluster randomisation typically involves a relatively small number of units, undertaken in advance of patient recruitment at those units and thus allowing for appropriate training within units. The second concerns randomisation of participants at an individual level, and therefore requires a separate allocation for each eligible participant. Elements of both types may be combined in hybrid randomisation procedures. General principles apply to all randomisation procedures but with differences in implementation. All trial-specific aspects of randomisation (e.g., number and nature of stratification variables) must be established in advance of any randomisation; any changes deemed necessary after randomisation has commenced must agreed by the TMG and documented and incorporated in protocol. 6.2 Participant registration Recording eligibility information on potential participants As soon as participants are identified, they should be given a study number so that their records can be maintained and tracked. Information should be recorded on a separate, primarily administrative, database often held on site. Before consent only information needed to facilitate identifying and contacting patients and to determine eligibility should be collected. Eligibility information from this database can be transferred to the research team for the trial. Ineligible or non-consenting patients may be transferred as aggregated counts or as a minimal non-identifiable dataset linked only by study number. The research team will use this to complete the CONSORT diagram Recording pre-specified information on actual participants Participants in the trial should retain their original study numbers, allowing a link with the eligibility database. Identifiable data on participants should be kept separate Recording consent and treatment allocation Written and electronic records of consent should be maintained. Treatment allocations should be recorded on the trial database, the WWORTH-SOP24RandomisationV Page 6 of 13 Not guaranteed if printed

7 randomisation database, and usually on paper (see WWORTH SOP21 IT Databases and WWORTH SOP22a Data Collection Management). Where these sources differ the randomisation database should usually take precedence for analysis purposes. 6.3 Principles and considerations when choosing or designing randomisation systems Predictability or balance? The ideals of unpredictability (where it is not possible to know or determine an allocation in advance) and balance (where equal numbers of participants are allocated to each group) are in conflict, especially where the trial design or practical considerations require not only overall balance but balance at individual centres, within strata, or interim balance at different times during the trial. Often a compromise is chosen, but the relative weight placed on the two criteria will vary between trials. For randomisation at an individual level, simple randomisation, where each participant has the same separate and independent chance of receiving a particular treatment, is completely unpredictable if the allocation is generated live by a database only when the randomisation is requested. Remotely held pre-generated simple random sequences are predictable only to those with access to the sequence. At the price of a small increase in predictability, a pre-generated sequence can be checked and rejected if it is unusually unbalanced. Non-random allocations (e.g. by day of the week or letter of surname), or others which are easily predictable, such as alternation or small blocks, should always be avoided. Especially in large trials, exact or even approximate balance is often not required. The desired allocation ratio in a relatively large trial may be altered from the usual equal balance with little effect on overall power unless the imbalance is more than 2:1. Interim balance should be considered as well as final balance. Most trials aim to recruit over a set time period, when the achieved sample size is unlikely to be equal to the planned sample size Method of access Whatever system is used, the principle of remote randomisation should be adhered to: randomisation should take place off-site, by someone not involved in assessing eligibility, and a remote record of the randomisation (additional to and independent of the main trial databases) should be kept to which site staff have no or limited (read only) access. WWORTH-SOP24RandomisationV Page 7 of 13 Not guaranteed if printed

8 For randomisation at an individual level, web randomisation should be considered, and will normally be used when immediate allocations are needed or randomisation may take place outside normal office hours. This requires the person requesting the randomisation to have internet access. If web randomisation is not feasible (e.g. randomisations requested during a visit to the participant s home), telephone randomisation to a central database (provided by WWORTH staff or contracted out) may be considered for timely allocations within office hours. randomisation may be appropriate when delays of several hours or more in returning allocations are allowable. These may be done individually or in batches of several participants. Batch randomisations are often done by . Non-remote on-site access may be necessary, but should retain as many as possible of the safeguards of remote randomisation. Envelope randomisation should be avoided wherever possible, including for emergency backup; if it is needed in a particular trial, extra safeguards and checks should be put in place. Sequences for envelope randomisation should be pre-generated and opaque, double sealed, numbered envelopes prepared at an independent central location, which should hold a separate secure copy of the randomisation sequence for each site. The allocation should ideally be accessed by someone at the site other than the recruiter Method of generating allocations Coin tossing, dice throwing or similar mechanical systems should always be avoided. Allocations should not be predictable, either by the trial centre (essential) or the randomiser (highly desirable), before they are submitted to the website or randomiser. In general, dynamic randomisation principles will be used to achieve this, but may be modified for trial constraints. In a dynamic randomisation scheme, parameters determine how closely balance between the groups is maintained. Some parameter values give a tight randomisation: allocations will be closely balanced between groups, but at the cost of more predictability. Randomised blocks may be used only where patients or units are randomised simultaneously in discrete blocks and allocations are returned as a complete block or blocks. Occasionally a pre-generated allocation sequence is required by the circumstances of the trial. In this case, a randomised block system may be used, but must be modified to reduce predictability by using both blocks of random variable length and random WWORTH-SOP24RandomisationV Page 8 of 13 Not guaranteed if printed

9 interpolation of one or more non-block allocations in the middle of a block. The number of stratification variables should be kept to a minimum, as this improves unpredictability and minor imbalances can be allowed for in the analysis. However in multi-centre trials, it is usually appropriate to include trial centre as a stratification variable, especially if the number of patients per centre is small Emergency randomisation Emergency randomisation procedures should be in place to cater for inability to access the webpage or database in the usual way (eg because of server faults or power cuts). They should adhere to as many of the usual randomisation principles listed above as practicable, but may be simplified (e.g. to give an equal chance of each treatment). More than one emergency procedure may be needed: a mobile telephone number is often the final back-up. As soon as possible, emergency randomisations should be entered (and flagged) on the main randomisation database by the trial statistician (who may delegate this task to another member of the main trial team). Records of all emergency randomisation materials used in the trial must be retained. 6.4 Preparation A trial approaches WWORTH, and the randomisation tasks are assessed. Costs are estimated, grant applications are made and negotiations undertaken. At this stage a draft contract may be drawn up between the trial team and WWORTH, and with external organisations if applicable. Once agreement on the overall form of randomisation (e.g. type of randomisation, allocation ratios between groups, stratification variables) has been reached and grants obtained, the database requirements are specified, strata for stratification variables are established, and other information that is needed for audit etc. is identified. Requirements and responsibilities for emergency randomisation are also identified. The practical needs of the trial are established (e.g. out of hours randomisations, and methods for communicating and confirming allocations). Initial costings are established. A randomisation contract is agreed, which should contain specifications, requirements and responsibilities The database and, if appropriate, web interface are then developed, or the WWORTH-SOP24RandomisationV Page 9 of 13 Not guaranteed if printed

10 generic database is adapted, usually by an internal or external IT specialist, and any specialist requirements, e.g. supply of package numbers, are addressed. Parameters (governing the overall allocation ratio between groups) are decided, and provisionally set, with scope to adjust these later in the trial if needed: see also Section below. 6.5 System testing For systems requiring live randomisation: The IT specialist team, trial management team and the trial statistician undertake extensive testing for security, face validity, reliability and stability. Emergency randomisation systems are also tested. The algorithm is tested for mathematical integrity, and the parameters tested for appropriateness. Wherever possible, this testing will incorporate extensive simulations of randomisations, to indicate the scale of possible departures from required balances at all appropriate stages of the trial. Simulations will also be used to gauge the sensitivity of algorithm s output to changes in parameter values. 7 The system and database is approved by the trial team For randomisation schemes not requiring live randomisation: Randomisation may be done simultaneously (e.g. cluster randomisation of a definitive list of existing centres); in several discrete blocks, or exceptionally by another system agreed with the WWORTH statistical team. A validation check on the methodology should usually be obtained from another member of the WWORTH statistical team before issuing the randomisation codes. 6.6 Implementation of systems The database training materials are written; any training needs are assessed and met. The final versions of the websites and databases are installed and activated; with (password-protected) copies on the H drive if appropriate. The research team is informed how to randomise to the trial and supplied with web addresses, passwords and authorisation, emergency randomisation procedures including telephone numbers, and other backup information. WWORTH-SOP24RandomisationV Page 10 of 13 Not guaranteed if printed

11 If it is required to maintain the trial statistician s blindness to allocation, emergency randomisations may be carried out by the trial data manager or another WWORTH statistician under the direction of the trial statistician. 6.7 Randomisation Phase The trial data manager and trial statistician continue to monitor the randomisation process. If the trial requires the statistician to be blinded as to allocation, direct access to the randomisation databases and emergency randomisations may need to be done by the data manager or another WWORTH statistician under the direction of the trial statistician, who may request blinded or anonymised versions for checking, reporting and quality assurance. If or batch randomisation is required, s should be copied to the trial data manager, who should keep them as a record of requests and allocations. The statistical and IT teams monitor the volume of randomisations received monthly, and occasionally (depending on the volume of randomisations, either 6 monthly or per 100 randomisations whichever is soonest) the integrity of the randomisations produced. 6.8 End of trial Once a trial has finished, the databases will be dismounted, and archived for audit and storage. The centre data will be checked against the randomisation database and all randomisation records and discrepancies will be documented and resolved using the underlying principle that the randomisation database gives the allocation for an intention to treat analysis. A copy of the randomisation database will be provided to the appropriate trial coordinator if requested. This data will be maintained for five years after the end of the analysis period and will be available for inspection by interested legitimate parties. 6.9 Staff training The two principal areas of staff training are: 1. Training staff providing randomisation: statisticians, trial team members and any other WWORTH members involved in emergency randomisations 2. Training of centre and site staff in use of the systems. WWORTH-SOP24RandomisationV Page 11 of 13 Not guaranteed if printed

12 6.9.1 Training staff providing randomisation When a new trial is introduced a document outlines the trial and the randomisation procedure for that trial is written. This document will also be mounted on the H drive for reference by the randomisation team Training of centre and site staff in use of the systems Where appropriate, new centre and site staff will be given a randomisation training session by the trial manager or data manager Quality assurance Quality assurance will be ensured in the following ways: 1. Adherence to the principles of randomisation, as outlined in Section 6.3 above. 2. Through systems testing, as outlined in Section 6.5 above. 3. Ongoing monitoring of the performance of the system, as outlined in Section 6.7 above. 4. Staff training, as outlined in Section 6.9 above. 7 Training Plan All WWORTH staff involved with trials must undertake the appropriate generic and trial-specific training to ensure that they meet with the specific employers mandatory training requirements and the specific requirements of the trial. For example, for SU staff, all new employees must attend induction, fire and safety training (as well as role-specific training courses, e.g. laboratory safety). For new staff, additional training requirements should be identified alongside the specific role requirements and the WWORTH Unit Manager should make provision for the new staff member to attend the necessary courses as soon after appointment as is practicably possible. It is the responsibility of the WWORTH Unit Manager (alongside the CI or TM) to identify all the SOPs that are relevant to a specific trial and in which the new member of staff should be trained. The WWORTH UM or the SOP author will provide group training for trial staff and/or one-to-one training, as required for new staff in relation to the specific SOPs identified. Training records should be filed both by the main employer and the staff member, in accordance with the specific employer requirements. Trial specific training should be filed in TMF or TSF as appropriate and every individual involved in a trial should have an WWORTH-SOP24RandomisationV Page 12 of 13 Not guaranteed if printed

13 individual training record (see WWORTH SOP02 Training). Where the tasks specified in the individual SOPs are delegated to WWORTH staff, CIs/PIs or TMs, these delegated staff must ensure that they have attended a training course on GCP and keep up-to-date through attending refresher courses. It is the responsibility of the CI/PI to ensure that all staff allocated duties on the study delegation log template of responsibilities are suitably trained in the activities linked to those duties (see WWORTH SOP16 Site Setup, Appendix 9 and Appendix 10). Each trial should maintain a central training log and ensure that WWORTH has access to that log, not least to integrate the logs of staff who work on more than one trial. Similarly trials should ensure that each site maintains a local training log, not least to integrate the logs of staff who work for more than one sponsor. All individuals involved in designing randomisation databases will be trained in principle use of this SOP by the Senior Statistician. Other WWORTH staff involved in the randomisation service will be trained by the Statistician in the use of this SOP. Clerical randomisation staff will be trained by the Statistician. Thereafter new staff members will receive one on one training from the Statistician in the use of this SOP. Follow up training is given via practical application. Staff will sign the training record once a successful randomisation has taken place. 8 References 1. Standard Operating Procedures (SOPs) Preparation, Review, Approval and Issue. 2. C. Cotterill-Jones. Wales Cancer Trials Unit 9 Related SOPs WWORTH SOP01a on SOPs WWORTH SOP02 Training WWORTH SOP03 Master Site File WWORTH SOP08 Archiving WWORTH SOP13 Protocol Development WWORTH SOP19a Pharmacovigilance WWORTH SOP21 IT Databases WWORTH SOP22a Data Collection Management WWORTH SOP28 Statistics WWORTH-SOP24RandomisationV Page 13 of 13 Not guaranteed if printed