Protocol development for international trials can often take longer than when developing a protocol to be used solely in the UK. There are a number of options for development and implementation of protocols when recruiting internationally, all of which should be considered at the grant application stage as these decision so that sufficient resource and time can be factored in from the outset. Protocols can be developed as a single protocol for use at all sites across the trial, or can be developed as parallel protocols.

Single protocol for use across all sites, where the protocol is developed by the UK host institution.
  If the single protocol route is chosen, this will need to be carefully developed to ensure this is applicable for all participating sites in a trial which may be a challenge given differences in local processes. A single protocol may be easier however to track across sites, with all sites on the same version and date.  
It is recommended that the protocol is written in English, along with other trial documents being used by sites. Patient documents such as the Patient Information Sheet/Consent Form, questionnaires and letters should be translated into the required local languages.
Requests for country specific changes
Considerations should be given to how to handle requests for country specific changes e.g. a request for a change from one ethics committee.   With the single protocol model, if a change is required and deemed necessary- the protocol would need to be updated across all sites.
Initial approvals and subsequent amendments
Obtaining initial approvals of the protocol and/or related documents (and any subsequent amendments) is more complex in an international trial due to there not being a single body where all required approvals can be obtained from.  For amendments, it is recommended that changes that are not urgent are grouped and made as a single amendment due to the additional workload in implementing changes to the protocol and/or related documents across all sites. Considerations should be given to the timing of an amendment, how long local approvals are likely to take and how approvals across sites will be tracked. It is likely that approvals across sites will be received at different times, therefore it is important that there is a robust mechanism for recording versions and dates of key documents at each site, along with date of implementation.
Protocol design considerations
Surgical interventions are complex due to there being a number of different components that form the overall treatment e.g. pre-operative care, different procedures in the various stages of an operation, surgeon decision making and post-operative care. When recruiting internationally this heterogeneity, and therefore also the challenges it poses to trial design and delivery, is exacerbated. A clear understanding of local healthcare systems and patient pathways is key for development of a robust protocol. This understanding will help to ensure protocols are applicable, realistic and implementable in each country. It is recommended that a local clinician from each country is identified early on during design of the trial to obtain their feedback about the trial design and how this may fit with local processes. The following aspects should be considered:  

Patient population/pathway
  • Timing of standard visits compared to visits required by the trial. Where possible, try to align these visits to ensure minimal research burden on trial patients and participating sites.
  • How are patients referred to the participating site for treatment? It may be that patients travel further for treatment in some countries, particularly where more specialised hospitals perform treatments under study. If patients are travelling from a long distance, is it feasible and appropriate for them to attend additional trial specific visits? Dependant on trial design and local processes, concessions could be made in scenarios such as this the use of postal consent, obtaining trial data over the telephone (e.g. complications) or use of electronic quality of life questionnaire completion.
  • What are the local spoken languages? Are patient reported outcome measures available in all languages? This may also have an impact on costs in terms of additional licencing fees or translation costs (link to finance), see PROMS section for further information.
Local healthcare arrangements
  • Establish how trial related interventions are funded locally. This may have implications if there is a big cost difference between the interventions under study, particularly if this cost is picked up by patients.
  • Differences in surgical equipment that could affect trial outcomes
  • Are trial specific investigations performed as standard? If not and are essential for the trial, will these incur additional costs? (link to finance)
  • If there is private healthcare insurance, will taking part in the trial have any effect on this?
Intervention delivery
  • It is good practice in surgical trials to clearly state in the protocol which aspects of the operation are mandatory and which aspects are optional or as per local standard practice. Consider any variations in delivery of surgical interventions between sites and how this would fit with your trial protocol, will all sites be able to comply with the protocol?
  • Dependant on the research question, a more pragmatic design where surgeons are able to perform operations as per their usual standard practice may help with recruitment of sites and patients. This will also act to lower the overall risk of the trial which may mean lower insurance premiums (link).  Even where a more pragmatic approach is taken, data should be collected (link) on how each operation was performed so this can be summarised at the end of the trial.
  • Often a baseline level of procedure experience will be set as a requirement for surgeons participating in surgical trials. Is this achievable in all trial interventions across all countries?
  • If you are considering blinding of patients, will you be able to do this robustly across all sites?
  • Where trial investigations are required e.g. scans to assess disease, are these standard across sites or are different methods used? Can the protocol be flexible to allow for methods usually used locally?
  • How standard is clinical terminology between countries? Where possible, use definitions used in published international guidelines to try to ensure consistency between sites. These guidelines can then be referenced both within the protocol and in any publications arising from the trial. It is also worth looking at what definitions have been used in previous surgical studies, to allow potential future comparisons of results. Terminology should be clearly defined within the protocol, this is particularly important when in relation to trial endpoints to ensure consistent and reliable reporting from sites. (link to data collection?)
General protocol advice
  • Where possible, an automated registration/randomisation service is recommended to allow trial patients to be entered into the trial at any time to allow for differences in time zones. Where office back-up cover is provided, timing of this cover should be made clear within the protocol e.g. between 09:00-17:00 GMT.
  • Consider the use of a web-based registration/randomisation system as well as telephone based registration/randomisation service. Automated telephone services may be difficult for some international sites to follow if this service is in English.  If this is not possible, it is recommended that sites are provided with a script of the questions that will be asked over the registration/randomisation service to assist with this.
  • Use international dialling codes for any telephone/fax numbers included in the protocols e.g. +44 (0) XXXXXXXXXX.
  • Keep the protocol as clear and simple as possible to ensure good compliance across all sites. Protocols can often be quite long documents, streamlining the protocol to only include essential information may help with implementation across sites and reduce the need for future amendments.
  • Do you need to include a cap on number of international patients recruited overall or by each country? E.g. if the trial is funded by a UK funder, do you need to ensure that a certain number of UK patients are included? Recruitment of a lot of patients from one particular site/country could limit external validity of the trial. Capping recruitment by sites/country will help to ensure results are more generalizable.