Research Governance – International Surgical Trials Toolkit

Any trial must abide by the regulations which govern participating countries.

As regulatory frameworks vary widely between different nations, establishing the specific requirements of regulatory bodies within each country, and anticipating how the trial team will ensure requirements are adhered to, is an important activity to initiate during the early stages of trial set up.

Trials must adhere to the regulatory framework of the country in which they are run; coordinating centres cannot mandate regulations and principles in-country. However the requirements of Sponsors and funders must be adhered to, with the Sponsor and funder acknowledging the need to accommodate diversity in the regulatory environment.

Sponsors of international trials must develop processes and approaches to facilitate the delivery of such trials: this is an essential consideration for a multinational trial.

Developing Protocol and Patient-Facing Documents

Identifiying Regulatory Framework(s)

Overarching Considerations

Although protocol development is covered in greater detail in a separate section, a key component in effective development of the protocol and patient-facing documents is to create flexibility which will allow collaborators to observe the principles of their own local regulatory frameworks, while also ensuring that UK regulations can be adhered to.

Protocols should be adaptable so that country- or site- specific information can be modified according to local requirements. Common considerations may be:

What is the age of majority?
Due to different definitions between countries, it may be necessary to adhere to regulations governing the recruitment of vulnerable populations in some participating nations.
Who is permitted to take trial-specific consent?
Appropriately trained nurses may be permitted to take consent dependent on country-specific guidelines; it may also be a requirement for operative and trial consent to be taken by different members of the clinical team.
Are any of the trial interventions considered an ‘IMP’?
The answer to this question has significant ramifications which may alter the way in which the trial operates with regards to regulatory requirements, interventions supply, safety reporting, etc. It is essential that if the trial does constitute a CTIMP in any of the participating nations, it has been identified as such from the outset.

Input from collaborators is essential in establishing local requirements and anticipating queries from regulatory bodies.

In the process of determining in-country regulations, the following points may be considered:

Which are the regulatory bodies in each country? Do regulatory approvals apply country-wide or are approvals required at a regional or hospital level?
Are any approvals required in addition to ethical clearance, for example, review by an Institutional Review Board or Scientific Committee? If so, must submissions be submitted in a particular order, or can they be submitted in tandem?
These considerations will impact the order in which applications will be submitted and the timelines associated with trial submissions in each country.

Trial Submission Process

Once the regulatory framework has been determined in each country, there are manifold variables which will affect the way in which submissions to regulatory bodies are made. Some points to consider while navigating this process are listed below:

Do regulatory bodies mandate the language in which the application must be made? Which documents require translation? In which language will the body’s response/approval be written? Will it be necessary to translate the communication?
It may be that while the application is accepted in English, patient information or other trial documents must be translated into local dialects and submitted as part of the application. Collaborators may offer to assist in the translation process, or translators may be procured directly; either way, it may be necessary to back-translate the document, to ensure the translation is accurate or at least conceptually true to the original text.
Are there any specific requirements for the application?
Regulatory bodies may request information to be submitted in specific formats; for example, finance schedules may be embedded in trial contracts; whereas a local regulatory body may wish to receive all finance information in one standalone document. It may be necessary to create or delegate responsibility for the creation of new documents which are specifically aimed at addressing requirements for each regulatory body.
Are there any costs associated with trial submissions?
These costs may vary dependent on the type of trial, type of submission, how the trial is funded, etc, and should be factored in when costing the trial.
How, and to whom, will application costs be paid?
If applications are prepared prior to contracts and payment routes being established, it will be necessary to consider how participating countries will receive money for trial applications.
Who will be responsible for responding to non-acceptance letters?
If the regulatory body does not approve the trial, careful consideration should be given regarding how to respond to the outcome.

Ongoing Obligations Following Regulatory Approval

Given the potentially heterogenous nature of the regulatory framework, there may be ongoing obligations that should be considered following approval, for example:

Upon approval, are there any unique conditions upon which the approval has been granted? For example, does the board mandate annual progress or safety reporting?
Approvals must be monitored to ensure that conditions are adhered to. Which organisation is responsible for ensuring that conditions are adhered to should be delineated in the contract; however, the coordinating centre may wish to record unique conditions centrally to ensure that obligations are adhered to.

The regulatory infrastructure may have broader significance than simply delivering research governance in-country. For example, Investigators may be unable to approach potential collaborators in-country until regulatory approvals have been obtained. This may influence the rate at which a multicentre trial can be delivered, which should be factored into site activation timelines and recruitment projections.

As with any trial, the research governance infrastructure may be subject to change or adaptation at any time. It is therefore key to ensure that collaborators report any changes which might influence the way in which the trial is run or approval to conduct the trial to the coordinating centre as soon as possible.

Dependent on resourcing, it may be possible to procure an in-country NGO with relevant experience in the regulatory framework and trials submissions process.

Standard GCP training materials may be too abstract for all of the participating countries who may not have research infrastructure comparable to that of the UK, therefore it may be necessary to utilise a more targeted adaptation of GCP training; a link to a global health –specific GCP training course is linked in the further resources section.

Exploring whether research activities have taken place in each country which have been coordinated from the UK may be useful in identifying contacts with local expertise. Identifying any obstacles or potential barriers from the outset will help to avoid delays in set up.