Substantial Amendments follows the Addition of New Sites & Investigators station and precedes the Urgent Safety Measures station. This process occurs in parallel with Safety Reporting, Progress Reporting, Ongoing Management & Monitoring, and GCP & Serious Breach Reporting. It also has the potential to occur simultaneously with an MHRA Inspection, Audit, Addition of New Sites & Investigators, Urgent Safety Measures, Temporary Halt, and Early Termination. Substantial Amendments are a legal requirement which is relevant to all trials.
For Clinical Trials of Investigational Medicinal Products (CTIMPs), a substantial amendment is defined in the UK as a change to the terms of the approval given by either the MHRA or the Research Ethics Committee (REC) or a change to the protocol or any other document submitted with the application, which significantly affects:
- The safety or physical or mental integrity of trial subjects
- The conduct or management of the trial
- The scientific value of the trial
- The quality or safety of any Investigational Medicinal Product (IMP) used in the trial.
The decisions on whether an amendment is substantial or non-substantial should be made by the sponsor. Examples are provided on the HRA website. It is the responsibility of the sponsor to decide whether a substantial amendment requires authorisation, or an ethical opinion, or both. Guidance is provided in the Annex C of the Standard Operating Procedures for Research Ethics Committees document.
Since 2020, project-based research should prepare amendments using the Amendment Tool and the details of how to notify relevant bodies can be accessed from the IRAS website.
The MHRA website provides guidance on submitting substantial amendments (currently, the European Commission form, available from the 'Annex 2' tab of the Amendment Tool, or on the EudraCT website’). The HRA web pages provide further detail on the UK process for effective management of amendments including a link to Guidance on the IRAS website on the completion of the Amendment Tool.
Other applicable regulatory bodies may also wish to be notified of amendments to a trial. Guidance can be found in the IRAS.
All amendments should be reported to the Funder as soon as possible.
- Addition of New Sites & Investigators station – For CTIMPs only; addition of a new site or investigator meets the definition of a substantial amendment.