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 competent authority (the MHRA in the UK) or the Research Ethics Committee (REC) or;
- a change to the protocol or any other document submitted with the applications,
which significantly affects one of the following:
- 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 in the European Commission Guidance document CT1 (PDF, 878 KB). The sponsor of a trial can make amendments at any time but when an amendment is considered substantial, the sponsor is required to submit a ‘valid notice of amendment’ to the MHRA and/or to the REC using the European Commission Notification of a Substantial Amendment Form (PDF, 47 KB)*.
‘Notice of Substantial Amendment’ forms can be created in the Integrated Research Application System (IRAS). The system also provides guidance on substantial amendments and their submission.
*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.
For CTIMPs, the content and format of the substantial amendment form is defined in Chapter 1 of the Eudralex Volume 10 Clinical Trials GuidelineLink open in a new window.The MHRA web site provides guidance on submitting substantial amendments. The HRA web pages provide further detail on the UK process for effective management of amendments.
In November 2014 for multi-site trials, the process for review of amendments by NHS R&D offices changed. The revised system introduced the categorisation of amendments into Category A, B, or C and also a 35 calendar day default approval of amendments for NHS organisations. The HRA web pages provide further detail on the UK process for effective management of amendments including a form for notifying NHS/HSC R&D office(s) of amendments, which are NOT categorised as Substantial Amendments.
Other applicable regulatory bodies may also wish to be notified of amendments to a trial. Guidance can be found in the IRAS.
The HRA is working to facilitate further coordination across regulation and governance including a review of the process of notifying change to on-going studies to ensure a proportionate approach is taken.
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.