Any substantial amendments
European Standard form: Substantial Amendment Notification Form
Submissions shall be made through the Common European Submission Platform (CESP).
From date of receipt of valid application
By explicit (written) notification
Detailed Guidance is available on the MHRA website: "Clinical trials for medicines: manage your authorisation, report safety issues - Change your protocol, update your authorisation, report safety issues, submit safety updates and complete your end-of-trial study report"
Part 3 sections 22-24 of the Medicines for Human Use (Clinical Trial) Regulations 2004