Change your protocol, update your authorisation, report safety issues, submit safety updates and complete your end-of-trial study report.
Reference Safety Information – updated guidance
The Clinical Trials Facilitation Group (CTFG) has updated the guidance for the reference safety information (RSI) for a clinical trial. The update, in the form of a Q&A document, follows detailed discussions between national competent authorities and sponsors, which arose from Clinical Trial application and substantial amendment procedures as well as GCP inspections. The full guidance can be found on the HMA website. As per the CTFG cover note, MHRA recommends full compliance with the Q&A from 1 January 2019.
Apply to change your trial’s protocol or documentation
These changes count as a substantial amendment to your clinical trial authorisation. You need to send a notification of amendment form, a revised application form and other documents to the Medicines and Healthcare Products Regulatory Agency (MHRA):
- covering letter outlining the substantial and any non-substantial changes
- signed notification of amendment form from the European Commission website
- updated XML and PDF versions of the clinical trial application form if it’s changed since the last submission
- reasons for the proposed changes
- proposed changes to the protocol or other document (eg investigational medicinal product dossier), showing previous and new wording
supporting data for the change, including:
- summaries of data
- updated overall risk-benefit assessment
- possible consequences for subjects already in the trial
- possible consequences for the evaluation of results
Submissions through the Common European Submission Portal (CESP)
Please make your submission through the Common European Submission Platform (CESP).
This system is available from the Heads of Medicines Agencies (HMA) and provides a simple and secure mechanism for exchange of information between applicants and regulatory agencies.
The purpose of the system is to:
- provide a secure method of communicating with regulatory agencies via one platform
- allow submission of an application once to reach all required agencies
- reduce the burden for both industry and regulators of submitting/handling applications on CD-ROM and DVD
If you are a first time CESP user and wish to setup up an organisation/university or trust to manage multiple users on the system, register with CESP here.
If you are a standalone user and wish to upload for Non Commercial Use on your own behalf, register with CESP here.
Once registered you will receive credentials to access the portal to your registered email address.
Please view MHRA clinical trials guidelines here.
General CESP training is available to all registered users via CESP’s training menu once logged into the system. Training on demand videos are available and you can also sign up to our free online weekly live demonstrations. CESP encourage all users to attend training before using the system.
View FAQs here.
Clinical trial applicants can also view the MHRA Clinical Trials Guidelines document.
We will assess your application within 35 days. Healthy volunteer trials and sponsor-determined phase I trials in non-oncology patients may qualify for a shorter assessment time (average 14 days). State in the heading of your covering letter if you think your trial is eligible.
If your application does not meet the requirements it will not be assessed. You will be told the reasons why your application is invalid, which could include:
- incomplete notification of amendment form
- required documents missing
Check theto ensure you’re submitting a valid application.
For queries about electronic documents and submissions email RIS.CT@mhra.gov.uk.
Outcome of assessment
We will tell you the outcome of your application by post or by email if you are based overseas.
If your application is not successful we will tell you why and you may resubmit your application.
There is a single fee of £225 for changes that need assessment, regardless of the number of assessor disciplines involved in the assessment.
Make a payment to MHRA
You can pay online, by cheque or by BACs transfer.
When paying you should quote your EudraCT number in the ‘MHRA 1 reference/invoice number’ field.
For further information on how to pay fees contact MHRA Finance Department on 020 3080 6533 or email: email@example.com.
Change your contact details
You should send an email entitled ‘Change to Contact Details of the contact person for a CTA (Number XXXXX/XXXX/XXX-XXXX) – EudraCT Number XXXX/XXXXXX/XX’.
The email must be sent as a signed and scanned attachment by the contact person listed on the application form and must include:
- EudraCT number
- CTA number
- Protocol number
- details of the previous contact person and/or contact details
- details of the new contact person and/or contact details, to include:
The new contact person or details should be updated on the application form (which is part of your initial application form) and an updated XML should be included in the next submission of a substantial amendment so that the details can be uploaded into EudraCT.
Change of legal representative
If you want to change the legal representative for your study you must submit a substantial amendment to MHRA. You may include other changes along with this amendment, but must ensure the covering letter clearly highlights there is also a change of legal representative.
There is no fee for this kind of submission unless other, additional amendments to the trial documentation are included.
Change of sponsor
If you want to change the sponsor for your study you must submit a substantial amendment to MHRA. You must not include any other changes with this amendment.
You can’t submit any other substantial amendments until you have confirmation from MHRA that the sponsor has been changed.
You must include these documents with your submission:
- a cover letter that includes the date of transfer of responsibilities
- a letter on headed company paper from the current sponsor confirming the transfer of the study
- a letter on headed company paper from the new sponsor confirming that they accept the role of sponsor for this study
- a signed notification of amendment (Annex 2) form (PDF)
- an updated PDF and xml file of the clinical trial application form (Annex I) signed by the new sponsor or person acting on behalf of the sponsor
Other company documents should not be submitted as part of this submission, e.g. protocol. There is no fee for a change of sponsor amendment. During the assessment of your amendment the old and new sponsor will receive an administrative letter confirming that the change has been registered. You don’t need to wait for MHRA confirmation before making the sponsor change,
Clinical trials named contact
Effective from 27 June 2016, persons other than the applicant named in the trial application form, who call or email the MHRA CTU helpline, reports to be from the sponsor/applicants company and knows the EudraCT number and security word/phrase (previously provided to MHRA by the named applicant) for a trial may obtain information on that trial.
For ongoing studies, the applicant named in section C.1 of the application form should notify the Clinical Trials Unit of their chosen security word/phrase by emailing firstname.lastname@example.org with ‘Clinical Trials named contact’ as the subject line and listing the EudraCT number(s) in the body of the email.
For new applications, the applicant named in section C.1 of the application form is requested to include the security word/phrase in the cover letter for the submission.
Urgent safety measures
In order to determine whether the action you are taking is an Urgent Safety Measure (USM) please refer to section 3.9 and 3.10 (142-150) of guidance document CT-1.
Call the MHRA’s Clinical Trials Unit on 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken. Please call no later than 3 days from the date the measures are taken. If we need more information a medical assessor will contact you.
Information you will be asked for on the call:
- EudraCT number (including for other trials which may potentially be affected) of the trials for which USM action has been taken
- EudraCT number of other ongoing trials with the same Investigational Medicinal Product
- Whether any other trials with a different sponsor may be impacted and whether the concerned investigators have been made aware
- The affected IMPs (including alternative/ Commercial names)
- Nature of the safety signal, and whether have there been any SUSARs
- What immediate safety actions have been taken and when
- The number of UK subjects who are currently receiving the IMP, the number of subjects who received it and the number affected by the USM
- Contact details in case of further questions
Where this information is not available during the initial call it should be provided as soon as possible.
You must then inform MHRA no later than 3 days from the date the measures are taken by email to email@example.com. Written notification in the form of a substantial amendment (annex 2) is also required.
The substantial amendment covering the changes made as part of the Urgent Safety Measure is anticipated within approximately 2 weeks of notification to the MHRA.
Any potential reason for delay to submission of the substantial amendment should be discussed and agreed with the MHRA at the time of initial notification or through a follow up call.
Submission of the substantial amendment should not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection.
When submitting your substantial amendment via CESP please select ‘Regulatory Activity Type: Clinical Trial’. Do not select ‘Urgent Safety Restriction Procedure’.
USM in trials approved under the Voluntary Harmonisation Procedure (VHP)
Where a USM affects a trial approved through VHP callers are advised to include VHP reference(s) in all correspondence and follow these steps:
- Follow country specific USM procedures – see above for UK.
- Inform VHP-Coordinator via email at firstname.lastname@example.org
- Submit substantial amendment to VHP as per usual route followed by the national application
Submitting substantial amendments to NCAs before their VHP approval will result in your application falling out of the VHP process.
You must report all suspected unexpected serious adverse reactions (SUSARs) which happen during the course of the trial to MHRA.
You must report fatal or life-threatening SUSARs as soon as possible, but no later than 7 days after you are first aware of the reaction. Any additional relevant information must be sent within 8 days of the report.
You must report non-fatal or non-life-threatening SUSARs as soon as possible but no later than 15 days after you are first aware of the reaction.
You must report all UK-relevant SUSARs to MHRA.
The agency’s definition of ‘UK-relevant’ includes:
- SUSARs originating in the UK
- SUSARs originating outside the UK where the sponsor has an ongoing trial in the UK involving the same medicinal product
You must keep detailed records of all adverse reactions relating to a clinical trial. MHRA may require you to send copies of records if there is an investigation.
Further information is on the European Commission website.
Report a SUSAR in 1 of the following ways:
You will need to register your details with us before using the eSUSAR website. You should complete the email@example.com with the subject line ‘eSUSAR registration’.and email it to
Information that you need to include in a SUSAR report can be found on the European Commission website.
For a copy of MHRA’s eSUSAR guide email firstname.lastname@example.org.
SUSARs which were not submitted via eSUSAR portal during the EudraVigilance cutover period 8-21 November 2017 should be submitted via EudraVigilance or EVWEB. SUSARs submitted to the MHRA via email during this time will not be submitted on your behalf
Submit development safety update reports (DSURs)
Your development safety update reports (DSURs) should take into account all new available safety information received during the reporting period.
The DSUR should include:
- a cover letter listing all EudraCT numbers of trials covered by the DSUR, including any trials approved via the VHP process. Please include an email address for correspondence.
- an analysis of the subjects’ safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
- a line listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s), including all SUSARs from third countries
- an aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)
Full details of what to include in a DSUR are on the European Commission website.
You must submit your DSUR using CESP. The same guidance for submitting clinical trials applications via CESP applies, but please select regulatory activity G0042 - Development Safety Update Reports.
MHRA will no longer be sending acknowledgements for DSUR. Please use your CESP submission details as evidence of your DSUR submission for your master file to demonstrate compliance with GCP.
At the end of the DSUR reporting period the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the investigator’s brochure as a substantial amendment. This amendment should be supported by the DSUR and approved before the reference safety information (RSI) is changed.
The RSI for any investigational medicinal product involved in a clinical trial must stay consistent during each reporting period.
Shortened DSUR available for Notification scheme approved trials
This is suitable for individual trials authorised under the Notification scheme which are not part of a multi-study development programme. As an alternative to producing a full DSUR for these trials you may use the Health Research Authority Annual Progress Report form which can be found here: https://www.hra.nhs.uk/documents/1013/annual-report-form-for-ctimps.docx
Please indicate in your cover letter that this is an Annual Progress Report (APR) in lieu of a full DSUR and include the EudraCT number and CTA reference number. You should include a list of all Serious Adverse Reactions in section 6 of the APR.
Suspend or terminate a trial
MHRA has the authority to make amendments to an authorisation or in certain circumstances suspend or terminate a trial. You can apply to MHRA to suspend or terminate your own trial.
Suspend a trial temporarily
If you suspend a trial temporarily you must notify MHRA and the Research Ethics Committee (REC) immediately or at least within 15 days.
The notification should be made as a substantial amendment using the notification of amendment form, clearly explaining what has been stopped and the reasons for the suspension.
Substantial amendments relating to temporary suspension and urgent safety measures must be submitted using CESP.
To restart a trial that has been temporarily suspended, you should make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.
Terminate a trial
End of trial
A declaration of the end of a clinical trial should be sent to MHRA within 90 days of the global end of the trial.
Any trial activities (i.e. follow-ups, visits) should be completed before the submission of the end of trial declaration form.
It is not possible to submit amendments to the trial once the declaration form has been received.
You must submit your end of trial declarations via CESP.
End of trial study report
The sponsor is responsible for uploading the end of trial summary results to EudraCT as per the commission’s guidelines on posting and publication of result-related information. The time frame for posting the summary is within six months of the end of trial for paediatric clinical trials or within one year of the end of trial for non-paediatric clinical trials.
You don’t need to submit this clinical trial summary report to the MHRA as well however you must send a short confirmatory email to CT.Submission@mhra.gov.uk once the result-related information has been uploaded to EudraCT, with ‘End of trial : result-related information: EudraCT XXXX-XXXXXX-XX’ as the subject line. You will not get an acknowledgment email or letter.
For information about your submission, including status and tracking enquiries, contact the clinical trials helpline on 020 3080 6456 (Monday to Friday 8:30am to 4.30pm) or email email@example.com. See Clinical trials named contact for further information.