Guidance

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.

As of 1 January 2022 the combined review service, formerly known as Combined Ways of Working (CWoW), is now the way that all new Clinical Trials of Investigational Medicinal Products (CTIMPs) applications are prepared, submitted and reviewed. Combined review offers a single application route and co-ordinated review leading to a single UK decision for CTIMPs.

Please note: CTIMP initial applications via combined review should be started and submitted using the new part of Integrated Research Application System (IRAS) and not in the standard part of IRAS. While the regulatory requirements and fees remain the same, the application submission, processing and assessment steps outlined below refer to non-combined review applications. For Combined review applications please refer to the Health Research Authority website.

Clinical Trials and coronavirus (COVID-19)

We have published guidance on managing clinical trials during the COVID-19 outbreak, and on clinical trials applications for COVID-19.

Amending your trial protocol or other documentation

Only substantial amendments need to be submitted to the MHRA. Changes count as a substantial amendment to your clinical trial authorisation if the amendment is likely to affect to a significant degree

(a) the safety or physical or mental integrity of the subjects of the trial,

(b) the scientific value of the trial,

(c) the conduct or management of the trial, or

(d) the quality or safety of any investigational medicinal product used in the trial.

For clinical trials authorised via the combined review process you should prepare and submit using new part of Integrated Research Application System (IRAS).

For clinical trials not approved or yet transitioned over to the combined review process, you should continue to use MHRA submissions. Further details on how to register and submit via this platform.

You need to send the following documents to the Medicines and Healthcare products Regulatory Agency (MHRA):

  • Covering letter detailing the trial reference numbers (IRAS ID, CTA number, EudraCT etc) along with Purchase Order Number, outlining the substantial changes (if there have been any non-substantial changes please also outline these separately)
  • A PDF copy of the locked Amendment tool. You should ensure that the amendment tool contains a clear description of the substantial amendment and reasons for the proposed changes. Alternatively, for ‘bulk’ amendments (where the same change affects many trials), the substantial amendment notification form** can be completed and submitted. The form is available here.
  • PDF file of the Clinical Trial Authorisation application form* generated in IRAS with changes highlighted, if the amendment affects the information previously submitted.
  • List of the proposed changes to the protocol or any other documents (e.g. IMPD) compared to the current MHRA-approved document, showing previous and new wording where applicable and a rationale to justify each substantial change. If applicable the following should be provided:
    • Summaries of data
    • Updated overall risk benefit assessment
    • Possible consequences for subjects already in the trial
    • Possible consequences for the evaluation of results

Assessment process

We will assess your application within 35 days. If you consider your trial requires an expedited assessment (for example, patient safety reasons), this should be stated in the covering letter along with the rationale for the expedited assessment request.

Invalid applications

If your application does not meet the requirements it will not be assessed. You will be told the reasons why your application is invalid.

Check the Common issues identified during clinical trial applications guidance (PDF, 43KB, 1 page) to ensure you’re submitting a valid application.

For queries about electronic documents and submissions email CT.Submission@mhra.gov.uk.

Withdraw your application before the final decision

You may withdraw your application at any point before an assessment decision on your substantial amendment is reached. To withdraw your application you should send an email to clintrialhelpline@mhra.gov.uk.

For applications that have gone through the Combined Review process, please refer to the guidance on the HRA website.

Outcome of assessment

We will tell you the outcome of your application by email.

If your application is not successful, we will tell you why and you may resubmit your application.

Fees

There are different fees based on your type of clinical trial application.

Please see the Make a payment to MHRA page on how to pay relevant fees.

Invoices for Clinical Trial Authorisation applications, and Substantial Amendment applications are sent directly to the applicant shortly after a valid submission has been established. The covering letter for the application should clearly highlight your Purchase Order (PO) number where available. The applicant is the person listed in section C1 of the Clinical Trial Application form, or section D1 of the Amendment form. We are unable to address the invoice to someone other than those listed in the sections above.

It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. Penalty fees may be incurred for non-payment, details of the penalties are set out in the Fees Regulations. Non-payment may also result in suspension of any licence or authorisation, followed by legal proceedings for unpaid amounts, as a debt due to the Crown.

You can contact MHRA Finance Department on 020 3080 6533 or email Sales.Invoices@mhra.gov.uk for more information on how to pay fees.

Change your contact details

For applications that have gone through the Combined Review process, please refer to the HRA website.

You should send an email entitled ‘Change to Contact Details of the contact person CTA Number XXXXX/XXXX/XXX-XXXX – EudraCT Number XXXX/XXXXXX/XX – IRAS ID XXXXXXX’.

Email: CT.Submission@mhra.gov.uk

The email should be sent by the contact person listed on the current application form, or other authorised persons and must include:

  • IRAS ID and/or EudraCT number
  • CTA number
  • details of the previous contact person and/or contact details
  • details of the new contact person and/or contact details

The new contact person or details should be updated on an updated application form. A copy of the updated application form should be included in the next substantial amendment.

For applications that have gone through the Combined Review process, please refer to the HRA website.

If you want to change the legal representative for your study, you must submit a substantial amendment to the 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. The submission must include a Clinical Trial Application form updated with the details of the new legal representative along the amendment tool.

There is no fee for this kind of submission unless other, additional amendments to the trial documentation are included.

Change of Sponsor

For applications that have gone through the Combined Review process, please refer to the HRA website.

If you want to change the Sponsor for your study, you must submit a substantial amendment to the MHRA. You must not include any other changes with this amendment.

You can’t submit any other substantial amendments until you have confirmation from the 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
  • an amendment form
  • an updated PDF file of the clinical trial application form signed by the new Sponsor or person acting on behalf of the Sponsor

Other trial related documents should not be submitted as part of this submission, e.g. protocol. There is no fee for a change of Sponsor amendment. The applicant 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, reporting to be from the Sponsor/applicant company knowing the EudraCT number and security word/phrase (previously provided to the 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 clintrialhelpline@mhra.gov.uk 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.

Reference Safety Information – updated guidance

Published guidance such as CT1 and CT3 and the CTFG Q&A on Reference Safety Information (RSI) remain applicable as a source of materials for understanding what the obligations entail in so far as they relate to the UK as a sovereign regulator. This will also help facilitate acceptance of the RSI in multinational clinical trials.

Additional guidance can be found here: Reference Safety Information (RSI) for Clinical Trials- Part III - MHRA Inspectorate (blog.gov.uk).

UK-specific clarifications:

  • As per current expectations, for trials that are being conducted in the UK, an RSI cannot be used for expectedness until it has approval from the MHRA. Thus, if additional SUSARs occur before the new RSI is approved, these should be reported as SUSARs in the usual expedited manner. If Sponsors wish to harmonise the implementation date of an RSI in a trial that includes EU and UK sites, then this can be the date where approval has been granted in all member states and the UK. In the interest of efficiency and harmonisation for multinational trials it is recommended that amendments including changes to the RSI are submitted to the UK and EU at the same time
  • The RSI approved by the regulatory authority at the time of occurrence of the ‘suspected’ SAR should be used to assess expectedness for both initial and follow up reports
  • For DSURs the Sponsor is reminded to use the RSI that was approved at the beginning of the reporting period by both the MHRA and European Member States.

Urgent Safety Measures

In order to determine whether the action you are taking is an Urgent Safety Measure (USM) please refer to regulation 30 of the Statutory Instrument (SI) 2004 Number 1031.

Call the MHRA’s Clinical Trials Unit on 020 3080 6456 to discuss the issue with a medical assessor, ideally within 24 hours of measures being taken. Please call no later than 3 days from the date the measures are taken.

Information you will be asked for on the call:

    1. The IRAS ID and/or the EudraCT number of; a. The trials for which USM action has been taken, b. Other ongoing trials with the same Investigational Medicinal Product(s) (IMP(s)) c. Trials run by a different Sponsor affected by the USM action
  1. The affected IMP(s) - commercial or developmental names
  2. Nature of the safety concern and whether it has been reported as a SUSAR
  3. Which USMs have been taken and when
  4. 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
  5. 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.

After discussing the USM with the MHRA assessor via phone you must provide the MHRA with written notification of the measures taken and discussed with the medical assessor, within 3 days from the date the measures were taken. For trials not approved via Combined Review you will be instructed to send an email to the medical assessor who assessed the USM over the phone, clintrialhelpline@mhra.gov.uk.

If at least one of the trials covered by the DSUR has gone through the Combined Review process, then the report should be submitted via the Integrated Research Application System (IRAS). More information can be found on the Health Research Authority (HRA) website.

Notification of a substantial amendment (Amendment tool plus any updated document including the changes agreed with the medical assessor) is also required. The substantial amendment covering the changes made as part of the USM should be submitted within approximately two weeks of notification to the MHRA.

Any potential reason for delay to submission of the substantial amendment should be discussed and agreed with the medical assessor at the time of initial notification or through a follow up call.

The USM-related substantial amendment must not include changes different from those required as an urgent safety measure. This is due to the fact that unrelated changes may result in rejection.

Please submit your substantial amendment using MHRA Submissions via the Human Medicines Tile. Please select ‘Clinical Trial’ as the Regulatory Activity and ‘CT - Amendment’ from the Regulatory sub activity dropdown list.

If your trial has gone through the Combined Review process, then the substantial amendment should be submitted via IRAS. More information on how to submit a Substantial Amendment via IRAS can be found on HRA’s website.

If you are not able to report a USM to the MHRA via the phone please send an email to clintrialhelpline@mhra.gov.uk within 3 days of taking urgent measures. The subject of the email will be ‘USM for trial IRAS ID/EudraCT number’. Please explain in the email the USM implemented, the reason and why you did not report it via phone. An MHRA assessor will contact you and provide advice regarding further actions.

Suspected Unexpected Serious Adverse Reactions (SUSARs)

The Sponsor of the trial or any other person to whom the Sponsor has delegated this responsibility to must report all suspected unexpected serious adverse reactions (SUSARs) which happen during the course of the trial to the MHRA.

Fatal or life-threatening SUSARs must be reported 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 initial report.

Non-fatal or non-life-threatening SUSARs must be reported as soon as possible but no later than 15 days after you are first aware of the reaction.

The Sponsor of a ‘trial performed in the UK’ (UK trial) must report the following UK-relevant SUSARs to the MHRA:

  • All SUSARs occurring in that trial in UK sites
  • All SUSARs occurring in that trial in sites outside the UK

  • All SUSARs originating in a non-UK trial of the same medicinal product if the trial is run by the same Sponsor of the trial running in the UK
  • All SUSARs originating in a non-UK trial of the same medicinal product if the Sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the Sponsor of the UK trial.

You must keep detailed records of all adverse reactions relating to a clinical trial. The MHRA may require you to send copies of records if there is an investigation.

Further information can be found in The Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No.1031.

Report a SUSAR to the MHRA in one of the following ways:

  • using the eSUSAR website. You will need to register your details with us before using the eSUSAR website. You should complete the eSUSAR registration form and email it to esusar@mhra.gov.uk with the subject line ‘eSUSAR registration’.
  • using ICSR Submissions, which replaces the EudraVigilance website (EVWB). The ICSR Submissions route is used to submit single reports.
  • using the MHRA Gateway, which replaces the Eudravigilance Gateway. The Gateway route is used to submit bulk reports. To gain access to the MHRA Gateway you need to register to another portal called MHRA Submissions.

If applicable, you will need to dual report UK-relevant SUSARs to the EMA’s Eudravigilance Clinical Trial Module (EVCTM), as well as to other National Competent Authorities, using the European submission routes.

Development Safety Update Reports (DSURs)

Your DSURs should take into account all new available safety information received during the reporting period.

The DSUR should include:

  • a cover letter listing all the IRAS IDs and/or EudraCT numbers of trials covered by the DSUR. 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)
  • Region-specific information as per Guideline on how to increase transparency (see below)

Full details of what to include in a DSUR can be found in the ICH E2F guidance.

You must submit your DSUR using MHRA Submissions via the Human Medicines Tile. Please select ‘Development Safety Update Report’ as the Regulatory Activity and ‘Other’ from the Regulatory sub activity dropdown list. Acknowledgements of receipt for DSUR submissions are generated by MHRA Submissions where a confirmation of submission is emailed to the reporter.

If at least one of the trials covered by the DSUR has gone through the Combined Review process, then the report should be submitted via the Integrated Research Application System (IRAS). More information can be found on the Health Research Authority (HRA) website.

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 must be supported by the DSUR and approved before the reference safety information (RSI) is changed.

Guideline on how to increase transparency when presenting safety information in the Development Safety Update Report (DSUR): region-specific requirements for Canada and the United Kingdom

In order to increase the transparency of the data included in DSURs prepared by manufacturers and/or marketing authorisation holders of an investigational drug the MHRA and Health Canada are asking that the region-specific information section of the DSUR is used to explain how safety data were reviewed during the reporting period.

Please see Guidance document (PDF, 65.6KB, 4 pages) for more details.

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.
  • phase 4 national (UK only) trials of licensed products that commanded a low fee from the MHRA and where all participants have completed treatment and are only in follow-up.

As an alternative to producing a full DSUR for these trials you may use the Health Research Authority Annual Progress Report.

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

The MHRA has the authority to make amendments to an authorisation or in certain circumstances suspend or terminate a trial. The Sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial.

Suspend a trial temporarily

If you suspend a trial temporarily you must notify the MHRA.

The notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension.

Substantial amendments relating to temporary suspension must be submitted using MHRA Submissions via the Human Medicines Tile. Please select ‘Clinical Trial’ as the Regulatory Activity and ‘CT – Amendment’ from the Regulatory sub activity dropdown list.

For applications that have gone through the Combined Review process, please refer to the HRA website.

To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Early termination of a trial

Complete the end of trial declaration form (MS Word Document, 60.5KB) and include a brief explanation of the reasons for ending the trial, particularly where the trial has been terminated early. This form must be submitted using MHRA Submissions via the Human Medicines Tile. Please select ‘Clinical Trial’ as the Regulatory Activity and ‘CT –EOT’ from the Regulatory sub activity dropdown list.

For applications that have gone through the Combined Review process, please refer to the HRA website.

End of trial

A declaration of the end of a clinical trial must be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form and a covering letter.

The legislation only requires the global end of trial to be submitted; however, a facility to inform us of the local (UK) end of trial via the end of trial notification form also exists. Local end of trial notifications will not be acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, we would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received.

If you wish to request an exemption to this requirement this must be done via a substantial amendment for approval. The amendment must clearly state to what documents your proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK.

Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end of trial declaration form.

It is not possible to submit amendments to the trial or the DSUR once the declaration of the global end of the trial form has been received by the MHRA. If the end of trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

You must submit your end of trial declarations using MHRA Submissions via the Human Medicines Tile. Please select ‘Clinical Trial’ as the Regulatory Activity and ‘CT – EOT’ from the Regulatory sub activity dropdown list.

If your trial has gone through the Combined Review process, then the end of trial declaration should be submitted via IRAS. More information on how to submit an end of trial via IRAS can be found on HRA’s website.

Clinical trial summary results

The time frame for publishing the summary of results is within one year of the end of trial. Please also see guidance on Completed Paediatric Studies - submission, processing and assessment.

Where applicable, you should publish your summary results within this timeframe in the public register (or registers) where you have registered your clinical trial.

You do not 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. The subject line of the email notification must state ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ and/or IRAS ID XXXXXXX’ once the result-related information has been uploaded to the public register. If your clinical trial is not on a public register or the results will not be published in the register (for example an adult phase I study), summary results should be submitted via MHRA Submissions. An acknowledgement letter will not be sent for this submission.

If your trial has gone through the Combined Review process, then the end of trial declaration should be submitted via IRAS. More information on how to submit an end of trial via IRAS can be found on HRA’s website.

You should also submit a final report to the Research Ethics Committee within the same timeframe for reporting the summary of results.

Sponsors of trials conducted in UK that are already registered in the EU Register are able to submit results to EudraCT. Steps to follow are described in the EMA webpage ‘Tutorials on posting results’. The MHRA will not be able to update the status of your study in the EU system.

Contact

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 clintrialhelpline@mhra.gov.uk. See Clinical trials named contact for further information.

Published 18 December 2014
Last updated 7 February 2022 + show all updates
  1. Update following transition to the combined review service

  2. Updated note regarding CTIMP applications

  3. Updated information regarding changes to a trial's protocol or documentation.

  4. Updated information on the combined review process.

  5. Added guidance on how to increase transparency when presenting safety information in the Development Safety Update Report (DSUR)

  6. Updated guidance on the submission of summary results.

  7. This document has been updated due to the end of the Brexit transition period to provide information on reporting safety issues and managing authorisations.

  8. Changes to end of trial section. Updates on end of trial legislation, local (UK) end of trial and exemptions.

  9. Updated 'End of trial' guidance to include new EMA information reminding all sponsors of clinical trials conducted in the EU of their obligation to make summaries of results of concluded trials publicly available in the EU Clinical Trials Database (EudraCT).

  10. Updated additional text under “Submit development safety update reports (DSURs)”

  11. Updated the eSUSAR registration form.

  12. Updated the guidance on changing legal representative or sponsor.

  13. Added substantial new information under 'Urgent Safety Measures' section.

  14. Updated Reference Safety Information - updated guidance section

  15. Added note about using CESP submission details as evidence of DSUR submission

  16. Edited the grey box at the top of the page which was about the EudraVigilance cutover period and now contains information on reference safety information. Also changed text in grey box above DSURs.

  17. Updated text in Urgent Safety Measure section

  18. Added information about how to submit SUSARs during the EudraVigilance cutover period, 8-21 November

  19. Information about proof of payment requirements updated.

  20. Updated contact information for fees section.

  21. Updated contact information.

  22. clinical trials named contact information

  23. First published.