V2.3 Last updated October 2019 - Please note: This guidance relates to post approval submissions and end of trial notifications for applications which have been submitted and approved via the Combined Ways of Working Pilot only.
Step 1: Submission
A PDF version of the form should be submitted along with any documents which are being amended via Eudralink to the Clinical Trials Helpline (firstname.lastname@example.org) including CWoW in the subject title. Please also e-mail email@example.com to confirm submission.
Where information in the EudraCT Annex I form is being amended, an updated version of the xml should also be provided. The changes may be highlighted but this is not mandatory.
Addition of a new site
If the amendment is to add a NHS/HSC site, please refer to the guidance available in IRAS. Please note that for the addition of non NHS/HSC sites, the requirements are the same as non CWoW trials with the exception of the substantial amendment being submitted via Eudralink. NHS/HSC SSI forms for NI and Scotland must continue to be submitted directly to the site.
If the amendment is to add a non NHS/HSC site, the template which can be found here, should be completed and a PDF version submitted via Eudralink to the Clinical Trials Helpline (firstname.lastname@example.org). with the substantial amendment form, PI CV and any other required documents.
Please note the following:
- All substantial amendments should be numbered sequentially, this includes substantial amendments to add a new site and PI.
- Submitting new substantial amendments when a substantial amendment is awaiting approval should be avoided (with the exception of the addition of a new site and PI). If there is an urgent requirement to submit a new substantial amendment when a substantial amendment is under review for the same trial, please contact email@example.com prior to submission of the new substantial amendment.
- Multiple amendments for the same trial may be submitted together in the same substantial amendment form; however, the sponsor is advised that rejection of any part of an amendment may require resubmission of the full amendment application. Under the Medicines for Human Use (Clinical Trials) Regulation 2004, an opinion can only be issued on the substantial amendment in its entirety. Therefore, if any part of the substantial amendment cannot be approved, none of the substantial amendment within the request can be approved. Therefore, sponsors should be mindful to avoid submitting numerous and/or broad ranging amendments within the same substantial amendment form. However, under the Combined Ways of Working pilot a request for further information may be made by either the MHRA or the REC (time permitting – the maximum timeline of 35 would still apply). The purpose of this is to avoid issuing a rejection where this could be achieved with the provision of further information. If any substantial amendment is considered urgent then this should be submitted as a separate substantial amendment; this is to avoid the risk of the urgent amendment being rejected or delayed because other substantial amendments submitted using the same form have been rejected or have a request for further information.
- For trials taking part in the NHS: In addition to the MHRA and REC decision, the existing process for supporting implementation through categorisation and HRA (England) and HCRW (Wales) approval will continue.
- Only substantial amendments should be submitted via this route. Amendments to studies taking place in the NHS (or HSC in Northern Ireland) which do not meet the criteria for a substantial amendment (substantial amendment details for the MHRA can be found here and details for the REC and HRA/HCRW Approval can be found here) should be submitted via the standard process for non-substantial amendments, as per the guidance found here.
- For substantial amendments which relate to an updated Investigator Brochure only, please ensure these are only submitted when required. In particular, these substantial amendments should not be submitted for REC review unless there is a safety update which will affect the welfare of current or future trial participants and will therefore need to be reflected in the participant information documents.
- A covering letter should be provided which contains the following table (in addition to what would standardly be included in the covering letter). Please indicate in the right hand column which documents are being submitted with the substantial amendment and, where relevant, the updated version number and/or document date.
|1. Substantial amendment form|
|3. Investigator's Brochure (IB)|
|4. Documentation relating to compliance with good manufacturing practice (GMP) for the investigational medicinal product|
|5. Investigational medicinal product dossier (IMPD)|
|6. Auxiliary (ie non-IMP) medicinal product dossier|
|7. Content of labeling of the investigational medicinal products|
|8. Recruitment arrangements|
|9. Subject information, informed consent form and informed consent procedure|
|10. New investigator|
|11. New site|
|12. Proof that data will be processed in compliance with union law on data protection|
|13. Other: please state below|
Step 2: Validation
Validation checks will be completed on the substantial amendment by the MHRA within 3 days. This will involve checking that all of the relevant documents (as stated in the substantial amendment table copied to the covering letter) have been submitted, and are readable. One validation check will be undertaken for the entire substantial amendment and only one validation letter will be issued by the MHRA. For substantial amendments to trials which involve sites in the NHS, the confirmation of categorisation will not be provided with the validation but will follow shortly afterwards.
Step 3: Co-ordinated assessment
The MHRA will determine whether the substantial amendment needs to be reviewed by the MHRA, the REC or both. This will be based on the information which is provided in the substantial amendment form (section A) and the information provided in the covering letter. Substantial amendments that need to be reviewed by the REC only will not incur a fee.
Where applicable, the relevant documents will be provided to the REC by the MHRA.
Step 4: Issuing an opinion
The final decision will be issued within 35 days. This will be a single e-mail with decision letter(s) attached.
Safety reports and progress reports
Safety reports and progress reports should continue to be submitted as per standard process for non CWoW applications until further notice.
End of trial notifications
Step 1: Submission
End of trial notifications should be submitted via IRAS.
If the trial has ended prematurely then a substantial amendment should also be submitted where it is necessary to seek ethical review of related actions such as informing participants and arranging continuing care and follow-up outside the trial.
***Please complete the end of trial notification form. A PDF version should be uploaded to IRAS by adding a new document row to the checklist:
When you are ready to submit an end of trial notification, please e-mail firstname.lastname@example.org to request that e-submission is enabled.
Step 2: Acknowledgement
You will receive confirmation that the end of trial declaration has been received.
Where a trial has been terminated prematurely you may receive further correspondence which requests further information or further action but this will be on a case by case basis.
Summary of version changes
|Document title||To reflect the broader scope of the document to include post approvals submissions other than amendments and end of trial notifications||2.3||7.10.19|
|Safety reports and progress reports||Section added to confirm that these reports should continue to be submitted as per normal process||2.3||7.10.19|
|Submission||Submission of substantial amendments should be via Eudralink and no longer via IRAS (until further notice)||2.1||3.5.19|
|Submission||All substantial amendments should be numbered sequentially, including the addition of a new site and PI||2.1||3.5.19|
|Submission||The submission of a new substantial amendment when an existing substantial amendment is under review should be avoided where possible||2.1||3.5.19|
|Submission||Clarify that substantial amendments to add a new site and PI should be submitted via Eudralink||2.1||3.5.19|
|Submission||Clarification that substantial amendments which are an update to the IB should only be submitted when required||2.1||3.5.19|