Version 3.4 Last updated October 2019
The purpose of this information is to provide instructions to sponsors participating in the MHRA regulatory centre and RES Combined Ways of Working Pilot.
Please note that under the Combined Ways of Working pilot, a single application is submitted by the Sponsor or Contract Research Organisation. This is considered to be on behalf of the Chief Investigator for Research Ethics Committee submission.
Step 1: Register your trial application
You will need to provide the following details (where possible):
- Trial title
- IRAS ID
- EudraCT number
- Phase of the trial
- Is the trial taking place in the NHS/HSC
- Which UK nation the trial is led from (trials taking place in the NHS/HSC only)
- Name and contact details of the sponsor
- Whether the trial is going through HRA radiation assurance
- Expected submission date
Step 2: Confirm your submission date
When you are confident that you will be able to submit your application within a particular time period (REC meeting submission period), please contact firstname.lastname@example.org to confirm a REC and meeting date.
There will be a small number of RECs involved in this pilot during the early stage. This means that you may not be able to submit to the REC which you would usually submit to. The RECs involved will increase as the pilot develops so please always check the HRA website for the most up to date information.
Once you have confirmed your submission and the application has been allocated to a REC meeting you will be issued with a REC reference number.
Step 3: Submit application via IRAS*
* Please note that the IRAS form is currently required to be submitted but under the pilot, the full IRAS form is not provided to the REC for review. It is therefore important that the protocol is written in a way which means that the study is described clearly and comprehensively. Additional documents may be provided to describe the recruitment and informed consent procedure if not included in the protocol (template available on the HRA website here).
We are working to simplify the submission process as much as possible but, by the nature of the current systems, this is a multi-step process:
- Complete the integrated dataset in IRAS (in the same way as for all CTIMPs).
- Upload supporting documentation to IRAS checklist (ensure to select the appropriate document type)
- On the day that you are ready to submit your application and you have your document set ready you will need to generate the MHRA (EudraCT equivalent) form in a pdf and xml format, by:
- Navigating to the MHRA submission tab in IRAS
- Selecting the button to submit the MHRA form. This will generate a pdf of the MHRA (EudraCT) form.
- Scrolling down to the bottom of the tab to save a copy of the XML of the MHRA (EudraCT) form.
- The PDF and XML versions of the EudraCT forms should be submitted as attached documents.
- Contact email@example.com to enable e-submission of the IRAS form
- Submit the IRAS form and supporting documents via the E-submission tab in IRAS
- Inform firstname.lastname@example.org once submitted.
Note: If you will not complete the above process by the date agreed in Step 1, contact email@example.com to rearrange your REC review as soon as possible.
Figure 1 - Application Pack
Where more than one document is being submitted under each document type, please start the document title with the corresponding number e.g 11a. Informed consent procedure and 11b. Participant information sheet and ensure that the title describes the document appropriately.
- Cover letter
- EudraCT form PDF and XML file
- Investigator’s Brochure (IB)
- Documents relating to compliance with Good Manufacturing Practice (GMP) for the IMP
- Investigational Medicinal Product Dossier (IMPD)
- Auxiliary (I,e non-IMP) Medicinal Product Dossier
- Scientific Advice and Paediatric Investigation Plan
- Content of the labelling of the Investigational Medicinal Product
- Recruitment arrangements
- Subject information, informed consent form and informed consent procedure
- Suitability of the investigator
- Suitability of the facilities (For non NHS sites the SSI form should continue to be submitted via IRAS until further notice)
- Proof of insurance cover or indemnification
- Financial and other arrangements
- Proof that data will be processed in compliance with current data protection legislation.
Step 4: Validation Process
Validation checks will be completed on your application within 3 days of receipt. This will involve checking that all required documents have been submitted and that the documents can be opened and are readable. If the application is not valid, you will be given the opportunity to correct this and will have until day ‘Submission+5’ to complete. The validation check will be undertaken by the MHRA via the HRA HARP database. When undertaking the validation check, the MHRA will also delete any documents from the HRA HARP database which are not required by the REC. These documents will be retained by the MHRA only.
For further information on which documents are required, please refer to the Application Dossier Guidance which can be found here.
Not all documents in the document checklist table (Appendix) may be appropriate for all trials. Where a document listed in the table is not submitted because it is not relevant or because the information is contained elsewhere in the application dossier, such as in the protocol, then you just need to detail this in the comments column for the purposes of validation.
When naming documents to be submitted, the full title may be listed in the cover letter but the naming of the document when saving it should be a short but clear version.
If valid, we will notify you and supply a ‘pilot reference number’ (in addition to the standard reference numbers - EudraCT, REC and IRAS) for the application.
Day 0 will be the date of receipt of a valid application.
Step 5: consolidated assessment; to be completed by day 30
MHRA and REC will work jointly to undertake the assessment which will result in two assessment outputs. Assessment one will include the full MHRA review and also a review by the REC of the risks, benefits, burdens and inconveniences. (Note that CMC-related information will be assessed by the MHRA only). Assessment 2 will be the REC review (other than the areas covered in assessment 1) and an administrative assessment, which is largely in relation to compliance with legislation (e.g data and tissue legislation).
The output at this stage of the process will either be an overall authorisation of the trial (CTA from MHRA and favourable opinion from the ethics committee) or a request for further information.
Step 6: Request for further information
If we require further information, we will email the person named on the EudraCT form as the sponsor contact to outline the further information required or the questions to be answered. This may include both assessment 1 and 2 or may involve just one of the assessments. Please note, it is the responsibility of the sponsor organisation to ensure that the appropriate person or persons within the organisation receive the request for further information. Generic rather than personal email addresses are strongly advised.
Step 7: Request for further information response
You will have 14 days to provide a full response.
The response should be sent via IRAS (e-mail firstname.lastname@example.org to enable e-submission and to confirm submission).
NOTE: We anticipate that there may be instances where you cannot respond in full to the requests for information. The UK clinical trials Regulation 2004 No SI1031 allows a fixed period of time, usually 14 days, to respond to a request for further information in relation to the CTA whereas the Regulation allows for the clock to be paused while awaiting a response to the REC. Therefore, if you are unable to respond in full to the request for further information (including assessments 1 and 2) within 14 days please contact the CWoW admin (email@example.com ) mailbox urgently to discuss whether the application needs to be suspended from the pilot and default into standard MHRA and REC processes. This is because we recognise that rejecting an application from the system at this stage would require a new REC submission and review. The preference would be that one REC review is undertaken and therefore we will continue with the application for REC purposes but a resubmission to the MHRA for a CTA may be required.
The following scenarios would apply:
|Respond to assessment 1 and 2 within 14 days||Application proceeds in the pilot|
|Respond to neither assessment 1 or 2 within 14 days||Application removed from the pilot. A new CTA application would be required. No new REC application required. Continue to respond to assessment 2 as this will apply to REC purposes.|
|Respond to assessment 1 but unable to respond to assessment 2||Application removed from the pilot. No new submissions required. Assessment 1 will apply for CTA purposes.|
|Respond to assessment 2 but unable to respond to assessment 1||Application removed from the pilot. A new CTA application would be required. Assessment 2 would apply for REC purposes.|
Step 8: Joint Decision; by day 60
After the review of a full response to all points raised (assessment 1 and 2), an outcome will be confirmed (authorised or not authorised) and two letters will be issued via e-mail.
An authorisation will be issued where the CTA is authorised and also the REC has issued a favourable opinion and will include both the CTA authorisation letter and the REC favourable opinion letter. A non-authorisation will occur because either the CTA has been rejected or the REC has issued an unfavourable opinion. The CTA and REC letters will both be provided and the reason for the non-authorisation will be made clear.
Additionally, for trials taking place in the NHS/HSC and led from sites in England and Wales, an additional letter confirming the HRA & HCRW Approval status will also be provided (subject to all authorisations being in place). For trials led by sites in Scotland and Northern Ireland, the combined process will involve co-ordination with the study wide review but the outcome will be issued separately.
Fortnightly Support and Feedback Call:
The purpose of the trial is to test a joint MHRA/RES process; this includes understanding the experience of applicants. As such, we want to ensure continued engagement with you throughout, to help you with any areas of need but also to ensure we’re capturing your experience and feedback in a consistent and usable way.
To support this, we will host a fortnightly call where we’ll be on hand to help you with any areas and to ask you questions about your progress.
Whilst our preference is for matters to be raised during this weekly call, we will of course be on hand should you have needs that don’t fit the scheduled call timeline.
The meeting will run alternate Mondays at 14:00 (to confirm the date of the next call please e-mail firstname.lastname@example.org)
Trials excluded from this stage of the pilot:
- Advanced Therapy Medicinal Product (ATMP) trials
- Trials requiring review by the REC constituted by Scottish Ministers under Section 51(6) of the Adults with Incapacity Act 2006.
Further information and guidance will be issued via the Combined Ways of Working Pilot page on the HRA website which can be found here .
Table 1 – Checklist (To be copied into the cover letter)
|1. Cover letter|
|2. IRAS EudrasCT form: PDF and XML file|
|4. Investigator's brochure (IB)|
|5. Documentation relating to compliance with good manufacturing practice (GMP) for the investigational medicinal product|
|6. Investigational medicinal product dossier (IMPD)|
|7. Auxiliary (ie non-IMP) medicinal product dossier|
|8. Scientific advice and paediatric investigation plan (PIP)|
|9. Content of the labeling of the investigational medicinal products|
|10. Recruitment arrangements|
|11. Subject information, informed consent form and informed consent procedure|
|12. Suitability of the investigator|
|13. Suitability of the facilities|
|14. Proof of insurance cover or indemnification|
|15. Financial and other arrangements|
|16. Proof that data will be processed in compliance with union law on data protection|
|17. Other documents (please list and state which review body the document is for in the comments column. documents which are for 'information only' should not be submitted but where such a document is submitted, this should be stated)|
The following is a list of documents which do not need to be submitted. This list is being developed via the CWoW pilot and is not an exhaustive list.
- Separate covering letters for each of the IB’s.
- Separate list of active trials (can be included in the cover letter)
- Raw data from viral validation studies.
- Literature references for quality data
- Additional documents confirming that another document was not required (e.g Scientific Advice (SAM) or a Paediatric Investigation Plan (PIP))
- UTN receipt
- EudraCT receipt
- EudraCT number confirmation
- Receipt of payment for MHRA review (the PO number should be included in the cover letter)
|Steps 1 & 2||to reflect the revised process that trials should be registered with email@example.com but a REC and meeting date can only be confirmed once the applicant is confident they can submit with a stated submission period||3.4||7.10.19|
|Step 6||Confirming that correspondence will be sent to the contact email supplied and it is the responsibility of the sponsor to ensure that the correspondence reaches the correct people. We also advise the use of generic rather than personal email addresses.||3.4||7.10.19|
|Throughout||Remove the telephone numbers as email communications is encouraged||3.4||7.10.19|
|Appendix 1 - document checklist||Addition of point 17 to add any other documents not listed and to state whether for a REC or MHRA review or both.||3.4||7.10.19|
|Appendix 2||Addition of a list of documents which do not need to be submitted.||3.4||7.10.19|