Coronavirus / COVID-19 - key guidance
- Guidance for sponsors, sites and researchers
|
IMPORTANT:
On 25 March 2021 the following changes to how amendments are processed will apply;
- All amendments to CTIMPs that require notification to the MHRA will no longer require the submission of a European Commission “Annex 2” form. The MHRA will now accept a copy of the completed Amendment tool when notifying amendments to a single CTIMP. The Annex 2 form, which is available on the MHRA website, can still be completed and submitted to the MHRA for ‘bulk’ amendments, where the same change will affect many trials simultaneously.
- The addition of a new NHS/HSC site, and the addition or change of a Principal Investigator (PI) in the NHS/HSC for CTIMP studies, will now be classified as non-substantial changes (Please note these changes should still continue to be classed as substantial when relating to non-NHS/HSC settings).
On 2 June 2020 changes were introduced to the way amendments are notified to Research Ethics Committees and NHS/HSC
- Project-based research (defined as any of the IRAS Project Filter question 2 categories except for RTBs and RDBs) should now prepare amendments using the Amendment Tool.
- Amendments should be submitted for review via online submission.
|
IMPORTANT
Where the guidance below refers to the online submission of amendments this relates to projects submitted through standard IRAS only. All trials submitted through the combined review service via the new part of IRAS, should instead consult the guidance available here.
Notifying Amendments to projects with NHS REC review and/or HRA and HCRW Approval / NHS/HSC R&D permissions
Further guidance on:
Requirements for notifying amendments to each of the following:
Notifying Amendments to project-based research with NHS REC review and/or HRA and HCRW Approval / NHS/HSC R&D permissions
On 2 June 2020 the process for preparing and submitting amendments to RECs and/or HRA and HCRW Approval / NHS/HSC R&D across the United Kingdom changed.
- For all project-based research, notice of substantial amendment and non-substantial amendment forms are no longer used and have been replaced by the Amendment Tool.
- Research Tissue Banks (RTBs) and Research Databases (RDBs) continue to use the Notice of Substantial Amendment Form generated in IRAS to notify substantial amendments to the REC.
- For all types of research, amendments and supporting documentation should be uploaded and submitted for review via online submission.
Amendment Tool
The Amendment Tool applies to all project-based research (defined as any of the IRAS Project Filter question 2 categories except for RTBs and RDBs) and replaces the Notice of Substantial Amendment (NoSA) Form and the non-substantial amendment form.
Please note that as of 25 March 2021 the European Commission “Annex 2” form will no longer be required when notifying amendments to the to the MHRA. The MHRA will now accept a copy of the completed Amendment Tool when notifying them of amendments to a single CTIMP. The Annex 2 form, which is available on the MHRA website, can still be completed and submitted to the MHRA for ‘bulk’ amendments (where the same change affects multiple studies simultaneously).
It is no longer possible to create a new NoSA in IRAS for project-based research, and the non-substantial amendment template form is no longer used. Any amendments must be prepared using the Amendment Tool as amendment forms will no longer be accepted.
The process for completing the Amendment Tool is as follows:
1. Download the Amendment Tool from the link below and fill in information about your amendment on the ‘Amendment Tool’ tab, referring to the on-screen guidance notes. You must clearly describe the amendment and the rationale for the amendment in the summary box. You should then separate out each type of change you are making as part of the amendment, entering details using the drop-down menus. The Tool contains a ‘glossary of amendment options’ tab which details and provides guidance on all of the types of change available. Referring to this will help you select the correct type/s of change. You can enter up to 10 separate types of change on the same Amendment Tool document. If the amendment involves more than 10 types of change, please contact amendments@hra.nhs.uk for support.
The declaration section should then be completed by the sponsor or person with explicit delegated authority from the sponsor (authorised delegate). Amendments must not be submitted without prior authorisation from or on behalf of the sponsor. Please check with the sponsor and refer to local SOPs for the processes within your organisation. The ‘Lock for submission’ button will turn green when this is completed
2. Click ‘Lock for submission’. This will generate a locked pdf copy of the completed tool. Save this to your computer ready for upload later.
3. If your project is a CTIMP and the amendment requires notification to MHRA (Medicines) please note that the European Commission “Annex 2” form is no longer required. The MHRA will now accept a copy of the completed amendment tool which should be included as part of both, submission to the REC, and notification to the MHRA. Details on how to submit amendments to MHRA (Medicines) are found below.
4. When you have final copies of all supporting documentation in place, and have saved the pdf of the Amendment Tool, you should proceed to online submission. There is also tailored submission guidance on the Amendment Tool ‘submission guidance’ tab.
The current version of the Amendment Tool is available here:
Amendment Tool v1.6 (06 December 2021).xlsm
Accessibility and support
The Amendment Tool is not currently compliant with the Web Content Accessibility Guidelines version 2.1 AA standard for use with a screen reader. In the longer term we hope to move this over to a new digital platform and make it fully accessible. If you are a screen reader user please email amendments@hra.nhs.uk with your IRAS ID and details of your amendment and one of the team will get back to you as soon as possible and complete the Tool on your behalf.
The Amendment Tool is an excel document which uses macros. A pop-up message may appear the first time you use the tool warning that macros have been disabled. In this case please select ‘Enable Content’.
The Amendment Tool works on both Windows PC and Mac operating systems. The functionality for creating a pdf is different on Mac computers. The Tool will detect a Mac Operating System and provide specific instructions when you lock the tool.
If you experience any technical difficulties in using the Tool, please contact amendments@hra.nhs.uk for support.
For queries on how to complete the Amendment Tool or questions on the results from it, support can be accessed as follows. Please flag in the email subject that your query relates to the Amendment Tool so that it can be identified and handled efficiently.
For England and Wales led studies: amendments@hra.nhs.uk
For Scotland led studies: Gram.nrspcc@nhs.scot
For Northern Ireland led studies: Research.Amendments@hscni.net
If you would like to provide feedback on the Amendment Tool please do so through one of email addresses above.
Online Submission of Amendments
IMPORTANT: Where the guidance below refers to the online submission of amendments this relates to projects submitted through the standard part of IRAS only. All trials submitted through the combined review service via the new part of IRAS, should instead consult the guidance available here.
As of 2 June 2020, all types of project submit amendments to the REC and/or HRA and HCRW Approval / NHS/HSC R&D coordinating functions via online amendment submission.
When you have completed the Amendment Tool (or Notice of Substantial Amendment form in the case of RTB and RDB projects) and finalised and gathered all supporting documentation for your amendment you should follow this link to online amendment submission.
The online amendment submission functionality requires you to log in to the IRAS Identity Gateway, which is separate login to your main IRAS account. If you have not used it before you may need to set up a new account. Please follow the on-screen instructions and refer to the guidance under ‘Help’ on the login page. If after this you have any difficulty creating an account, please contact the Service Desk for support on: service.desk@hra.nhs.uk
When you have logged in, refer to the on-screen step-by-step instructions which will guide you through the process.
You will be asked to enter the IRAS ID, and answer some simple questions about your amendment. Some of these questions require you to enter information exactly as it appears on the Amendment Tool (or amendment form in the case of RTB/RDB projects), so have this available to refer to.
If you do not have an IRAS ID, or if you have entered the correct IRAS ID but the system is not recognising it, please contact amendments@hra.nhs.uk.
You can then upload all documentation relating to your amendment and proceed to submit. You can drag and drop up to 15 documents at a time into the upload drop box. Please note that file names for supporting documents must contain fewer than 60 characters (including spaces).
Upon submission you will receive an automated email to confirm submission of your amendment. The amendment will be shared with REC and/or for study-wide review as applicable.
After you have submitted your amendment
Please refer to the guidance provided here on what happens, and what you need to do after submission of your amendment as the process differs depending on where the project is located.
For substantial amendments notified to the REC, you should await email communication from the REC with the outcome of their review before implementing the amendment.
Support
Please be aware that the amendment tool training video has been withdrawn, as it is no longer reflects the functionality of the latest version of the tool. If you need help using the amendment tool, please contact amendments@hra.nhs.uk.
For any technical queries about accessing or using online amendment submission, contact: service.desk@hra.nhs.uk Any queries about the amendment itself should be directed to the REC that issued favourable opinion for the study.
Any queries about the amendment itself for non-REC studies can access support as follows. Please flag in the email subject that your query relates to an amendment and include the project IRAS ID so that it can be identified and handled efficiently.
For England and Wales led studies: amendments@hra.nhs.uk
For Scotland led studies: Gram.nrspcc@nhs.scot
For Northern Ireland led studies: Research.Amendments@hscni.net
Back to the top
Modified Amendments
Where the REC gives an unfavourable opinion of a substantial amendment, the sponsor or Chief Investigator may submit a modified amendment taking into account the Committee’s concerns. In this case a new amendment tool should be completed, indicating that it relates to a modified amendment at the relevant question. It should then be submitted to the REC alongside all supporting documentation by email. Where applicable, the REC will share the amendment and Amendment Tool with the relevant national coordinating function for the lead nation.
Modified amendments must not be submitted using online submission.
REC email addresses can be looked up on the HRA website
Amendments to add the involvement of adults lacking capacity for the first time, or extend involvement of adults lacking capacity to a new nation
Because of the specific REC review requirements, it is not possible for this type of amendment to use online submission.
The type of amendment and level of information you need to provide will vary depending on the location of the lead nation and nation/s where the amendment will be implemented. You should therefore contact the REC that originally issued favourable opinion for the study, flagging in your covering email that the amendment involves adding the involvement of adults lacking capacity. They will be able to advise on how to submit and any additional steps you need to take. REC email addresses can be looked up on the HRA website
When extending the involvement of adults lacking capacity to a new nation, researchers should consider the different standards and legislation that may apply. It may be necessary, for example, to create new consent and participant information documents as part of the amendment submission. The HRA website provides more information on the requirements that apply in England, Wales, Scotland and Northern Ireland, and also provides helpful templates that can be used when designing consent and information documentation.
Grouping amendments that contain more than one updated protocol
Sometimes, you may prefer to group together amendments that contain more than one updated version of a protocol in one submission. For example, this might apply where an international CTIMP wishes to notify UK bodies of multiple global changes in one go.
By following the recommendations below, in addition to the usual amendment process (outlined above), you can help support the review of your application and reduce delays.
- Single Amendment Tool - use one amendment tool to cover all updates. Summarise all the changes from the current approved documents to the versions to be reviewed and implemented.
- Protocols - you don't need to create a single document showing changes from multiple versions. Instead, provide each new version of the protocol in sequence, showing tracked changes from the previous version.
For example, if the approved protocol is version 5, and you’re submitting two consecutive protocol amendments (version 6 and 7). Submit version 6 for information only and version 7 for implementation. All changes from version 5-7 need to be summarised within the amendment tool.
- All other documents (except the protocol) – only submit the version you want to implement in the UK.
- Participant information – you should provide participant information in both clean and tracked change versions. Include all the changes from the current version in use, to the proposed.
- Covering letter - In your covering letter explain which version of the protocol needs approval and which versions are for information and audit trail purposes only.
Sharing amendments with participating NHS/HSC organisations
Once you’ve submitted your amendment for review, you’ll need to tell any participating NHS/HSC organisations about it by following the relevant nation specific guidance. Additionally follow these tips to support participating organisations with their review and avoid confusion:
- Use the appropriate HRA template emails when communicating the amendment to sites.
- Explain in the covering email why you're grouping amendments and why they contain multiple versions of the protocol.
- Provide clear instructions on whether all documents, including those being shared for information only, should be filed in the site investigator file.
- Clearly label the protocol to be implemented.
NHS/HSC organisations should follow the process for reviewing and implementing amendments based on their category.
Only the latest version of the protocol will be implemented by sites once all regulatory approvals are in place.
Back to the top
Notifying amendments to the Research Ethics Committee
Further ethical review is required for any substantial amendment made once a favourable opinion has been issued. A favourable opinion must be obtained prior to implementing the amendment, unless it is an urgent safety measure.
For CTIMPs and clinical investigations of medical devices only, substantial amendments should also be notified prior to receiving a favourable opinion where, exceptionally, significant changes are requested by the Medicines and Healthcare products Regulatory Agency (MHRA) as part of the regulatory approval process and these changes are relevant to ethical review.
For guidance on submission of substantial amendments to the MHRA, please see https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues.
Guidance on notifying amendments to project-based research can be found here.
Notifying substantial amendments – Research Tissue Banks (RTBs) and Research Databases (RDBs)
Please use the Notice of Substantial Amendment form available in IRAS. This is created from the Amendment tab associated with the RTB/RDB form.
The completed Notice of Substantial Amendment form should be electronically authorised by all parties listed on the form’s authorisations tab in IRAS.
When authorisations are in place, submit of the final PDF of the form (created via the Submission Tab of amendment form) to the REC, together with all relevant enclosures via online amendment submission according to the instructions provided on the amendment form’s submission tab.
Non-substantial amendments for RTB and RDB projects do not need to be notified to the REC.
If you wish to update the REC of any minor changes, for example to update key study personnel contact details, you can do this by email. REC contact details are found here.
Further guidance
For further guidance about notifying substantial amendments to RECs and review procedures, please see the Health Research Authority (HRA) website
Back to the top
Notifying amendments to NHS/HSC R&D offices
For guidance on managing amendments to research conducted in the NHS/HSC please refer to the guidance
here.
Back to the top
Notifying amendments to MHRA Medicines
Please note that as of 25 March 2021 the European Commission “Annex 2” form will no longer be required when notifying amendments to the MHRA. The MHRA will now accept a copy of the completed
Amendment Tool when notifying them of amendments to a single CTIMP. The Annex 2 form, which is available on the
MHRA website, can still be completed and submitted to the MHRA for ‘bulk’ amendments (where the same change affects multiple studies simultaneously).
Any substantial amendment to a CTIMP must be notified both to the MHRA and the ethics committee before it is implemented, unless it is an urgent safety measure.
Notification is not required for amendments not meeting the criteria for substantial amendments.
Substantial amendments
A substantial amendment is a change to the terms of the request for clinical trial authorisation or the ethics committee application, or to the accompanying particulars or documents, which significantly affects one of the following:
- The safety or physical or mental integrity of study participants
- The conduct or management of the study
- The scientific value of the study
- The quality or safety of any investigational medicinal product used in the study
Notifying amendments to MHRA Medicines for trials initially submitted through the standard part of IRAS
IMPORTANT: The following section is only relevant to trials initially submitted though this part of IRAS. For all trials submitted through the combined review service using the new part of IRAS please refer to the amendment guidance found in the step by step guide to combined review. |
Notifying substantial amendments
A copy of the completed
Amendment tool should be included as part of both, submission to the REC, and notification to the MHRA.
When notifying the MHRA of a substantial amendment to a CTIMP, the following must be included in the submission:
- Covering letter detailing the trial reference numbers 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 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 on the MHRA website
- An updated PDF file of the Clinical Trial Application Form with changes highlighted, if the amendment affects the information previously submitted. Please Note: The original clinical trial application form can be updated in IRAS by following the instructions under the submission tab. Alternatively, if your application was prepared in EudraCT you will need to import the EudraCT dataset into
your existing project in IRAS following the instructions below . The imported data can then be edited in IRAS as usual. Please be aware that using this option will overwrite any existing data in IRAS.
- Copy of the proposed changes to the protocol or any other documents (e.g. IMPD), showing previous and new wording where applicable supporting data for the amendment, including as applicable:
- Summaries of data
- Updated overall risk benefit assessment
- Possible consequences for subjects already in the trial
- Possible consequences for the evaluation of results.
Notifying amendments to MHRA Medicines for trials that initially submitted their Clinical Trial Application (CTA) through EudraCT.If your initial CTA was prepared in EudraCT, an existing project associated with the trial should already exist in IRAS. This will be the project that was used to make an application to the Research Ethics Committee (REC). If you were not the person that prepared this application to the REC you may need to request that ownership of the project in IRAS is transferred to you by the current project owner. Instructions on how to permanently transfer a project in IRAS can be found in our e-learning.
Once you have ownership of the project in IRAS please complete the steps in either of the two options below;
To import IMP data only from EudraCT into an existing IRAS project:
- select the project in IRAS
- navigate to the project filter questions and the select the MHRA medicines form in question 4 of the project filter
-
- Select the MHRA Medicines form from the list of forms on the main navigation screen
- follow the instructions under the ‘Import/Export’ tab
- make sure you select the option for 'IMPs Import'
Once the data is imported, Part B Section 1 of the integrated dataset in IRAS will then be populated with the information already completed in EudraCT that is needed by other review bodies. This information on the IMP(s) is included in the REC and IRAS forms. As you have already prepared your EudraCT application you do NOT need to complete any other questions in Part B Section 1 other than the IMP information that has been imported from EudraCT.
To import all data from EudraCT into an existing IRAS project:
- select the project in IRAS
- navigate to the project filter questions and the select the MHRA medicines form in question 4 of the project filter
- Select the MHRA Medicines form from the list of forms on the main navigation screen
- follow the instructions under the ‘Import/Export’ tab
- make sure you select the option for 'Full Import'
- be aware that existing data in Parts A and B will be over-written
Once the information has been imported you will be able to amend the form as necessary and obtain electronic authorisations.
When ready to download a PDF of the MHRA medicines form please navigate to the ‘Save/Print’ tab. Under the option titled ‘Print a form for review at any time while you are working on it’ select the option: ‘Print this form for review’.
The downloaded form will show a ‘draft’ watermark, however this will not cause a problem and can still be submitted to the MHRA as part of the amendment submission.
Please be aware that if you prepare your form using this method a submission history of the amended MHRA medicines form will not be saved in IRAS. We recommend that you save a local copy of the amended form for your records.
For detailed amendment submission guidance, please see the MHRA website.
Back to the top
Notifying amendments to MHRA Devices
The following guidance applies to amendments to clinical investigations of medical devices subject to regulation by the Competent Authority.
You must notify MHRA Devices of
all proposed changes to the investigation (not only those classified as substantial amendments for the purposes of ethical review) and await a letter of no objection from MHRA Devices before you implement them. This includes changes made at the request of the REC. Failure to notify proposed changes could result in the manufacturer being liable to prosecution.
When notifying MHRA of changes, please provide the following information in writing:
- the MHRA reference number for the trial;
- details of the proposed change(s) to the clinical investigation plan or the design of the device;
- the reason for the change(s); and
- a signed statement by or on behalf of the manufacturer that the proposed change(s) do not predictably increase the risk to the patient, user or third party.
- A copy of the completed Amendment Tool
Notifications should be sent directly to MHRA Devices. Details of where to send notifications can be found on the MHRA website at:
https://www.gov.uk/guidance/notify-mhra-about-a-clinical-investigation-for-a-medical-device
Back to the top
CAG should be notified of
all amendments to the information provided in your original application. This is because support to process confidential patient information without consent is based on the precise details originally provided to CAG and so any change will
not be covered by the existing support until a formal amendment is made
and the amendment is supported.
You will need to complete and submit an
amendment form to CAG where changes are intended to any of the following:
- Data flows
- Data items
- Data sources
- Purpose of application
- Data controller (please note that an amended application form and supporting documents setting out the new data controller arrangements will be required, you are advised to contact the Confidentiality Advice Team prior to submission)
- Data processor
- Duration amendment
If you are unsure whether an amendment needs to be submitted after reviewing the template and/or you need further guidance please contact the Confidentiality Advice Team (CAT; see
Contact Us). The CAT may advise that you submit the amendment for information only at this stage.
Once you have submitted the completed amendment form the Confidentiality Advice Team will confirm if the amendment contains sufficient information, whether it is valid and the process and timelines for its review. You may be asked to provide further information prior to confirmation that your amendment is valid.
If the amendment can be reviewed outside a full CAG meeting an outcome should be provided within 35 days of receipt of a valid amendment, if the amendment is referred to a full CAG meeting an outcome can be expected within 60 days of receipt of a valid amendment. The Confidentiality Advice Team will inform you if your amendment is referred to a full CAG meeting as soon as possible. Please note that final approval for the amendment will not come into effect until a final approval letter is issued. The possible outcomes of the review of the amendment are that the amendment is:
- Fully supported
- Conditionally supported
- Not supported
Back to the top
ARSAC should be notified of any changes concerning the administration of radioactive substances as this may affect the approval granted. Such changes include, but are not limited to:
- Changes to the number of administrations of radioactive substances from Section A1 of the original Preliminary Research Assessment (PRA) form
- Addition or removal of a procedure involving the administration of radioactive substances
- Addition of a new study population with a different clinical condition (including changing the age of the participants)
- Addition of healthy volunteers receiving administrations of radioactive substances
- Changes to the radiation risk information in the participant information sheet (PIS) following changes to the protocol
Such changes will normally meet the criteria for notifying substantial amendments to the Research Ethics Committee (or GTAC). Follow these steps to submit an amendment application to ARSAC:
- Create an Amendment to Research Application on the ARSAC online portal at the same time as you submit the notice of substantial amendment to the Research Ethics Committee. You will need to create an account if you do not have one already.
- Complete all required questions and attach the following:
- Notice of Substantial Amendment
- updated PRA form if there are changes to the number of administrations or procedures involving radioactive substances (note: you will need to revise the integrated dataset Part A or B3, or both and then create an up-to-date PDF of the PRA form via the submission tab in IRAS)
- any other relevant documents, for example a participant information sheet
Further guidance on how to use the online portal is available .
Once you have submitted your amendment application, ARSAC will send you details on how and when to pay the fee:
- low dose studies (<1mSv total participant dose): £200
- multi-centre and single centre studies with >1mSv dose: £250
While ARSAC assesses the amendment, you remain authorised within the limits of the initial approval and administrations may continue in line with this.
Once the study has been approved an approval document will be added to the portal for you to download and share. Individual installations can then proceed with the amended study for all procedures on their licence and the approval document. It is not necessary for each installation to notify ARSAC of amendments.
Research notifications
You should notify ARSAC of minor changes to research trials to ensure the approval remains valid. Changes include, but are not limited to the following:
- change to the research trial title
- closure of a trial
Notifications should be made to the ARSAC Support Unit by email to
ARSAC@phe.gov.uk and are not subject to a fee.
Further guidance may be found on the
ARSAC website or by contacting the ARSAC Support Unit. ARSAC contact details are available on the
Contact Us page.
Back to the top
The National Research Coordinator (details provided on
Contact Us page) should be notified of all amendments to the information provided in your original application.
It is not necessary to submit a Notice of Substantial Amendment form.
Amendments to the scope or nature of an approved research project must not be made without prior agreement.
Back to the top
Notifying amendments to HRA and HCRW Approval
Where a project has HRA and HCRW Approval you are expected to notify amendments according to the guidance
here.
Back to the top
Page last updated: 22 March 2024