IMPORTANT
From 28 April 2026, changes to all approved studies are no longer called 'amendments'. Instead, they'll be referred to as 'modifications'.
Where the guidance below refers to the online submission of modifications 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 Modifications to projects with NHS REC review and/or HRA and HCRW Approval / NHS/HSC R&D permissions
Further guidance on:
Requirements for notifying modifications to each of the following:
Notifying modifications to project-based research with NHS REC review and/or HRA and HCRW Approval / NHS/HSC R&D permissions
- For all project-based research the Modification Tool will replace the Amendment Tool.
- Research Tissue Banks (RTBs) and Research Databases (RDs) continue to use the Notice of Substantial Amendment Form generated in IRAS to notify substantial modifications to the REC.
- For all types of research, modifications and supporting documentation should be uploaded and submitted for review via online submission.
The only exception to this is for projects which have transitioned to the Plan and Manage Health and Care Research service under development.
Modification Tool
The Modification Tool applies to all project-based research (except for RTBs and RDBs) that have not transitioned to the Plan and Manage Health and Care Research service under development. It replaces the Amendment Tool
Please note that the European Commission Substantial Modification Notification Form is no longer required when notifying modifications to the MHRA. The MHRA requires a copy of the completed Modification Tool when notifying them of modifications to a single CTIMP. If the same substantial modification impacts many non-combined review trials, the sponsor can make a single application through MHRA Submissions covering all relevant trials (in addition to the application to the ethics committee through IRAS). In this case, the sponsor should complete and submit the substantial modification notification form instead of the modification tool. (Details can be found on the MHRA website) Please note that bulk submission of modifications is not currently possible where any of the trials affected were approved through the combined review process.
The process for completing the Modification Tool is as follows:
1. Download the Modification Tool from the link below and fill in information about your modification on the ‘Modification Tool’ tab, referring to the on-screen guidance notes. You must clearly describe the modification and the rationale for the modification in the summary box. You should then separate out each type of change you are making as part of the modification, entering details using the drop-down menus. The Tool contains a ‘glossary of 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 Modification Tool document. If the modification 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). Modifications 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 and all other details required by the Modification Tool are 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 modification requires notification to MHRA (Medicines) please note that the European Commission “Annex 2” form is no longer required. The MHRA requires a copy of the completed Modification Tool which should be included as part of both, submission to the REC, and notification to the MHRA. Details on how to submit modifications 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 Modification Tool, you should proceed to online submission. There is also tailored submission guidance on the Modification Tool ‘submission guidance’ tab.
The current version of the Modification Tool is available here:
Accessibility and support
The Modification Tool is not currently compliant with the Web Content Accessibility Guidelines version 2.1 AA standard for use with a screen reader. We are working to make the Plan and Manage Health and Care Research service currently under development fully accessible. If you are a screen reader user please email amendments@hra.nhs.uk with your IRAS ID and details of your modification and one of the team will get back to you as soon as possible and complete the Tool on your behalf.
The Modification 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 Modification 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 Modification 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 Modification 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 Modification Tool please do so through one of email addresses above.
Online Submission of Modifications
IMPORTANT: Where the guidance below refers to the online submission of modifications 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.
When you have completed the Modification Tool (or Notice of Substantial form in the case of RTB and RDB projects) and finalised and gathered all supporting documentation for your modification you should follow this link to online modification submission.
The online modification 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 modification Some of these questions require you to enter information exactly as it appears on the Modification Tool (or amendment form in the case of RTB/RDB projects), so have this available to refer to. The Tool will provide guidance on the appropriate options to select in legacy systems which are not being updated.
The Modification Tool has been revised to provide the correct classifications under the new regulations. However, IRAS has not been updated and will still require you to submit using the old classifications. The Modification Tool will provide guidance on which option to select in order to ensure the REC and/or MHRA receive the modification in the correct format for them to process.
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 modification and proceed to submit.
Please note that although the tool you downloaded is called ‘Modification Tool’ when you upload to IRAS you need to upload it as an ‘Amendment Tool’ document type. The process for uploading documents here is the same process you would follow when submitting documents as part of your initial application.
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 modification. The modification will be shared with REC and/or for study-wide review as applicable.
After you have submitted your modification
Please refer to the guidance provided here on what happens, and what you need to do after submission of your modification as the process differs depending on where the project is located.
For substantial modifications notified to the REC, you should await email communication from the REC with the outcome of their review before implementing the modification.
Modifications of an important detail and minor modifications do not require a REC review outcome.
Support
If you need help using the Modification Tool, please contact amendments@hra.nhs.uk.
For any technical queries about accessing or using online modification submission, contact: service.desk@hra.nhs.uk Any queries about the modification itself should be directed to the REC that issued favourable opinion for the project.
Any queries about the modification itself for non-REC studies can access support as follows. Please flag in the email subject that your query relates to a modification 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
Using a Modification History Log
To keep track of modifications to your project you should consider using a modification history log. You should share the log with research sites with each relevant modification. This allows research sites to quickly see an overview of the current and previous changes to the study. Research sites may not have received all the study modifications due to them not affecting their site. Do not share the modification history log with a site when making a change that is not relevant to that site, it only needs to be sent with the next relevant amendment. As a sponsor you can use the provided template, or you may wish to use your own version either way this should be a single log per study. Where sponsors use their own templates, research sites should accept this and not transcribe to the template version.
Use of this template or sponsors own version is encouraged but not mandatory.
Modification History Log Template 1.0 (25 June 2025)
Back to the top
Requests for Further Information (RFI)
Where the authorities do not approve the proposed substantial modification, the sponsor will be given one opportunity to provide further information and have the application reconsidered.
For trials not approved through combined review, the further information must be provided to the relevant authority by email and must not be submitted using online submission.
Guidance on responding to requests for further information to the MHRA is provided on the MHRA website.
Guidance on responding to requests for further information to the REC is provided on the HRA website
Modifications 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 modification to use online submission.
The type of modification and level of information you need to provide will vary depending on the location of the lead nation and nation/s where the modification will be implemented. You should therefore contact the REC that originally issued favourable opinion for the study, flagging in your covering email that the modification 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 modification 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 modifications that contain more than one updated protocol
Sometimes, you may prefer to group together modifications 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 modification process (outlined above), you can help support the review of your application and reduce delays.
- Single Modification Tool - use one modification 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 modifications (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 modification tool.
- All other documents (except the protocol) – only submit the version of the changed document 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 modifications with participating NHS/HSC organisations
Once you’ve submitted your modification 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 modification to research sites.
- Explain in the covering email why you're grouping modifications 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 modifications based on their category.
Only the latest version of the protocol will be implemented by research sites once all regulatory approvals are in place.
Back to the top
Notifying modifications to the Research Ethics Committee
- For CTIMPs and clinical investigations of medical devices only, substantial modifications 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.
Initial review outcomes
There are 4 possible outcomes from the initial REC review of a substantial modification request, these are:
- favourable opinion
- favourable opinion subject to conditions
- unable to issue a favourable opinion and requests further information
- unfavourable opinion
Requests for further information
The revised process will allow the REC to request further information when considering substantial modification requests.
This means that if the REC identify issues that prevent a substantial modification request from being approved, the sponsor will be informed of these issues and will be able to respond before a final decision or opinion is issued. Requests for further information for substantial modifications will only be issued where it’s not possible for the REC to give a favourable opinion or a favourable opinion with conditions.
If a request for further information is required, it will be sent within 35 calendar days of the substantial modification request being confirmed as valid. If a sponsor receives a request for further information, they’ll have a maximum of 60 calendar days to respond. A sponsor can respond at any point within the 60 day timeframe. If they do not respond within 60 days, the substantial modification request will not be approved and will be given an unfavourable opinion by the REC.
If the sponsor needs longer to prepare a response to the request for further information, they can request an extension from the REC.
They will need to explain in their request why they need an extension and when they expect to respond.
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 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 modification 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.
Minor amendments for RTB and RDB projects do not need to be notified to the REC.
Further guidance
For further guidance about notifying substantial modifications to RECs and review procedures, please see the Health Research Authority (HRA) website
Back to the top
Notifying modifications to NHS/HSC R&D offices
For guidance on managing modifications to research conducted in the NHS/HSC please refer to the guidance here.
Back to the top
Notifying modifications to MHRA Medicines
Please note that the European Commission “Annex 2” form (Substantial Modification Notification Form) is no longer required when notifying modifications to the MHRA. The MHRA requires a copy of the completed Modification Tool when notifying them of modifications to a single CTIMP. If the same substantial modification impacts many non-combined review trials, the sponsor can make a single application through MHRA Submissions covering all relevant trials (in addition to the application to the ethics committee through IRAS). In this case, the sponsor should complete and submit the substantial modification notification form instead of the modification tool. Please note that bulk submission of modifications is not currently possible where any of the trials affected were approved through the combined review process.
Any substantial modification 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.
A modification of an important detail should be notified to both the MHRA and REC, but do not require a REC outcome.
Notification is not required for minor modifications .
Substantial modifications
A substantial modification 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 modifications to MHRA Medicines for trials that initially submitted their Clinical Trial Application (CTA) through EudraCT.
If your initial application for clinical trial approval 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 modification 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 modification submission guidance, please see the MHRA website.
Back to the top
Notifying modifications to MHRA Devices
The following guidance applies to modifications to clinical investigations of medical devices subject to regulation by the Competent Authority conducted in Great Britain only. For studies involving Northern Ireland, please see the MHRA website.
You must notify MHRA Devices of all proposed changes to the investigation (not only those classified as substantial modifications 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 the MHRA of changes, please provide the following information in writing:
- A covering letter with the MHRA reference number for the clinical investigation;
- a table with a summary of each proposed change with justification for each change;
- red-lined (showing changes being made) and clean copies of all amended study documentation; 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.
- 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
A copy of the completed Modification Tool
Notifications should be sent directly to MHRA Devices at CI-amendments@mhra.gov.uk. Further information can be found on the MHRA website.
Back to the top
Submitting modifications to the Confidentiality Advisory Group (CAG)
CAG should be notified of all modifications 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 modification is made and the modification is supported.
You will need to complete and submit a CAG modification 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 modification
If you are unsure whether a modification 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 modification for information only at this stage.
Once you have submitted the completed the CAG modification form the Confidentiality Advice Team will confirm if the modification 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 modification is valid.
If the modification can be reviewed outside a full CAG meeting an outcome should be provided within 35 days of receipt of a valid modification, if the modification 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 modification is referred to a full CAG meeting as soon as possible. Please note that final approval for the modification will not come into effect until a final approval letter is issued. The possible outcomes of the review of the modification are that the modification is:
- Fully supported
- Conditionally supported
- Not supported
Back to the top
Notifying modifications to ARSAC
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 modifications to the Research Ethics Committee (or GTAC). Follow these steps to submit a modification application to ARSAC:
- Create an Modification to Research Application on the ARSAC online portal at the same time as you submit the notice of substantial modification 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
Once you have submitted your modification application, ARSAC will send you details on how and when to pay the fee:
- low dose studies (<1mSv total participant dose): £260
- multi-centre and single centre studies with >1mSv dose: £310
While ARSAC assesses the modification, 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 modifications.
Research notifications
If your research trials title changes you should notify ARSAC through the online portal to ensure the approval remains valid.
Notifications should be made to the ARSAC by following these steps.
- Create a Research notification application on the ARSAC online portal. You’ll need to create an account if you do not have one already.
- Complete all required questions on the online form and attach the supporting documentation requested.
If you need further guidance on how to use the ARSAC online portal we recommend you view the ARSAC guidance on this.
For further information on applying to ARSAC you should visit the ARSAC website. ARSAC contact details are available on the Contact Us page.
Back to the top
Notifying modifications to HM Prison and Probation Service (HMPPS)
The National Research Coordinator (details provided on Contact Us page) should be notified of all modifications to the information provided in your original application.
It is not necessary to submit a Notice of Substantial Modification form.
Modifications to the scope or nature of an approved research project must not be made without prior agreement.
Back to the top
Notifying modifications to HRA and HCRW Approval
Where a project has HRA and HCRW Approval you are expected to notify modifications according to the guidance here.
Back to the top