On 22 March 2022, the Department of Health and Social Care (DHSC) issued an important communication to research sponsors and funders to specify that urgent action must be taken to address the current research delivery challenges in the NHS.
This page provides guidance for sponsors who need to act because of this review and have now decided to amend or close their studies. It is important to remember that regularly reviewing the continuation of any study is an important component in ensuring it remains ethically robust.
The principles below reflect existing guidance but have been brought together for ease of reference in the context of reviewing the research portfolio.
The amendment tool provides guidance on the relevant options to select for each scenario. The scenarios below have been summarised into a table for ease of reference.
Contents
General considerations for all studies when making decisions about amendment or closure
Participant issues to be considered for all studies when making decisions about amendment or closure
General considerations for all studies when making decisions about amendment or closure
Public involvement
Portfolio review should include public involvement to help make the best decisions, to attend to the health, well-being, and experiences of participants in the research and the interests of the relevant public contributors. It should also ensure that learnings from studies that may close are also captured and disseminated in the interests of patients and the public.
The addition of public involvement in portfolio review or dissemination does not itself require an amendment to be submitted.
Risk Assessment
The Sponsor must assess the risk/benefit and ethical considerations of key changes proposed such as:
- stopping a study and consequences for post-research care
- stopping recruitment before reaching sample size
- stopping follow up or reducing numbers of follow up visits or method of follow up
Principal Investigator oversight
An important part of the review is to encourage sponsors to consider the burden on Principal Investigators (PI) and participating site teams, and to assess whether the study could be delivered in a different way that uses more remote oversight models. For interventional studies there is HRA and MHRA guidance published in IRAS describing the appropriate level of PI oversight required to help inform risk assessment and the way that studies may be delivered.
Specifically, it describes sponsor considerations for:
- determining whether an activity associated with an interventional research study should be overseen by a Principal Investigator
- whether such oversight may only be effective if provided by an individual employed by the organisation delivering the activity, or if effective oversight could be provided by a Principal Investigator employed by another organisation.
Making results available
Sponsors should ensure that the usual responsibilities for updating registers, reporting the end of study and results, and providing results to participants are met.
Speeding up submission – electronic vs ink signatures in research approval documents
There is no requirement for ink signatures on any research approval documents. In relation to NHS sites, use of time-efficient methods of exchange of contracts and agreements, including exchange of confirmation by email, is encouraged and has been accepted for many years. The MHRA has guidance on amending your operating procedures if your own current processes still require the use of ink signatures.
Contractual implications
Changes to recruitment and follow-up or early closure of a study should be agreed between sponsor and site. For consistency across studies, and to minimise negotiation, the following approaches should be taken:
- to cease further recruitment at a site, reduce the recruitment target to the current recruitment figure. This can be done in writing without being treated as a formal contract variation.
- to close a study at a site:
- if the study has formal contractual arrangements, the sponsor should terminate the contract. All model templates have formal termination clauses.
- if the study uses the Organisation Information Document (OID), a simple written agreement between the sponsor and site to terminate should be used.
Participant issues to be considered for all studies when making decisions about amendment or closure
It is not good science nor good ethics to continue to support and recruit participants to studies that are unlikely to give rise to meaningful results. We know that not all research activity will proceed as planned. It is therefore good practice to undertake regular reviews of the delivery of a study to decide whether to continue.
Wherever possible, decisions about studies should aim to maximise the value of participants’ contributions. Key issues for participants are:
- considerations for participant safety and ongoing provision of care
- transparency regarding any change to the value of their contribution to research.
- transparency regarding the reasons for any change to their direct involvement in a study
- consideration of the need to provide continued valid consent
- transparency in publication
Participant Safety
When reviewing studies for amendment or closure the safety of participants of course remains a priority. If the safety of a participant could be put at risk because of changes being implemented, including withdrawal from active treatment, then the sponsor must ensure that there are mechanisms in place to enable the local team to ensure the continued safety of all participants.
During the beginnings of the COVID pandemic, the MHRA provided detailed guidance on handling of particular scenarios for clinical trials and devices, which sponsors might find helpful.
Consent
For any research involving consent, assent, or advice, it should be normal practice to review ongoing participation in a research study with participants or representatives. Any amendment that makes changes to participant activity, or premature closure of the study must include a process for informing participants of these changes and either obtaining their consent or safely handling their withdrawal from the study.
Seeking written consent on paper forms from a participant may not be the most efficient process to use. Sponsors should consider alternative approaches to seeking consent in line with published guidance on proportionate consent and e-consent.
Post-research care
If the sponsor decides to end the intervention for any participants and participants will finish the intervention earlier than set out in the protocol, a substantial amendment is required (an amendment is NOT required if a participant decides to withdraw early or a clinician withdraws a participant for some reason).
Sponsors should consider whether additional arrangements should be put in place for the post-trial period if any participants were benefitting from the study intervention. If it is a blinded trial, also consider whether or not to break the blind at the end of the study to inform post-trial care. Sponsors should consider continuing the treatment if any of the following apply:
- it is reasonable to expect that it will be possible to give the study intervention safely after the study
- it is reasonable to expect a clinically important benefit
- the intervention is not available through the NHS locally
- treatment options are limited
For controlled trials, consider whether treatment after the trial should only be offered to patients receiving the intervention during the study, or whether it should also be offered to those in the control arm. Particular care should be taken in life-limiting or rare diseases and where alternative treatment options are not available.
Sponsors must make logistical and financial arrangements for continued treatment before confirming the decision about the end of the study, and before informing participants.
If there are logistical, financial, safety or legal reasons for not being able to continue treatment, these must be justified to the REC. Further guidance on post research care is available on our website.
Amending the study in the amendment tool
Where it is decided because of this review that a study can be amended to improve deliverability, amendments should aim to decrease the burden on sites. General amendment guidance and a copy of the amendment tool can be found in IRAS Help. Suggestions and guidance are provided below both for amending and closing studies.
Please contact the HRA via queries@hra.nhs.uk if you have any questions, before implementing changes across all studies as a result of this review.
| DETAILS IN AMENDMENT TOOL | DETAILS IN AMENDMENT TOOL | ||
|
TYPE OF CHANGE |
AREA OF CHANGE |
SPECIFIC CHANGE |
CATEGORY AND REVIEW |
| Substantial changes to the study consent process requiring a change to the participant information sheet | Study documents | Other significant change to study documents (e.g. information sheets, consent forms, questionnaires, letters) that will have additional resource implications for participating organisations - Please specify in the free text below |
Category A or B amendment, depending on whether the change affects some or all sites. Probably additional resource required at sites |
| Changing physical visits to remote | Participant procedures | Participant procedures - minor change that can be implemented within existing resource at participating organisations - please specify in the free text below | Category C, no further study wide review. Provide information to sites |
| Any other changes to study visits or procedures—including scientific changes to protocol to allow early closure | Participant procedures | Carefully select the option applicable to the situation | Categorised and processed according to existing guidance. |
| Changes to how devices, supplies or investigational medicinal products are provided to participants-CTIMP | CTIMP IMP | Alternative arrangements to provide participants with IMP (e.g. delivery directly by courier) where there is no increased risk to the participant | Category C, non-notifiable amendment. Send directly to sites. |
| Changes to how devices, supplies or investigational medicinal products are provided to participants- NON-CTIMP |
Participant procedures |
Participant procedures - minor change that can be implemented within existing resource at participating organisations - please specify in the free text below. | Category C, no further study wide review. Provide information to sites |
| Substantial change to recruitment target | Study design | Participant numbers - Significant change to sample size | Category A or B amendment, depending on whether the change affects some or all sites. |
| Substantial change to inclusion/exclusion criteria | Study design | Inclusion/exclusion criteria - Significant change (e.g. to age range) likely to affect safety or scientific value of study | Category A or B amendment, depending on whether the change affects some or all sites. |
| Changes to monitoring arrangements—CTIMP, no change to PIS | CTIMP safety | Study oversight - Change in arrangements for monitoring (e.g. remote instead of on-site) where the arrangements will not contradict those previously described to the participant and the necessary security arrangements will be in place. | Category C, no further study wide review. Provide information to sites |
| Changes to monitoring arrangements—CTIMP, PIS to be changed | CTIMP safety | Study oversight - Change in arrangements for monitoring (e.g. remote instead of on-site) where the new arrangements need to be described in updated information for the participant. |
Category A or B amendment, depending on whether the change affects some or all sites. Probably additional resource required at sites |
| Changes to monitoring arrangements—NON-CTIMP, no change to PIS | Study Design | Other minor change to study design that can be implemented within existing resource in place at participating organisations - Please specify in the free text below | Category C, no further study wide review. Provide information to sites |
| Changes to monitoring arrangements—NON-CTIMP, PIS to be changed | Study Design | Other significant change to study design that will have additional resource implications for participating organisations - Please specify in the free text below | Category A or B amendment, depending on whether the change affects some or all sites. Probably additional resource required at sites |
| Closing to recruitment with full data collection | NOT an amendment. Inform sites and NIHR | NOT an amendment. Inform sites and NIHR | NOT an amendment. Inform sites and NIHR |
| Early closure-non interventional | Stop or Restart | Permanent closure or withdrawal of a non-interventional study | Category C, no further study wide review. Provide information to sites |
| Early closure- interventional, PIS to be changed | Stop or Restart | Permanent closure or withdrawal of an interventional study where the arrangements for post-study care will be in line with those previously described to the participant | Substantial amendment for REC, and the MHRA if the study involves drugs or medical devices. Category A or B amendment, depending on whether the closure affects some or all sites. |
| Early closure- interventional, no change to PIS | Stop or Restart | Permanent closure or withdrawal of an interventional study where the arrangements for post-study care will be in line with those previously described to the participant | Category C amendment. Non-substantial for REC, Substantial for MHRA if the study involves drugs or medical devices. No study wide review required. Provide information to sites |
How to make amendments to the Consent process
It may be possible to seek consent remotely to reduce burden on front line staff or clinical space.
Changes to physical arrangements for consent using the same text such as providing text on a tablet, or as witnessed verbal or phone consent, should be agreed and documented at site but is not a substantial amendment.
Any substantial changes to the study consent process will require a change to the participant information sheet.
How to make changes to where, how, or when patients are seen or other changes to study procedures, including follow-up
In some cases, changes can be introduced by the sponsor to reduce the burden on services or improve deliverability (for example, reducing the number of visits or the number of activities per visit, giving sites additional options for handling patient visits, changing participant site visits to phone calls or postal questionnaires). Sponsors should not make any such changes that would create additional burden to NHS staff or resources.
Changing physical visits to remote ones, without making any other change, should be handled as a non-substantial amendment.
How to make changes to how devices, supplies or investigational medicinal products are provided to participants
Where changes need to be made to how treatment or an investigational medicinal product is provided to participants, sponsors must assess the risks relating to the product and consider any shipping and storage arrangements. Where a product is being sent directly to a participant’s home, the participant must at least consent verbally to providing contact details for shipping purposes, although written consent can also be used.
Where individual sites need to arrange to courier treatments to patients, this does not need to be reported as an amendment but should be agreed with the sponsor and a risk assessment documented.
How to make changes to recruitment
Any change to a defined sample size, or changes to the study’s inclusion and exclusion criteria to improve the chances of meeting the target, would require the submission of an amendment. Any significant change to the agreed sample size or the inclusion and exclusion criteria is a substantial amendment. Any change to the end points to reduce the sample size so that recruitment can finish early is a substantial amendment.
How to make changes to site monitoring arrangements
Maintaining oversight of sites is a vital sponsor responsibility, but the monitoring process can be a considerable burden on site capacity (for example, when a research nurse has to spend an entire day going through patient notes and CRFs with the monitor). Sponsors are encouraged to adopt risk-based monitoring techniques using a combination of centralised monitoring of data alongside reduced source data verification or source data review, to reduce burden on the NHS.
Remote monitoring and source data verification must not result in confidential patient information being sent to the sponsor or stored by the sponsor if this has not already been addressed in the participant information sheet. The MHRA has produced detailed guidance on requirements for access to electronic health records.
Changing from on-site to remote source data verification does not require an amendment to the participant information sheet if this guidance is followed and the participant information sheet does not specifically refer to source data verification occurring exclusively within the physical premises of the site. Such changes to remote monitoring are a non-substantial amendment. The amendment tool currently only refers to temporary changes to monitoring arrangements due to pandemic impact, but the same options should be used if the changes to monitoring are permanent. The amendment tool is being updated to reflect this.
Sponsors should consider what monitoring needs to be done in real time, and what checks can be undertaken later, taking a risk-based approach. Where it is necessary for the sponsor to physically receive or store confidential patient information in order to undertake immediate source data verification for reasons of participant safety and data integrity, (for example, for phase I dose escalation), the participant information sheet and consent form should be revised and submitted as a substantial amendment, using the amendment tool, along with the risk assessment justifying the changes to access to confidential patient information. Such amendments will be categorised and assessed according to existing guidance.
The HRA information leaflet on research transparency has been updated to reflect remote monitoring. All participant information sheets should link to this page, which should be made available to participants
The MHRA have published detailed guidance on considerations for monitoring.
Similarly, for any non-CTIMPs that currently have on-site monitoring, changing this to remote monitoring is a non-substantial amendment unless the participant information sheet specifically refers to on-site monitoring.
Any change to the monitoring arrangements for a non-CTIMP where it is necessary to update the participant information sheet to describe the arrangements is a substantial amendment.
Submission of amendments
All amendments need to be submitted in the usual way using the amendment tool and online submission. Substantial amendments will be reviewed by the relevant regulatory authorities as well as being provided to affected sites. Any non-substantial amendments that also do not require regulatory assessment based on the guidance below will receive an automated confirmation of receipt on submission. This should then be provided to affected sites as described in the tool.
As always, any type of amendment to a research study should be sent to affected sites in accordance with existing guidance. To support site implementation, you should make sure that the changes and local implications are clear, and any changes to documentation are provided in tracked changes as well as clean versions.
For multi-centre studies involving sites in Scotland or Northern Ireland, amendments should be provided to the national coordinating functions for dissemination to the participating R&D offices as usual. Sponsors should continue to share with the Principal Investigator (PI)/delivery teams. For single centre studies in Scotland or Northern Ireland, all correspondence to sites should be copied to R&D/I department and the PI/delivery teams.
In England and Wales all correspondence to sites should be copied to R&D/I department and the PI/delivery teams. Templates are available to support provision of information.
Closing the study
Not all decisions to close a study to recruitment or to terminate a study early would be classified as substantial amendments. However, the following are likely to be regarded as substantial: a significant change to the sample size that affects the statistical basis of the protocol, changes to the definition of the end of the study (like ending a study after treatment instead of after follow up), or changes to the end-points in order to reduce follow up. See How to make changes to where, how, or when patients are seen or other changes to study procedures, including follow-up above for details of the requirements for submitting such amendments.
How to close to recruitment
Once a Sponsor decides to close to recruitment having confirmed that the data collected is adequate for analysis, all sites and the NIHR should be informed that the study is closed to recruitment and moved to follow up if appropriate.
Closing a study to recruitment does not necessarily require an amendment but changing the sample size with an impact on the statistical analysis or changing the end points to reduce the sample size would require an amendment.
Sites struggling to recruit should raise their issues with the sponsor as early as possible. Sites should not make unilateral decisions to close.
How to close a study early
If the decision to close a study prematurely involves a change to the definition of the end of the study, then a substantial amendment should be submitted.
When it is decided that a study should be closed prematurely the end of the study should be declared to regulatory authorities, and sites and participants should be informed.
Non-interventional studies
For any studies not involving provision of treatment to participants, where a study is terminated early, an end of study notification should be provided to the REC (where applicable), and the national coordinating function (and sites should be informed. Participants should be informed as per the Protocol and PIS.
Interventional studies
For any studies involving provision of treatment to participants, careful consideration should be given to post-study care.
If the closure requires changes to the information provided in the participant information sheet or additional information to be provided to participants, a substantial amendment should be submitted to amend the participant information sheet and, if required, the consent form/process. Participants must be fully informed about the implications of early termination and their choices in terms of post-study care. Such amendments will be categorised and assessed according to existing guidance.
Whether or not the participant information needs to be amended, early termination of a study should be declared to regulatory authorities, and the national coordinating function and sites should be informed. If a clinical trial has been terminated early for safety reasons it should be registered with immediate effect even if a registration deferral has been allowed by the HRA.