6. Approvals and authorisations

6.1 NHS Research Ethics Committee favourable opinion received for applicable studies

Introduction

The UK has a hybrid system of research ethics committees (RECs). There are two main categories of committee:

• NHS RECs, and
• non-NHS RECs (e.g. institution-based higher education RECs)

Working in a centrally administered system, NHS RECs can consider and give an opinion on research anywhere in the UK. NHS RECs review research applications to give an opinion about whether the research is ethical. They are entirely independent of research sponsors, funders and investigators.

The UK policy document ‘Governance Arrangements for Research Ethics Committees’ document describes what a REC should be like and when their review is needed.

NHS RECs are:

• ‘Recognised’ (i.e. legally recognised by UKECA) to give an opinion on CTIMPs
• ‘Authorised’, meaning they are set up under GAfREC (Governance Arrangements for Research Ethics Committees), but not recognised by UKECA to consider CTIMPs

NHS RECs may have expertise in a particular area, e.g. medical devices, adults lacking capacity, prisoners, US DHHS funded research. These RECs will be flagged for particular expertise.

NHS RECs should reach one decision when considering research applications:

• Final opinion, i.e. favourable with standard conditions; favourable with additional conditions; or unfavourable
• Provisional opinion with request for further information
• Provisional opinion pending consultation with referee

Note: The Ministry of Defence Research Ethics Committee (MoDREC) is set up by the MoD and recognised by UKECA to consider clinical trials. MoDREC approved research that continues in the NHS or adult social care sectors in the UK after participants move into their care, does not need to be considered by an NHS REC. The only exception to this is research that needs to be considered under the Adults with Incapacity (Scotland) Act 2000.

Study-wide considerations

Does the study require NHS Research Ethics Committee (REC) favourable opinion?

Confirm if the study needs NHS REC opinion.

Use the Health Research Authority (HRA) decision tool ‘Do I need NHS Ethics approval?‘ to decide if the research needs NHS REC favourable opinion.

In some circumstances nation specific REC review is required.

• where the study proposed to recruit adults lacking capacity in Scotland then review by Scotland A REC is required. Where the study proposes to recruit adults lacking capacity in Scotland and in other UK nations then ethical review is required both by Scotland A REC and also by a REC in another UK nation
• where the study involves persons or information about persons under the care of an organisation covered by the Nursing Homes Regulations (Northern Ireland) 2005, the Residential Care Homes Regulations (Northern Ireland) 2005, the Independent Health Care Regulations (Northern Ireland) 2005 or otherwise intends to take place in a Social Care setting in Northern Ireland then it must have review by a Health and Social Care REC in Northern Ireland. Where such a study additionally proposes to recruit participants in other UK nations then this favourable opinion granted by the REC in Northern Ireland will be applicable to the other UK nations and no additional review is required

Has the NHS REC favourable opinion letter and all relevant correspondence been received?

Confirm receipt of the NHS REC favourable opinion letter and all relevant correspondence.

It is important that the favourable opinion letter and all relevant correspondence is collated and made available/ distributed to all participating nations to ensure that:

• any queries raised and addressed as part of the REC review are not re-examined unnecessarily
• the applicant is unable to revise a study document leaving out information already asked for by the REC

Have the conditions of NHS REC favourable opinion been met?

Confirm the applicant has met any conditions identified as part of the NHS REC favourable opinion.

In giving a favourable opinion, the NHS REC may specify conditions the applicant has to meet before to the start of the study (or the start at each site). These will be clearly set out in the NHS REC favourable opinion letter.

The applicant writes to the NHS REC to tell them they have met the conditions. If necessary, they must also include copies of final documents for reference purposes.

The NHS REC will confirm receipt using an ‘Acknowledgement of documentation provided following favourable opinion with conditions’ letter. This will give a complete list of the final documents approved for the study.

Have the documents needed for UK study wide review been received?

For non-CTIMPs study wide reviewers should confirm receipt of all the correct documents (i.e. correctly labelled, version numbered and dated) needed to carry out UK study wide review.

When carrying out the UK study wide review, it is not necessary to receive or to review all documents sent to the NHS REC or listed in NHS REC favourable opinion letters.

These documents are not required to carry out the UK study wide review and should not be requested:

• letter from statistician
• summary CV of Chief Investigator (CI)
• referee’s report or other scientific critique report
• summary, synopsis or diagram (flowchart) of protocol in non‑technical language
• details of Data Monitoring Committee
• summary of product characteristics (SmPC)
• covering letter on headed paper
• letter from Sponsor
• confirmation of EudraCT number
• manufacturer Authorisation
• certificate of analysis
• outline of active trials
• list of competent authorities
• GMP documents
• GLP documents
• IMPD
• EUDRACTPDF/XML

Note: If there are any new or updated documents because of NHS REC review, it is necessary to get the new or updated documents.

Any errors or omissions in the NHS REC favourable opinion letter, is the responsibility of the Sponsor, or delegate, to liaise with the NHS REC to have corrections made.

6.2 CTIMPs – Clinical Trial Authorisation (CTA) letter received

Introduction

No clinical trial of an investigational medicinal product (CTIMP) in the UK can be started or carried out, recruit participants or advertise to recruit participants until the Medicines and Healthcare products Regulatory Agency (MHRA) authorises it.

The MHRA also provides a proportionate notification scheme for lower-risk trials, defined as ‘Type A’ trials. In ‘Type A’ trials, the Sponsor considers that the risk to participants from the IMP is no greater than that of standard care.

The Sponsor is responsible for determining if the research is a CTIMP requiring a Clinical Trial Authorisation. All trials whether ‘full’ applications or applications under the notification scheme, require a Clinical Trial Authorisation. The authorisation may be in different formats depending on proportionality.

The Sponsor or delegate makes an application (or notification) for authorisation using the appropriate IRAS application forms with accompanying documents.

The MHRA can carry out the review of an application in parallel to the review by the participating NHS/ HSC organisation. An NHS/ HSC organisation should not delay beginning its review until the MHRA grants an authorisation.

There is no requirement for the Sponsor to supply a copy of the application, submitted to the MHRA, to the NHS organisation for review as well.

The participating NHS/ HSC organisation should not initiate a CTIMP until the MHRA grants that CTIMP a Clinical Trial Authorisation (or equivalent under the Clinical Trial Notification Scheme).

Study-wide considerations

Does the study require a Clinical Trial Authorisation?

Confirm if the study needs authorisation from the MHRA.

Use the MHRA’s online algorithm ‘Clinical trials for medicines: apply for authorisation in the UK - GOV.UK‘ to decide if the research needs authorisation. If in doubt, the Study Wide reviewer may request that the applicant obtain clarification from the MHRA (by completing the relevant form and sending it with the protocol to clinicaltrialhelpline@mhra.gov.uk ), or may themselves seek clarification (via the same email address, with a copy of the protocol but without the form).

Has the MHRA Clinical Trial Authorisation and relevant correspondence been received?

Confirm receipt of the MHRA Clinical Trial Authorisation (including acknowledgement where accepted under the Notifications scheme) and all relevant correspondence.

It is important that the authorisation (or acknowledgement where accepted under the Notification scheme) and relevant correspondence is collated and made available/ distributed to all participating nations to make sure that:

· any queries raised and addressed as part of the assessment are not re-examined unnecessarily

· the applicant is unable to revise a study document leaving out information already asked for by the MHRA

Does the authorisation have any conditions to meet?

Identify and highlight any conditions the authorisation specifies the Sponsor needs to meet during the study.

The MHRA will normally only issue conditions that do not require a response, or that will require a substantial amendment sometime during the study.

6.3 Devices – MHRA Notice of no objection received

Introduction

The sponsor is responsible for determining whether a study involving a medical device is an investigation that requires a notice of no objection from the Medicines and Healthcare products Regulatory Agency (MHRA).

A Notice of No Objection must be obtained from MHRA Devices for a clinical investigation of a medical device undertaken by the manufacturer for UKCA/CE/CE UKNI marking purposes. This will be either an investigation of a non-CE marked product, or an investigation of a CE marked product that has been modified or is to be used outside its intended purpose. Further, sponsors of a ‘Proof of Concept’ / prototype clinical study must obtain from the MHRA a No Objection letter confirming the study does not require a formal clinical investigation’

MHRA approval is not always required in the case of:

• medical devices manufactured ‘in-house’ in a healthcare establishment
• clinician led off-label use of a medical device

The MHRA review of a Medical Device application can be carried out in parallel to the review for the NHS and REC. There is no requirement for the Sponsor to supply a copy of the Medical Device application, submitted to the MHRA, to the NHS for review as well.

The NHS organisation should not allow the study to start until the Medical Device application has been granted a Notice of no objection.

For studies requiring an MHRA notice of no objection, UK Study Wide review will not be completed (and, in England and Wales, HRA/HCRW Approval will not be issued) before the MHRA notice of no objection has been issued and the sponsor has confirmed in writing that any conditions on the notice have been met, including evidencing this where requested.

In England and Wales there is no expectation that the applicant send their MHRA notice of no objection to the HRA/HCRW, as these will be communicated directly, although the HRA/HCRW may choose to contact the applicant to confirm that any applicable conditions have been met.

Study-wide considerations

Where required confirm the Medical Device application has been granted a Notice of no objection by the MHRA.

Has the MHRA Notice of no objection letter for the medical device application been received?

When reviewing if the MHRA Notice of no objection has been received, consideration should be given to the following. A MHRA Notice of no objection does not exempt an NHS/HSC organisation from adhering to the MHRA’s guidance and an NHS/HSC internal guidance on managing medical devices, to ensure that all devices are safe before use.

Notice of no objection without conditions

A MHRA Notice of no objection letter without conditions should be accepted as received.

Notice of no objection with conditions

A MHRA Notice of no objection letter may be received indicating conditions as part of the authorisation.

• confirm that there is evidence that the conditions of the Notice of no objection have been met
• if appropriate, correspondence between the Sponsor and the MHRA related to addressing any conditions should have been received

Clarifications made in the medical device application submitted to the MHRA

During their review of a Medical Device application the MHRA may request clarifications in relation to the application.

• if correspondence is received relating to any clarifications made in Medical Device application submitted to the MHRA, the clarifications should be highlighted to the research site
• in some cases, it may not be appropriate to view all correspondence between the Sponsor and the MHRA, as the correspondence may be commercially confidential, not relevant to the NHS

Amendments

Confirm that any substantial amendments requiring review by the MHRA for continued Notice of no objection have been supplied to the MHRA.

6.4 Other regulatory approvals and authorisations received

Introduction

Some studies will require approvals from bodies other than REC and MHRA. The study-wide reviewer should assess which approvals are required and whether such approvals should be in place before the study may start. Where an approval is required before the study may start in any UK nation, UK SW review should not be concluded until it is in place. There are instances where such approval/s is/are required but the study may start in one or more UK nation before they are in place (e.g. an outstanding HMPPS approval, required for England and Wales, should not delay a study starting in Scotland and/or Northern Ireland). In such instances, UK SW review should be concluded even where the approval/s is/are not in place, but the reviewer should emphasise the outstanding approval/s required in their SW review document.

Administration of radioactive substances

The Ionising Radiation (Medical Exposure) Regulations 2017 and the Ionising Radiation (Medical Exposure) Regulations (Northern Ireland) 2018 (both referred to as IRMER) place requirements on the authorisation and conduct of research projects involving the administration of radioactive medicinal products to humans.

Central ARSAC research approval must be obtained for all research projects that:

· require the administration of radioactive substances, and/or

· specify the frequency, activity or processing for an administration that would otherwise be considered standard care

Central ARSAC research approval is not required for projects where:

· the protocol does not specify any administrations of radioactive substances, and/or

· the only administration of a radioactive substance mentioned in the protocol is an inclusion criterion that would be received by all participants as part of standard care - for example, a trial where all participants must have received a radioiodine therapy to be considered eligible

There is further guidance on the IRAS website about which exposures are considered research exposures and therefore whether ARSAC approval may be required.

Central ARSAC Research Approval is applied for via IRAS. The SW reviewer should assess whether a study requires ARSAC research approval before it may commence and, where it does, should not complete their SW review until this approval is in place.

For research studies involving the administration of radioactive materials which are additional to normal care at a site, the site itself and a relevant nuclear medicine professional at that site require an ARSAC licence covering the exposures (as research exposures). SW review does not assess which sites might need to be covered in this way, nor are any SW checks necessary that any sites are covered. These are local concerns.

Procedures involving the administration of radioactive materials include:

· PET-CT

· Nuclear Medicine Bone Scans

· MUGA

Diagnostic X-rays, CT scans and DXA do not involve the administration of radioactive materials.

Accessing patient information without consent

In England and Wales

The Health Research Authority’s (HRA) Confidentiality Advisory Group (CAG), has been established for the purposes of section 251 of the NHS Act 2006, and the COPI regulations 2002, to provide independent expert advice to the HRA on whether applications to access confidential patient information without consent for research should or should not be supported. Supported applications allow the controller(s) of the relevant data sources, if they wish, to provide specified information to the recipient for the purposes of the relevant activity without being in breach of the common law duty of confidence. Support provides a lawful basis to allow the information to be processed by the relevant parties for the specified purposes without incurring a breach of the common law duty of confidence.

The role of CAG is to review applications and advise whether there is sufficient justification to process requested confidential patient information for the purposes described in the application. Applications to the CAG are required for access by persons outside of the care team to:

· identifiable patient information relating to people living in, or receiving healthcare in England and/or Wales without explicit consent, prior to the disclosure of confidential information, or

· Human Fertilisation and Embryology Authority (HFEA) Register Data

The Health Research Authority Confidentiality Advisory Group should also be notified of all amendments to the information provided in the original application to CAG. 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. Amendments should be submitted using the CAG specific amendment form available here. The amendment will be considered in accordance with the CAG SOPS, and a formal letter issued that will confirm whether or not it has been approved or if further information is required. All amendments must be listed in the annual review that the applicant should submit to the CAG.

In Scotland

If your project seeks access to NHS Scotland data including unconsented or consented administrative data from national or multiple NHS Scotland Boards then approval is required from the NHS Public Benefit and Privacy Panel for Health and Social Care

For projects seeking access to data from a single Scottish site Caldicott Guardian approval may also be required from the relevant Scottish Health Board.

In Northern Ireland

There is no equivalent legislation in place that enables confidential personal information to be shared without consent for research.

Human Fertilisation and Embryology Authority (HFEA)

A licence from HFEA is required for:

· research involving human embryos and gametes

· disclosure of protected information from the HFEA Register

Human Tissue Authority (HTA, England, Wales and Northern Ireland)

The HTA does not approve individual projects or license activity itself but organisations that store human tissue for research (‘establishments’), including the following activities:

· removal of relevant material from the deceased for the scheduled purpose of research

· storage of relevant material (from both the living and the deceased) for the scheduled purpose of research

A licence is not required for storage in connection with a specific research project with approval from a REC.

Organisations where clinicians or clinical units collect and supply biological samples or data to a research tissue bank or research database are not considered to be research sites. For example, a hospital may provide biological samples surplus to diagnostic use to a research tissue bank. If the biological sample or data is not collected specifically for the purposes of a particular research project, then the organisation is a Tissue Collection Centre (TCC).

Study‑wide considerations

ARSAC

Local ARSAC licenses are issued at a site and individual level and there is no requirement for local ARSAC licenses to be issued prior to completing the study-wide review.

Accessing patient information without consent

Confirm the study has received the appropriate approvals to access patient information without the patient’s consent (or another legal basis is in place, as applicable and appropriate). Each nation considers the request to access patient information without consent differently. The study‑wide reviewer should also highlight that the approval to access patient information without consent may not be applicable to another nation, and that the reviewers in those other nations should consider this before satisfying the check.

Accessing criminal offenders

Confirm the study has received the appropriate approvals to access criminal offenders. Each nation considers the access to criminal offenders for research studies differently. The study-wide reviewer should also highlight that the approval to access criminal offenders may not be applicable to another nation, and that the reviewers in those other nations should consider this before satisfying the check.

In England and Wales

In England and Wales approval should be obtained from Her Majesty’s Prison and Probation Service (HMPPS) for any research project which requires access across HMPPS (including headquarters), including any community-based/custodial provider in England or Wales, e.g. Community Rehabilitation Companies (CRCs) and their subcontractors, Contracted Prisons and Young Offenders’ Institutions (YOIs) and Secure Training Centres (STCs).

In Scotland

After obtaining clearance from the Scottish Prison Service Research Access and Ethics Committee (RAEC) applications for research proceed as per standard processes via IRAS. Further guidance can be found at Permissions | NHS Research Scotland | NHS Research Scotland.

In Northern Ireland

HMPPS is not applicable to Northern Ireland. Advice on health and social care research involving prisoners in Northern Ireland, can be obtained from research.development@setrust.hscni.net

Studies funded by the US Department of Health and Human Services (DHHS)

Confirm that the study has been reviewed by an appropriate Research Ethics Committee (REC), i.e. a REC that has been flagged ‘IRB Registered.’

As well as being flagged to review research studies funded by the DHHS they must also be able to review the type of study being supported. For example, a clinical trial of an investigational medicinal product (CTIMP) with funding support from the DHHS must be reviewed by a committee that is both recognised to review the relevant type of CTIMP and registered with the OHRP. Details of the committees that are registered with the US Office for Human Research Protections (OHRP) can be obtained from the National Research Ethics Service (NRES) Central Allocation System (CAS).

HFEA

Confirm that an HFEA licence has been issued.

HTA (England, Wales and Northern Ireland)

Where the application refers to a licensed research tissue bank, confirm that an HTA licence has been issued.

Where the research involves collection of tissue from sites for a licensed research tissue bank, highlight that the sites are Tissue Collection Centres.

Genetically Modified Organisms (GMOs)

There are two broad categories of use of Genetically Modified Organisms (GMOs), each with their own legislative framework and supervisory authorities:

· Contained Use, overseen by the Health and Safety Executive (HSE) which has a UK wide remit. Contained Use activities are further divided into risked-based classes. Authorisation from the HSE is for a Contained Use within a specific class at registered premises. A new application is not required to undertake any further activities in the same class at the same premises

· Deliberate Release, which is overseen by DEFRA in England and equivalent authorities in Scotland, Wales and Northern Ireland. Authorisation is for certain premises to release GMOs

As the authorisations for GMOs are issued for premises and cover a type of activity rather a specific research study, there is no requirement for GMO authorisations to be issued prior to completing the study-wide review. Where a research study involves the use of GMOs, this should be noted in the study-wide review. It is not expected that the study-wide review will determine the type of activity (Contained Use or Deliberate Release), or a class of activity within these types. The output of the study-wide review for NHS/HSC organisations should flag that the research study involves the use of GMOs and that the organisations should consider whether they have existing authorisation for this type of activity at their premises, or if they will require a new authorisation from the relevant supervisory authority for the use of GMOs required for the study.