4. Risk to organisation

A complex array of organisations and individuals may be involved in a study. There should be appropriate and clear agreement of the allocation of responsibilities and rights.

4.1 Allocation of responsibilities and rights are agreed and documented

Introduction

The UK Policy Framework for Health and Social Care Research 2020 states that:

Contracts between sponsor (and, where appropriate, CRO) and participating NHS organisation(s) play an important role in allowing all parties to meet the responsibilities set out in the policy framework. A suite of UK template contracts has been established (and is added to/maintained as needed) to ensure that the content of these agreements is appropriate and can be agreed study by study without lengthy negotiation.

The UK templates are tailored to meet specific needs (for example, commercial or non-commercial, interventional or non-interventional, etc.) and cover, as appropriate, matters such as insurance and indemnity, rights and responsibilities, financial arrangements and confidentiality. It is important that the template(s) included within the IRAS submission is (are) appropriate to the study type and the activities of the NHS organisations to be undertaken, as set out in the application, and that the level of detail provided in the template(s) is sufficient to assess accuracy and consistency with the overall application (for example, in terms of level of insurance cover). The contract also has a key role in the protection of the personal data of potential and actual research participants.

GDPR Article 28(3) requires that:

As the sponsor determines the data to be processed for the study, the purpose of this processing and the means of the processing, the sponsor is the controller of data processed for the purpose of the study. Where the site or PIC processes personal data for the purpose of the study, the site or PIC is the processor of the sponsor and a GDPR Article 28(3) data processing agreement is required.

The UK templates each include clauses that (taken together with an appropriately drafted protocol, included within the contract by reference) form Article 28(3) compliant data processing agreements. The suite of agreements includes Participant Identification Centres (PIC) agreements, as well as site agreements.

Where no controller/processor relationship is established between the sponsor and an NHS organisation, GDPR does not require a legally binding agreement. This may be the case, for example, where a site is not itself processing personal data on behalf of the sponsor, because the research team is external to the site and the role of the site is restricted to NHS staff being interviewed or observed by the external team. It would also be the case where an NHS organisation is referring patients to another NHS organisation, for consideration for inclusion in an interventional research study, but is doing so primarily for clinical purposes and hence not in accordance with sponsor instruction.

In the latter instance, the NHS organisation has no formal role in the study and hence no agreement is needed. In the former instance, although no data processing agreement is needed, use of the appropriate template agreement is still appropriate because its other clauses, such as insurance and indemnity, rights and responsibilities, financial arrangements, and confidentiality, remain relevant. In all cases where an NHS organisation is participating in a study as a site or PIC, a formal agreement should be in place to document this.

Whilst each of the four UK nations has its own processes for negotiating and executing the contracts between sponsor and site(s)/PIC(s), there are common checks that should be undertaken by the lead nation as part of the UK Study Wide review.

Study wide reviewers, while not responsible for reviewing the content of the agreement per-se should still consider it in relation to other aspects of their study wide review to ensure general consistency between the agreement and other aspects of the study. Inconsistencies may arise either because of modifications to the model agreements or because of unusual study arrangements that are not reflected in the proposed model agreements.

In England and Wales, the HRA/HCRW Initial Assessment and Approval Letters both clarify for the participating NHS organisations the form(s) that the agreement(s) will take for the NHS organisations participating in the study (for example, is the sponsor proposing use of an unmodified template agreement, will they be using the Organisation Information Document etc.) Study wide reviewers should detail the sponsors intentions in the SW review.

In Scotland and Northern Ireland equivalent information is provided in the SW review (and in some cases processes are in place to negotiate contracts centrally).

Commercial studies

The suite of commercial template agreements is designed to be used without modification for commercial contract research in the NHS.

In England and Wales, NHS organisations (and, by extension, commercial sponsors and CROs) are required to use only the appropriate unmodified agreement for commercial contract research. In exceptional circumstances this requirement may be waived by the letter of HRA/HCRW Approval for the study. In some cases (CRO mCTA and mCTA), such waivers cannot be issued without prior UK agreement from the UK Four Nations Contracting Leads Group. Similarly, proposals for modifications to CRO-mCTA or mCTA for use with sites in Scotland or Northern Ireland will also be escalated to the UK Group. Requests for modifications to the other commercial agreements may be escalated to the contracting leads, as considered necessary (and it is likely that formal escalation will become the norm for all commercial agreements, as the full suite of templates embeds and matures). Sponsors and CROs are strongly advised to use only the appropriate unmodified model agreement, to avoid potentially significant delay.

It is expected that NHS/HSC organisations will accept unmodified mCTAs without further review of the standard template elements. In England, this expectation is a contractual requirement arising from NHS England's National Directive on Commercial Contract Research Studies. In Wales, the same expectation applies on a policy basis.

Where no appropriate model commercial UK template agreement exists for the type of study, the expectation that an unmodified template should be used does not apply. A bespoke agreement may be used. It is recommended that such agreements are based upon the most suitable existing national template. The UK contracting leads group is identifying gaps in the suite of agreements and working to fill these with new templates, agreed with relevant stakeholders.

Non-commercial studies

For all non-commercially sponsored studies, unless there is a single participating NHS/HSC organisation and it is the same legal entity as the NHS/HSC Sponsor for the study, an Organisation Information Document(s), supplemented by an IRAS Schedule(s) of Events or SoECAT(s) should be provided in the IRAS submission. For studies that are not clinical trials, clinical investigations, or are otherwise interventional (in other words, for all non-interventional research), the Organisation Information Document should form the agreement between the sponsor and the participating NHS/HSC organisations. The Organisation Information Document forms a key component of the UK Local Information Pack for non-commercial research projects and should therefore still be submitted for interventional studies even when it is not to be enacted as the contract.

Some NHS organisations operate a joint research office (or similar arrangement) with the legally distinct entity that is the sponsor. Where this is true the data only Organisation Information Document may be used, at the discretion of the parties, to contractually manage only the data processing aspect of a non-interventional study. It should be clear in the sponsor cover letter for the submission where this is the case and evidence may be requested that the participating NHS site is content with this arrangement. In the same circumstance, where the study is interventional and hence governed by mNCA, no Organisation Information Document is needed.

In some studies, some NHS/HSC organisations will undertake different activities to others (for example, some sites may only be recruiting and following up participants, whilst other sites undertake the research procedures. In other cases, some sites may be delivering one arm of the study and other sites another arm). In such scenarios the sponsor will need to create and submit an outline Organisation Information Document for each group of NHS/HSC organisation undertaking the same activities.

For non-commercial, interventional research, the model Non-Commercial Agreement (mNCA) should be used as the contract between sponsor and NHS/HSC site. This should be provided in the IRAS submission and Local Information Pack in addition to the appropriate Organisation Information Document(s) (in this scenario, the OID is used to provide supplementary information, whilst not itself forming the contract).

Whether the mNCA or Organisation Information Document is proposed as the agreement, it is strongly recommended that an unmodified template is used. The templates should be used as set out in their accompanying guidance. Where a template based on the model agreement is submitted but includes modification, the sponsor will be asked to explain the rationale for such modification. Where an agreement not based upon a model template is used, the sponsor will be asked to explain the rationale for not using a model agreement. Once justification is obtained, the UK SW reviewer should include this information in the SW review.

In England and Wales, the details of the proposed modifications and the rationale for each should be provided to participating NHS/HSC organisations in the HRA/HCRW Initial Assessment and Approval letters.

In Scotland the proposed agreement, including any proposed modifications, will be reviewed by the Study wide reviewer as part of the governance review and will need to be agreed before Research Permission is granted.

In Northern Ireland the study wide governance report should detail what agreement is being used so that this can be reviewed by participating HSC organisations.

Participant Identification Centres (PICs)

PICs are NHS organisations that process personal data on behalf of the sponsor to identify potential research participants for another legal entity. Hence a controller (sponsor) / processor (NHS organisation) relationship is established between the sponsor and the PIC and a controller/processor agreement is required. PICs are not research sites and should not be treated in the same way as research sites. Both the commercial and non-commercial PIC agreements are drafted as sub-contracts, allowing the site to subcontract with the PIC as sub processor of the sponsor, although the sponsor remains responsible for overseeing such subcontracting.

Both the commercial and non-commercial PIC agreements pass through the data processing terms of their header agreements (mCTA and mNCA respectively) such that the PIC, as sub-processor of the participating NHS/HSC organisation, is bound to that organisation under the same terms as that organisation is bound to the sponsor (in line with GDPR). The m-C-PICA also includes a finance appendix such that costs associated with PIC activities may be passed through to the PIC from the participating NHS / HSC organisation (in line with the finance appendix of the mCTA in place between that organisation and the sponsor) and a description of the activities to be undertaken by the PIC.

Direct contracting from the sponsor to the PIC is acceptable, although no national template is provided for this. The inclusion of PIC activity can (and should) be included in the IRAS submission at the outset of a study even if no specific PICs have yet been identified.

An NHS/HSC organisation is operating as a PIC when it:

• identifies potential research participants by processing personal data (e.g. through carrying out a search of patient records database to identify individuals that meet a study’s eligibility criteria) for the purpose of a research study (as opposed to for clinical care purposes); and
• is following the sponsor(s) instructions in identifying potential research participants; and
• directs these potential participants elsewhere without undertaking any further research activity for that study (i.e. the research occurs at another legal entity)

Organisations are not considered PICs when:

• a location within a single legal entity is undertaking PIC style activities from a separate physical location within the same legal entity (e.g. one hospital identifying potential participants to be referred to another hospital within the same NHS/HSC Trust/Board) the legal entity should be treated as an investigator site or other participating organisation and set up and contracted accordingly. Separate contracting is not required to cover the PIC style activities at different locations within the same legal entity
• they are referring to interventional studies potential participants identified in the course of normal activity (e.g. MDT, clinic, etc.) and for the purpose of clinical care. Such activity is not PIC activity, as the organisation undertaking it is an independent data controllers processing personal data for its own purpose (they are not processing data under the instructions of a sponsor, they are making normal clinical referrals for the purpose of patient care)
• they are only displaying posters, etc. to bring to the attention of their patients, or others, opportunities to participate in research projects
• they are undertaking additional activities associated with the research that would make them a research site. Where this is the case it is not a PIC but an investigator site or other participating organisation and should be set-up and contracted accordingly

A data processing agreement is a requirement for a PIC. The PIC agreement to be used in the study (where use of PICs is indicated) should be provided in the IRAS submission (or in the amendment to add PICs as a new approach to identifying potential participants, as applicable). Where the sponsor proposes a modified template, including where they propose to directly contract with PIC organisations, they should provide detailed justification for this in their IRAS submission and, where the terms differ from those in the template, this may need to be escalated to the national contracting lead, or equivalent, within the lead nation.

Where Participant Identification Centres are to be used there should be a clear process for providing information to potential participants and this should be described in the IRAS application. It should be clear (both in the application and to the potential participants) who is responsible for which aspects of the process. This should include clarity for the potential participant on under whose care they would be for the purpose of the study (that they would be transferring from the duty of care of the PIC and into that of the research site, for the purpose of the research activity).

Study-wide considerations

Confirm the intentions of the sponsor (and CRO, as applicable) as to the agreement(s) it intends to propose to participant NHS/HSC organisations. Different agreements may be needed for different participating types of NHS/HSC organisations, for example where the study makes use of Investigator sites and PICs. These agreements should be selected in line with 4 nations expectations, for example is a commercial template proposed for a commercial study, is an interventional template proposed for interventional study, if the Organisation Information Document is being proposed as the agreement, consider whether this is appropriate to the circumstance etc.?

Confirm if an unmodified template agreement is to be used for the study or whether any modifications in the template are being proposed and ensure that any modifications have been explained/justified by the applicant:

• where modifications are proposed to the mCTA or CRO mCTA, these must be escalated to the four nations contracting leads group. Modifications proposed to other agreements may also be so escalated but should first be considered in line with nation specific arrangements

If a non-template agreement is being proposed, ensure that the reasons for this (e.g. that no appropriate template exists) have been described by the applicant. Only where it is agreed that no suitable national template exists will this usually be accepted. Escalation to national contracting lead (and, thereafter, to the four nations contracting leads group, as required) is likely to be appropriate where another rationale is provided.

Have the correct appendices been included in the template to be proposed to the site (for example, where material is being transferred, the material transfer clauses, where personal data is being transferred, the data transfer clauses (in the mNCA), where a party other than the sponsor is signing on behalf of the sponsor, the confirmation from the sponsor empowering this third party, etc.)?

Where an Organisational Information Document has been provided for a non-commercially sponsored study it should describe the study consistently with the other study documents provided

Has/have the templates provided been ‘localised’ to the study (localisation, to site level by, for example, adding the name of the site, site level finance information, etc. is not expected in IRAS submissions) in adequate detail and are the arrangements therefore described consistent with other elements of the study (for example, in relation to insurance and indemnity and the transfer of human biological materials, personal data, etc.)? An agreement would normally specify:

• the sponsor organisation for the study
• the distribution of the key responsibilities
• and, where appropriate:
  • the arrangements for financial management (with reference to criteria 4.3)
  • the arrangements for monitoring of the study. pharmacovigilance or safety reporting (with reference to criteria 5.2)
  • arrangements relating to insurance and indemnity including the level of compensation for negligent and non-negligent harm (with reference to criteria 4.2)
  • any services contracted out to a third party (e.g. central laboratory services; centralised ECG interpretation; study monitoring and data collection).
  • the arrangements for the transfer of Human Biological Materials (with reference to criteria 5.4)
  • the arrangements for the handling and transfer of personal data (with reference to criteria 5.1)

4.2 Insurance / indemnity arrangements assessed

It is a sponsor’s responsibility to ensure there is appropriate provision for compensation in the event of injury or death attributable to a study, and any insurance or indemnity to cover the liability of the investigator and sponsor(s).

Introduction

The UK Policy Framework for Health and Social Care states that it is the responsibility of the sponsor to ensure that adequate insurance arrangements are in place to cover liabilities which may arise in relation to the design, management and conduct of the research project. The application should make clear the insurance and indemnity arrangements that are to be in place for the management, design and conduct of the study. The insurance arrangements should be relevant to the study and described appropriately for participants in the PIS, in a manner proportionate to the study type.

A copy of the insurance certificate is expected for all studies except those sponsored by NHS organisations. The insurance should cover the inclusion criteria of eligible participants. In some circumstances (e.g. research in conditions or with participants commonly excluded from insurance policies such as participants of childbearing potential and participants who are breast-feeding) it is appropriate that this is accompanied by confirmation from the Sponsor that there are no applicable exclusions that would affect the insurance cover available for study participants. If the sponsor is unable to provide such confirmation (where it is considered appropriate to seek this), or it remains unclear whether there may be applicable exclusions to the policy, a copy/copies of the full insurance policy document/s may be requested.

A list of all insurance exclusions (or a statement from the sponsor that there are none) should be provided in the case of Phase I CTIMPs.

It is expected that NHS organisations do not request renewals of insurance certificates since it is the sponsor’s responsibility to maintain insurance as set out to the REC. Any relevant change to the insurance arrangements would constitute a substantial amendment and hence be notified to REC for review.

It should be clear within the application whether the insurance limit is capped for the study as a whole or per patient. The sponsor of a clinical trial (which should be taken to include clinical investigations) not providing £5M of insurance cover should provide a justification for this. Study wide reviewers should provide this justification to participating NHS/HSC organisations to consider in their local review.

Negligent harm indemnity

Where the sponsor is not the NHS (where no evidence of insurance/indemnity is required) the sponsors insurance certificate (and, where relevant, the policy) shall usually specify Professional/ Employers liability and, where relevant, Clinical Trials Liability.

Management of the study

The sponsor will normally hold insurance or provide indemnity to cover their liabilities as sponsor which would cover the overall management of the study. Where an NHS organisation is a sponsor, then cover is provided through NHS schemes. No proof of insurance is expected for NHS sponsored research. Where the sponsor is not the NHS (for example where it is a commercial company, or a higher education institution) insurance will be provided through an insurance scheme. A copy of the relevant certificate (and, where considered appropriate, the full policy) should be provided.

For studies limited to recruiting NHS staff and/or independent contractors as participants and not requiring REC review, proof of insurance/indemnity for the management of a study will not be requested.

Design of the study

As per the requirements of the UK Policy Framework for Health and Social Care the design of the study is the responsibility of the study sponsor. While the sponsor may take whatever advice it sees fit, or subcontract to a third party, it remains ultimately responsible for the study protocol and the design of the study expressed therein (and in other relevant documents). Where the sponsor proposes that liability for the design of the study be covered by another party a suitable justification should be provided for this.

Where an NHS organisation is a sponsor, then cover is provided through NHS schemes. No proof of insurance is expected for NHS sponsored research. Where the sponsor is not the NHS (for example where it is a commercial company, or a higher education institution) insurance will be provided through an insurance scheme. A copy of the relevant certificate (and, where considered appropriate, the full policy) should be provided.

For studies limited to recruiting NHS staff and/or independent contractors as participants and not requiring REC review, proof of insurance/indemnity for the design of a study will not be requested.

Conduct of the study

The conduct of the research refers to the study procedures, as described in the protocol, which are conducted by the research team with participants, data or human biological material. Employers of the research team are normally responsible for the actions of their staff who conduct research procedures as part of their employment. If an NHS member of staff performs research activities (in their capacity as an NHS member of staff – i.e. as part of their NHS job) in a non-NHS location, then NHS cover still applies.

Where the research involves NHS patients under the care of NHS organisations, cover for harm to participants resulting from clinical negligence is provided through NHS indemnity schemes. No proof of this cover is expected. Cover for the purposes of non-clinical negligence remains the responsibility of the employing organisation.

Primary care

Independent contractors (e.g. GP practices, NHS dental practices) or the staff members they employ are covered by:

• in England the Clinical Negligence Scheme for General Practice (CNSGP) and,
• in Wales, the General Medical Practice Indemnity (GMPI). These are state indemnity scheme covering NHS services provided by the GPs
• Northern Ireland currently advise that GPs contact their insurer and let them know they are participating in a study providing any information requested by the insurers regarding the nature of the study and their particular role
• in Scotland there is no State backed indemnity scheme for independent practices

No evidence is required of the cover provided.

Non-negligent harm indemnity (also known as No Fault compensation)

For commercial studies arrangements for no fault compensation should be provided in accordance with the Association of British Pharmaceutical Industry (ABPI) or Association of British Healthcare Industry (ABHI) schemes. The ABPI/ABHI compensation guidelines form part of the model agreement and may not be modified. Where a commercial sponsor proposes modification of the model agreement, or otherwise does not propose to provide ‘no fault compensation’ justification should be requested and escalated as per nation specific processes.

For non-commercial studies, arrangements for no fault compensation cannot be made in advance by the NHS or other public bodies (e.g. MRC). Such organisations, although not accepting liability, may consider making an ex gratia payment on a voluntary basis in the event of a claim. Some universities or higher education institutions may choose to provide no fault compensation for research involving their employees. If this is the case a copy of the policy should be provided. It is the role of RECs to decide whether or not a study can go ahead without a scheme of compensation for harm caused where there is no negligence.

Equipment indemnity

Where equipment is under investigation and is the subject of the research proposal indemnity should be detailed, for commercial sponsors, in the study contract and evidence of insurance provided that appropriately covers the equipment being used – for example, products liability insurance. This may vary between participating nations (for Scottish purposes it may state that the Master Indemnity Agreement will apply whereas for participating organisations in England, Wales and Northern Ireland indemnity should be provided under the terms of the agreement).

In the case of non-commercial sponsors study wide assessors should clarify what the indemnity arrangements are in order to convey this information to participating NHS/HSC organisations with appropriate insurance and indemnity covered in the appropriate template agreement – with evidence of correct insurance in place.

Additionally, a research site might not have access to a piece of specific equipment to undertake the study, e.g. an ECG machine that transmits data directly to a central reading facility. In this case the Sponsor might make arrangements for the piece of equipment to be loaned or gifted to some or all research sites. Although such provision might be arranged by the Sponsor, the supplier may not be the Sponsor and hence the sponsor may be reluctant to itself indemnify that equipment. In a research study, the Sponsor must provide or arrange insurance, and should clarify the proposed insurance arrangements and explain whether it will directly indemnify participating organisations (with may be through the Master Indemnity Agreement (In Scotland) or through other means, (such as the study contract), or whether insurance will be provided by a third party such as the equipment manufacturer.

Study-wide considerations

Before a study is initiated an agreement about compensation in the event of harm to participants should have been reached. If any organisation, or the sponsor themselves, offers compensation without proof of negligence, they should have made the appropriate arrangements.

Review the following aspects of the insurance/ indemnity arrangements:

• assess whether there should be an insurance certificate (not expected for studies where NHS indemnity covers the liability that arises from the management, design or conduct of the study or for studies being undertaken in a Primary Care setting, e.g. GP Practises or NHS Dental Practises)
• consider the level of insurance/ indemnity and whether it is appropriate to the study type and purpose taking into account any justifications provided by the sponsor for levels below £5M
• are any specific exclusions to the cover detailed? (A full listing, or sponsor statement that there are no exclusions, should be provided for each Phase I CTIMP)
• for studies where study specific equipment is to be loaned or gifted to a research site confirm what equipment is to be loaned or gifted and whether this is equipment which is the subject of the research proposal or equipment being provided to facilitate the study at site SW review should clarify the planned arrangements for equipment that is to be loaned or gifted. This should be reflected in the options chosen in the model agreement and may well be nation specific (e.g. could rely on MIA in Scotland but not in England, Wales or Northern Ireland)
• a description of the study insurance/indemnity and compensation should be provided in the PIS which is proportionate to the study type. This should always be provided in the case of clinical trials and other interventional studies. If a description of ABPI compliant compensation arrangements is given in the PIS it should not be limited to provision of costs for medical treatment

4.3 Financial arrangements assessed

The way in which a study is financed is important to NHS organisations as they are legally accountable for use of public funds.

Introduction

It is important that NHS/HSC organisations are aware of the activity involved in supporting a study and what it costs. NHS/HSC organisations should be aware of the planned expenditure and attribution of costs to ensure financial probity, compliance with the law and with the rules set out by HM Treasury regarding the use of public funds.

Where the study is funded through one or more programme grant(s), the IRAS application should reflect the amount or percentage of funding that is to be used for the study. This will give a clearer indication of the study funding than the value of the total programme grant.

For non-commercially sponsored studies, the Organisational Information Document is intended to contain a description of what funding (if any) is to be provided to each site type to cover research costs. It also requests that the sponsor specifies what support should be in place locally to deliver the study. The Schedule of Events/SoECAT is designed for sponsors to attribute the site costs of their research. Where a SoECAT has been completed, and the study team intend to apply for adoption on the portfolio, the SoECAT should be validated by a CRN AcoRD expert. One copy of the Schedule of Events/SoECAT should be provided for each participating NHS/HSC site type detailing the activities taking place at that site type.

For commercially sponsored studies in England and Wales an electronic interactive Costing Tool (iCT) should be completed and submitted through the NIHR Central Portfolio Management System (CPMS). Evidence of this submission should be provided by uploading the CPMS “Submission status: In progress” email as part of the IRAS submission.

In Scotland researchers should follow the relevant NRS guidance for Determining a Price for Commercial Research Studies across Scotland and the relevant process for non-commercial costings and detail in National Differences section of Study-Wide Governance Report if applicable.

Study-wide considerations

Non-commercial studies

• ensure the letter from funder is received (if applicable). N.B. This may be clearly described as a final award, or grant, or may include conditions. Either is acceptable
• consider whether the financial management arrangements have been appropriately described
• consider the appropriateness of arrangements to reimburse other parties
• ensure that the activities described in the IRAS Schedule of Events/SoECAT are consistent with other study documentation, e.g. protocol and participant information sheet (assurance may be taken on this from an AcoRD Specialist authorised SoECAT. N.B. SW reviewers should accept an authorised SoECAT as having been appropriately authorised, without further checks on the identity of the authorising party, as it is a locked document with the password available only to authorised AcoRD Specialists)

Commercial studies

• in England and Wales, the NIHR interactive costing tool (iCT) should be completed and submitted to NIHR for all studies prior to IRAS submission, irrespective of whether the researchers wish to apply for adoption on the portfolio. Evidence of this submission should be provided by uploading the CPMS “Submission status: In progress” email

Post-study arrangements

• participants should not be given false or unrealistic expectations of post-study access to the study intervention. Where the application (particularly the participant information) suggests that post-study access to study therapies will be afforded to participants, the SW review will obtain from the sponsor evidence as to how this access will be funded and arranged

In Scotland

• study wide reviewers should obtain assurance that the sponsor will follow the relevant NRS guidance for Determining a Price for Commercial Research Studies across Scotland and the relevant process for non-commercial costings and detail in National Differences section of Study-Wide Governance Report, if applicable