This response was prepared in consultation with the Chief Scientist Office.

The NRES Standard Operating Procedure for RECs (version 3.3, April 2007) section 1.36 states the following:

'If the application is a CTIMP, and the research is to be conducted at one or more sites in Scotland, and the Chief Investigator is professionally based in Scotland, it should be allocated by the Central Allocation System to "the Ethics Committee" constituted by Scottish Ministers under the Adults with Incapacity (Scotland) Act 2000. This committee is currently known as the AWI REC in Scotland. If the Chief Investigator is professionally based outside Scotland, the application may be allocated to any Type 3 recognised REC. The ethical review of a CTIMP involving adults with incapacity in Scotland is governed by the provisions of the Medicines for Human Use (Clinical Trials) Regulations 2004. The provisions of the Adults with Incapacity (Scotland) Act 2000 are superseded by the Medicines for Human Use (Clinical Trials) Regulations 2004 where any conflict applies.'

According to the guidance above, in this situation, the AWI REC in Scotland does not need to approve the trial as the Chief Investigator is professionally based outside Scotland.

For all NHS REC approved studies

The appointment of a new Chief Investigator (CI) can be regarded as a substantial amendment since it has implications for the conduct and management of a clinical trial.

It is advised by the National Research Ethics Service (NRES) and detailed within their Standing Operating Procedures (SOP) that A Notice of Amendment Form, a copy of the CI’s CV, a signed Declaration sheet at Part B Section 7 of the Research Ethics Committee (REC) application form must be submitted to the main REC. However, if the CI is also to be a new Principal Investigator (PI), this must be noted on the Notice of Amendment Form and the new CI must submit an amended Site Specific Information Form (SSIF), the completed Notice of Amendment Form and their CV to the local REC for Site Specific Assessment (SSA). Subsequently the main REC will give an opinion on both appointments i.e. as CI and PI.

Additionally for CTIMPs If a CTIMP, the MHRA must also be informed of the substantial amendment (it is the Sponsor’s responsibility to decide whether the amendment is sent to the MHRA to seek notification or authorisation).

Source(s)
Section 5.75 - 5.76 - Appointment of a new Chief Investigator NRES SOP, September 2007

Applications for Clinical Trials of Investigational Medicinal Products (CTIMPs) on or after 1 May 2004 require a EudraCT number which is a unique reference number and the main identifier for clinical trials with at least one site in the European Community. The EudraCT database is a European clinical trials database which provides all international competent authorities with a common set of information about all CTIMPs conducted in the European Community.

Source(s)
‘Welcome to EudraCT’ European Clinical Trials Database (public site)
EudraCT Website, Version 4.1.1
The EudraCT Database
Clinical Trials Tool Kit Material

The Medicines for Human Use (Clinical Trials) Regulations 2004 define an investigator brochure (IB) as a document containing "a summary of the clinical and non-clinical data relating to an investigational medicinal product which are relevant to the study of the product in human subjects". It is required as part of the supporting data for a clinical trial authorisation for a medicinal product for human use in Phase I, II, and III trials and must be validated and updated at least once a year.

A Summary of Product Characteristics (SmPC) can be used in place of an investigator brochure where a marketed product is being used within the terms of its marketing authorisation e.g. as in most non-commercial trials which involve IMPs that are already marketed in the UK (or other EU countries). The MHRA have clarified that the requirement to update applies to the investigator brochure and not the SmPC that replaces it (unless the drug’s manufacturer updates the SmPC).

Source(s)
Section 4.3 - Assessment of Expectedness
MRC/DH Joint Project Workstream 6 – Pharmacovigilance
Pharmacovigilance Document: Final Version for CT Toolkit (12 Jan 2007)

Section 1.36 and 7 - Investigator’s Brochure
Detailed guidance on the contents of an IB can be found in the Guideline for Good Clinical Practice, ICH Topic E 6 (R1)

Yes, where research comes under the scope of the Medicines for Human Use (Clinical Trials) Regulations 2004 and as amended in 2006*, the Sponsor has specific legal responsibilities and must be based in a EEA State (European Economic Area) or have a legal representative based in a EEA State.
When the research takes place in the context of the health or social care in England but does not come under the scope of the Medicines for Human Use (Clinical Trials) Regulations 2004 (and the amended Regulations 2006), the Sponsor must be based in the UK or have a legal representative based in the UK.

Source(s)

Responsibilities of Research Sponsor – Section 3.8
Research Governance Framework for Health and Social Care, Second Edition, April 2005

Responsibilities of the Sponsor – Section 3.19
Scottish Executive Health Department, Research Governance Framework for Health and Community Care, Second Edition, 2005

Responsibilities of Research Sponsor – Section 3.8.1
Research Governance Framework for Health and Social Care in Wales, November 2001

Responsibilities of Research Sponsor – Section 3.20
Research Governance Framework for Health and Social Care, Department of Health, Social Services and Public Safety, December 2006

This response was prepared in consultation with the National Research Ethics Service (NRES) and NHS R&D Forum.

NHS Ethical Approval

NRES have published a general policy on expedited review of ethical applications in their Standard Operating Procedures for RECs (version 3.3, April 2007, Section 8). Please see the link below.

In summary, there is no statutory provision for the expedited review of applications but NRES recognises there may be circumstances whereby an application should be reviewed urgently e.g. where there is a threat to public health.

In these cases, the Chief Investigator (CI) or Sponsor should contact the Operations Director at NRES directly for advice (individual RECs have no authority to expedite applications) and they will consult with the necessary parties before making a decision on whether the application can be submitted for expedited review.

Please see Section 8 of the SOP for more information on the procedure for applying for expedited review.

NHS R&D Approval

There is no national expedited system for R&D review. However, in the case of a single centre study such as the one below involving one PCT, it would be reasonable for the CI to liaise directly with the relevant R&D office to request an expedited review. It would usually be the responsibility of the R&D Director to agree to conduct an expedited review.

As there are no national requirements for review meetings as there are for NRES, it would be for local agreement to set up the appropriate arrangements. R&D offices are expected to handle requests for R&D review appropriately and should ensure that they are able to consider such requests and make necessary arrangements.
In the case of multi-centre studies it could potentially be more difficult to arrange this. Therefore the advice service will seek advice from the DH to see whether in these circumstances they would agree to issue a letter to confirm the urgency of the need for R&D review.

Once the UK Clinical Research Network (UKCRN) central sign-off system is established (as part of the NIHR Comprehensive Clinical Research Networks CCRNs) there may be more scope for coordinating the NHS R&D review process in England. Please see the UKCRN website (link below) for information on the CCRNs.

Source(s)

NRES Standard Operation Procedures for NHS RECs (v3.3, April 2007)
UKCRN webpage on Comprehensive Clinical Research Networks

A cell culture would be regarded as ‘relevant material’ (i.e. licensable by the Human Tissue Authority1) if it contains cells that have been removed directly from the human body (i.e. it contained original cells from the biopsy or cell sample). Cultured cells would no longer be regarded as relevant material when the culture contains only daughter cells derived from the original cells by division in culture, as these daughter cells would no longer be regarded as originating from a human body. In practice this may mean that you have to justify when you decide that a culture is no longer relevant material. In order to decide you should take into consideration the type of cell in culture i.e. slowly dividing cells like neurons will remain as relevant material for longer periods when grown in culture than more rapidly dividing cells.

Source(s) 1. Human Tissue Authority website – Licensing

England, Wales and Northern Ireland

The consent provisions of the Human Tissue Act 2004 will apply. Please see the MRC Regulatory Support Centre Consent Summary for information on when consent is required for research purposes. This summarises the provisions of the Act and the Human Tissue Authority's Code of Practice on Consent http://www.hta.gov.uk/guidance/codes_of_practice.cfm

Scotland

There are two pieces of legislation that apply to research involving human tissue in Scotland:

1. Human Tissue Scotland Act 2006
2. Human Tissue Act 2004 - Section 45: Non-consensual DNA analysis

For more information on consent and other issues, please see the MRC Regulatory Support Centre Scotland Summary.

According to the Human Tissue Authority (HTA), it is not a requirement of a licence that tissue banks supply tissue only to ethically approved projects. It may be a requirement of the ethical approval of the tissue bank, as the information sheet may well say that samples will only be used in future ethically approved projects, and consent is given by the donors on that basis. If this is the case, to comply with these consent terms, all projects aiming to use the banked tissue should have ethical approval. It is advisable to check the wording of the information sheets and approved ethics submission, to see if this is the case.

If the person receiving the tissue was storing it in the UK and they did not have NHS REC approval then they would need a licence to store this material. However, the situation is different when you are exporting tissue outside of England / Wales / Northern Ireland. The HTA Code of Practice for the import and export of tissue has not been finalised. On finalisation of this Code, we will provide information on import and export.

England, Wales and Northern Ireland

The licensing provisions of the Human Tissue Act 2004 will apply. Please see the MRC Regulatory Support Centre Licensing Summary for information on when a licence is required to store tissue for research purposes.

Please see the Human tissue Authority website for more information on licensing www.hta.gov.uk

Under the EU Tissues and Cells Directive, the HTA also issues licences for storage of human cells for human application. This may be relevant for some research projects.

Scotland

There is no requirement for a licence to store human tissue for research in Scotland, unless the research involves storage of human cells for human application, since the HTA issues licences for human application in Scotland as well as the rest of the UK.

England, Wales and Northern Ireland

Samples from the deceased

A licence is required for storage of relevant material* which has come from the body of a deceased person, where the person storing it is intending to use it for education or training relating to human health, except where at least 100 years have elapsed since the date of the person’s death.

Samples from the living

A licence is not required for the storage of relevant material* which has come from the body of a living person, where the person storing it is intending to use it for education or training relating to human health.

(Source: http://www.hta.gov.uk/guidance/licensing_guidance/licensing_and_consent_exemptions.cfm)

*For information on relevant material, please see the Human Tissue Authority guidance http://www.hta.gov.uk/guidance/licensing_guidance/definition_of_relevant_material.cfm

Scotland

There is no requirement for a licence for the storage of human tissue from the living or deceased for education or training.

England, Wales and Northern Ireland

For most of the Human Tissue Act, the term Relevant Material is used (these sections of the Act do not apply to Scotland). The Human Tissue Authority has produced some comprehensive guidance on ‘relevant material’ under the Human Tissue Act 2004. Please visit their web page for this information. http://www.hta.gov.uk/guidance/licensing_guidance/definition_of_relevant_material.cfm

England, Wales, Northern Ireland and Scotland

For the section of the Human Tissue Act 2004 (section 45) on Non-consensual DNA analysis (which also applies to Scotland), the term ‘bodily material’ is used. Bodily material is defined as material that has come from the human body (living or deceased) and which consists of or includes human cells. This includes hair and nails, and does not specifically exclude gametes. There are exemptions to this, which include the following:

• material that has come from the body of a deceased person who died at least 100 years before commencement of section 45 of the Act (100 years before 1 September 2006);
• where the bodily material is an existing holding (obtained before 1 September 2006) and used for research in connection with disorders or functioning of the human body;
• where the results of DNA analysis are used for research in connection with disorders or functioning of the human body, provided the bodily material comes from a living person, the person carrying out the analysis is not in, and not likely to come into, possession of identifying information (samples can be coded) and the research is approved by an NHS Research Ethics Committee; or
• an embryo outside the human body.

The section Consent and the use of DNA (sections 116-123), of the Human Tissue Authority's Code of Practice on Consent gives a comprehensive list of ‘excepted purposes’ and ‘excepted material’. http://www.hta.gov.uk/guidance/codes_of_practice.cfm

Consent

The HT Act 2004 states that it is an offence to have bodily material with the intention of conducting analysis of the DNA in it without ‘qualifying consent’, with some exceptions (see below for ones that relate to research).

Extracted DNA and RNA (where no whole cells remain) are not classed as bodily material in the Human Tissue Act 2004 (HT Act 2004). Bodily Material is defined as material which has come from a human body and which consists of, or includes human cells (except embryos outside the human body). This includes hair and nail, and does not specifically exclude gametes.

The offence does not apply if the results of the analysis are to be used for excepted purposes, including (identified specific ones that could relate to research):

• Medical diagnosis or treatment
• The tissue is from a living person, it is anonymised and the research has been approved (or approval is pending) by a NHS Research Ethics Committee
• The research involves adults with incapacity and certain circumstances apply e.g. for the purposes of a clinical trial under UK Clinical Trial Regulations
• It is an existing holding (pre 1 Sept 2006) and uses include:
• research

Research involving just RNA or DNA does not require NHS ethical approval for the consent exemption to apply, since RNA and DNA are not classed as bodily material if no whole cells remain. During passage of the Act in parliament it was heavily argued that extracted DNA and RNA would not come under the consent provisions of the Act, hence the offence in the Act relates only to bodily material. Having said this it is obviously good practice to anonymise DNA and RNA, to ensure that consent is in place (especially if feeding back information to patients), and that ethical approval is in place.

It is clearer if this is turned on its head and we look at when consent is legally required under the HT Act 2004.

Consent is legally required for research if bodily material is:
• From a living person and samples are identifiable; or
• From a living person and samples are anonymised but no NHS REC approval; or
• From a deceased person and collected after 1 Sept 2006 (anonymous / identifiable)

Explicit consent for genetic analysis

England, Wales, Northern Ireland If consent to use material has been obtained under the Act for a scheduled purpose, other than anatomical examination or public display, it is not necessary to obtain separate consent where that use involves DNA analysis, e.g. therefore if consent for research is in place, explicit consent for DNA analysis is not required.

Good practice would dictate that the spirit in which the Act was implemented should be followed, hence when genetic analysis is being conducted, explicit consent for this should be obtained where the offence applies.

Scotland In Scotland, only Section 45 is applicable therefore explicit consent for DNA analysis is required.

Anonymised in this context means: All necessary reasonable steps are taken to prevent identifying the person from whom the material has come by the person conducting the analysis. This does not mean that samples must be permanently unlinked. The code can be retained by anyone who is not conducting the analysis.

Licensing

Storage of relevant material for research requires a licence unless it is stored for a specific ethically approved project, where the ethical approval has come from an NHS REC. Relevant material is defined as material that consists of or contains cells. Therefore the storage of extracted DNA or RNA (where no whole cells remain) does not require a licence.

Source(s)

Human Tissue Act 2004
Human Tissue (Scotland) Act 2006
Human Tissue Authority website – definition of relevant material
Human Tissue Authority Code of Practice – Consent
MRC Human Tissue Summary: Consent
MRC Human Tissue Summary: Licensing
MRC Human Tissue Summary: Scotland

This response applies to England only. Responses for other countries in the UK will be posted on this site in due course.

Negligent Harm

NHS indemnity, in England through the Clinical Negligence Scheme for Trusts (CNST), covers clinical negligence and negligent harm to patients and volunteers in research that involves NHS staff and/or NHS patients^1,2

The relevant NHS body will take financial responsibility for compensation for negligent harm unless the study were covered by such other indemnity as may have been agreed between the NHS body and those responsible for the trial i.e. the Sponsor.

The following are examples of potential events/risks which might be considered as negligent harm resulting from a research study:

• Staff negligence
• Inappropriate use of equipment
• Poorly maintained equipment
• Use of a product outside of licence
• Harm relating to premises i.e. fall on wet floor/li>
• Staff not adhering to inclusion/exclusion criteria

For all NHS research activity (commercial or non-commercial) liability for clinical negligence on the part of NHS staff lies with the health-care professional’s NHS or honorary NHS employer.

In the event of harm arising out of the design of the study, the employer of the Chief Investigator would be vicariously liable. If the employer is an NHS organisation, the NHS indemnity schemes would need to be consulted to check if this type of cover is provided³.

Non-negligent harm

Apart from liability for defective products, legal liability does not arise where a person is harmed but no one has acted negligently. In some circumstances, an ex-gratia payment may be considered. Even if non-negligent harm is unlikely to occur in a research study, participants should be made aware if there are no insurance arrangements for non-negligent cover.

Source(s)

1. NHS Indemnity: Arrangements for Clinical Negligence Claims in the NHS
2. Research in the NHS: Indemnity Arrangements
3. NHS Litigation Authority Schemes