University of Brighton Guidance on applying for ethical approval in the NHS 1.

Proposals requiring NHS ethical approval

All NHS-related research requires approval from an NHS Research Ethics Committee (REC) before it can commence. This includes research carried out on NHS property, using NHS facilities or staff, or involving NHS patients or service users, their organs, tissues or data, or their relatives or carers, as described in Section 3.1 of the Governance Arrangements for NHS Research Ethics Committees (GAfREC). It also includes research which involves people who lack capacity to consent to participation, and is therefore covered by the Mental Capacity Act 2005. However, the NHS ethical approval system is currently under review, and it is possible that the criteria for which research requires NHS ethical approval may change. This document will be updated to reflect any changes when they come into effect. Studies which fall into the categories of audit or service evaluation do not require ethical approval. However, they do need to be registered with the audit department of the relevant NHS Trust. A table is attached as Appendix 1 which can be used to help determine whether a study is research, audit or service evaluation. If there is any doubt regarding which heading the study comes under, researchers are advised to send a brief outline of the proposal to the Chair of the relevant NHS REC in order to seek advice. 2. Other approvals required for NHS-related proposals

In addition to ethical approval, management and governance approval is required from the NHS for all NHS-related projects. There is now a site-specific information (SSI) form which forms part of the National Research Ethics Service (NRES) ethical application form, which is a combined form for use both by NHS R&D offices (for any research where the site is within the NHS) and by the Research Ethics Committee system (where site-specific assessment is required for the ethical review whether for a NHS or non-NHS site). Section 9 below gives further details. However, applicants should also contact the manager of the R&D department of the relevant NHS Trust at an early stage to find out if any other approval is required, as governance procedures vary between Trusts. Contact details of R&D Managers of local Trusts are provided in Appendix 4. For some NHS-related projects the University will need to act in the role of research sponsor (ie the organisation responsible for the managing and monitoring of the research). The University has a separate Guidance on Research Governance in Health document which covers the processes involved in agreeing for the University to act in this capacity. For clinical trials of investigational medical products (CTIMPs) the sponsor is required to have clinical trial authorisation (CTA) from the Medicines and Healthcare products Regulatory Agency (MHRA). Application for CTA can be made either in parallel or in sequence with the application for ethical approval. Appendix 2 gives guidance on how to decide whether a piece of research constitutes a clinical trial. 3. Application forms and guidance notes

The NHS National Research Ethics Servics (NRES) has a single form which must be used for applications to any of its RECs. The form is web-based and is available at www.corec.org.uk The first page of the form asks questions relating to the nature of the research, and from the answers given, a form specific to the type of project is created. Section A of the form deals with questions relating to ethical review of the study as a whole, while section B asks for a list of proposed research sites and includes declarations to be signed by the Chief Investigator and sponsors representative. There then follows a site-specific information (SSI) section which is a

combined form for use both by NHS R&D offices (for any research where the site is within the NHS) and by the Research Ethics Committee system (where site-specific assessment is required for the ethical review whether for a NHS or non-NHS site). Further details on sitespecific assessment and the SSI form are given in section 9 below. Question specific advice is available via pop-up boxes on the NRES application form and it is advisable to read this carefully. NRES also has several useful guideline documents which are available on their web site at http://www.nres.npsa.nhs.uk/recs/guidance/guidance.htm These include their Governance Arrangements for NHS Research Ethics Committees (GAfREC), their Standard Operating Procedures for Research Ethics Committees (SOPs) and a guidance sheet on information sheets and consent forms. Care should be taken when consulting GAfREC as some sections of it have been superseded by the more recent SOPs, and it is therefore advisable to check the SOPs to ensure that information is current. If the applicant requires further information, guidance or advice in addition to these documents, they should consult the Manager of their local Office of Research Ethics Committees (OREC). Contact details of the Manager of Kent, Surrey & Sussex OREC are provided in Appendix 4. 4. Types of committee

There are two types of REC: Recognised RECs have been recognised by the UK Ethics Committee Authority (UKECA). Authorised RECs are established under GAfREC but not recognised by UKECA

Clinical trials of investigative medicinal products (CTIMPs) must be reviewed by a Recognised REC. There are three types of Recognised REC: Type 1 can consider applications for CTIMPs using healthy volunteers at sites across the UK Type 2 can consider applications for CTIMPs using patients in a single SHA domain Type 3 can consider applications for CTIMPs using patients from more than one SHA domain.

For the purpose of NHS ethical review, a research domain is defined as the geographical area covered by a single Strategic Health Authority (SHA). A site is normally a single organisation responsible for conducting the research at a particular locality, such as a NHS Trust or a GP practice. However, this is not always the case and research may be carried out at sites outside the NHS, including the University. More detailed guidance is given in the SOPs and in cases of doubt applicants should seek further clarification from their local OREC. For non-CTIMP research, the situation is as follows: All multi-site studies which take place in more than one domain must also go to a Recognised REC, and will normally be allocated via the Central Allocation System to a Type 3 MREC (Multi-centre Research Ethics Committee). Multi-site studies taking place in a single domain can go to any REC (Research Ethics Committee) in that domain, but would normally go to the REC of the lead site. If an agenda slot is not available, the applicant may approach an REC for one of the other sites. Single site studies can go to their nearest REC.

Applications for all CTIMPs and multi-site studies taking place in more than one domain should be sent to the Central Allocation System (CAS) for allocation to an REC, whereas applications for single site studies and multi-site studies taking place in a single domain should be booked in directly with the REC. 5. The application process

Once applicants have completed the NRES form, they should telephone the REC office or CAS to check the correct allocation of the application, book an agenda slot, check the closing date for submission and obtain a REC reference number. Applications through CAS need to be submitted to the REC within 4 working days. For applications direct to RECs the coordinators may require submission within 4 working days, or at any specified time until the closing date for the next meeting. For single site applications parts A and B of the form should be submitted together with the SSI form, unless the proposal is SSA exempt (see Section 9 below). For multi-site proposals only parts A and B need to be submitted at this stage. The application is then subject to a validation check, and if deemed valid, a letter confirming validation is sent to the applicant. At this stage the SSI forms can be submitted to the relevant REC for each site requiring SSA (see Section 9). Once a valid application has been submitted, there is a maximum 60 day turnaround time by which the REC must have reviewed the application and given the applicant an opinion on it. The main REC will review the protocol prior to their meeting, and the researcher may attend the REC meeting to answer queries. If the researcher is a student, their supervisor may also attend, and supervisors are encouraged to do so as this is often helpful in clarifying points regarding the students research. Once the application has been reviewed, the applicant will be notified of the RECs decision within 10 days of the meeting. 6. Validation

Delay can be caused if an application is returned as being invalid, so it is important to ensure the following: All questions have been completed, including the applicants checklist, and the form has been signed by the Principal Investigator or Student and the Supervisor (in the case of student research). All supporting documentation has been supplied, including the research protocol, CVs of the applicants, and any information sheets, consent forms and letters to participants as well as a statement regarding the Universitys insurance cover which is available from the applicants Head of School or their nominee. The REC reference number is on all documentation, and supporting documents such as the protocol, information sheets and consent forms are marked with version numbers and dates. The current version of the form has been used and the correct options selected on the front page of the form, so that the appropriate pages of the form drop down. The text of the form is in English, and completed in typescript with the print clearly legible. The form has been submitted both electronically and in hard copy Common problems

7.

Many applications are not approved because of common problems which can easily be avoided. These include:

Use of technical language either in the summary of the study (Question A10) or in the participant information sheet. The language used should be suitable for lay people to read, and should avoid acronyms, jargon and technical terms. Applicants should bear in mind the target audience when writing the participant information sheet, particularly where participants are likely to have a limited understanding of English (eg children or people with learning disabilities). It is recommended that applicants ask someone from the target user group to read through the information sheet to ensure it is understandable and appropriately written. Arrangements have not been made for participants who might not adequately understand verbal or written information given in English (Question A29). Where appropriate, arrangements should be made for translation of recruitment materials and information sheets, and provision of interpreters for translation of verbal explanations. Evidence has not been given of scientific peer review of the proposal (Question A45). For student research evidence needs to be supplied as to what issues have been raised by the supervisor and how these have been addressed. A guidance note on this is provided as Appendix 3. The participant information sheet and/or consent form are incomplete or misleading. Applicants are advised to use the format for these supplied in the guidance sheet available on the NRES web site (see Section 3 above). The sponsor of the research has not been identified (Question A59). Agreement needs to have been reached between the University, the relevant NHS Trust and any other parties involved (eg funding bodies) as to who will act as research sponsor. The University has a Guidance on Research Governance in Health document which outlines the process for determining who will act as sponsor. Decision of the REC

8.

The REC can reach one of the following decisions on applications reviewed at its meeting: A final opinion, whether favourable or unfavourable A provisional opinion pending outcome of Site Specific Assessments A provisional opinion, with a request for further information or clarification from the applicant No opinion, as a referee will need to be consulted before a decision is reached

Notification of the RECs decision will be given to the applicant in writing within 10 days of the meeting. Few applications receive a final favourable opinion immediately following review, and applicants should be prepared for the fact that they may need to revise and resubmit the application. Where a REC has given an unfavourable opinion, the applicant has two options: They can submit a new application, taking into consideration the feedback from the REC and addressing any concerns which they identified. Revised applications are processed and reviewed in the same way as new applications, but it should be made clear on the application form that the proposal has previously been reviewed, and the REC reference number of the original application should be cited. They can obtain a second review of the original application from another REC by giving notice of appeal to NRES.

Applicants are strongly advised to follow the first of these options, as if an appeal is made and the second REC gives an unfavourable opinion, there is no further provision for appeal. If the applicant is in any doubt about which option is appropriate, they should consult the coordinator of the REC, or the Manager of their local OREC. 9. Site Specific Assessment

For single site research, the SSI form should be sent to the REC with parts A and B of the NRES form, unless the study is SSA exempt, in which case no SSI form is required. For research taking place at more than one site, the main ethical review is carried out by one REC the main REC, and a Site-specific assessment (SSA) is undertaken for each site and investigator taking part in the research, unless the study is SSA-exempt. SSA-exempt studies are those involving routine or low risk research procedures that do not require the appointment of Principal Investigators at each site. They include: Routine investigations or assessments, such as taking blood or urine samples. Questionnaires or surveys. Qualitative research methods. Collection of data or human tissue. Routine clinical monitoring. Laboratory tests and analysis. Facilitating the recruitment of participants.

More detailed guidance is available in the SOPs. The applicant should state at Question A6 of the form whether in their opinion the research does not require SSA at any site. However, the REC reviewing the application will decide whether SSAs are required. SSI forms for proposals involving more than one site may be submitted as soon as the main application for ethical review has been validated. The ethical review and SSAs should be carried out in parallel so that the outcome of the assessments can be included in the opinion given by the main REC within the 60 day time limit. The main issues to be considered by an REC in making an SSA are the suitability of the Principal Investigator, the adequacy of the local facilities, and any local arrangements which are in place or need to be made regarding potential participants, indemnity or insurance, notification of health care staff etc. The REC carrying out the SSA should ensure that the assessment is made and the main REC notified of the outcome within 25 days of receipt of a valid application. For non-NHS sites, the SSI form is used purely for SSA by the relevant REC. For NHS sites, however, the SSI form should also be sent to the NHS R&D office contact for the site, as it contains additional information which is required for R&D review. 10. Monitoring of projects approved by an REC

Progress reports on projects which have been approved by an REC are required on an annual basis, one year after the date on which the favourable opinion has been given and thereafter until the project is completed. The forms for this are available on the NRES web site. For multi-site research, the progress report only needs to be sent to the main REC which reviewed the proposal. When a project has ended the Principal Investigator should notify the REC of completion of the research within 90 days, and a final report should be submitted within one year of the end of the project. If a study is terminated earlier than scheduled, the REC should be notified within 15 days, with the reasons for the early termination explained.

Any adverse reactions or events which are encountered during the course of the project should also be reported as they occur, as should any deviations from the original protocol, as these may necessitate further ethical review. The approving REC may also review its ethical opinion of the research at any time.

Glossary Authorised REC An REC established under GAfREC but not recognised by UKECA. An authorised REC may review all applications except those relating to CTIMPs. Central Allocation System, the booking system administered by COREC for applications to be reviewed by recognised RECs. Central Office for Research Ethics Committees (the former name of the National Research Ethics Service). Clinical Trial Authorisation, the authorisation from the MHRA to conduct a CTIMP. Clinical Trial of an Investigational Medicinal Product. The area covered by a Strategic Health Authority. Governance Arrangements for NHS Research Ethics Committee, a guidance document available on the COREC web site. In the case of multi-site studies, the REC undertaking the ethical review of the application. Medicines and Healthcare products Regulatory Agency. National Research Ethics Service Office for Research Ethics Committee, a network of COREC offices responsible for professional oversight and support of all RECs in the UK. A Research Ethics Committee established in any part of the UK in accordance with GAfREC. A REC legally recognised by UKECA to give an ethical opinion on a clinical trial of an investigational medicinal product. Site-specific assessment, an assessment of the suitability of the investigator, site and facilities made for any study with a Principal Investigator at each research site. The Standard Operating Procedures issued by COREC. These are available on the COREC web site. United Kingdom Ethics Committee Authority.

CAS

COREC

CTA

CTIMP Domain GAfREC

Main REC

MHRA NRES OREC

REC

Recognised REC

SSA

SOPs

UKECA

Appendix 1

DIFFERENTIATING BETWEEN AUDIT, SERVICE EVALUATION AND RESEARCH The table below may be used to assist researchers in deciding which category their work falls under. A useful guidance booklet entitled What is Clinical Audit? is also published by the United Bristol Health Care NHS Trust, and is available on the NRES web site at http://www.nres.npsa.nhs.uk/recs/guidance/guidance.htm#audit

RESEARCH

CLINICAL AUDIT

Designed and conducted to Designed and conducted to generate new knowledge provide new knowledge to provide best care Quantitative research Designed to answer the hypothesis based question: Qualitative research Does this service reach a explores themes following predetermined standard? established methodology Measures against a standard

SERVICE EVALUATION Designed and conducted to define current care Designed to answer the question: What standard does this service achieve? Measures current service without reference to a standard Doesnt involve a new treatment Involves no more than administration of simple interview, questionnaire or record analysis Does not involve allocation to treatment groups: the HCP and patients choose treatment Does NOT involve randomisation

May involve a new treatment May involve additional therapies, samples or investigations May involve allocation to treatment groups NOT chosen by HCP or patient May involve randomisation

Doesnt involve a new treatment Involves no more than administration of questionnaire or record analysis Does not involve allocation to treatment groups: the HCP and patients choose treatment Does NOT involve randomisation

ALTHOUGH ANY OFTHESE THREE MAY RAISE ETHICAL ISSUES, UNDER CURRENT GUIDANCE:RESEARCH REQUIRES R.E.C. REVIEW AUDIT DOES NOT REQUIRE R.E.C. REVIEW SERVICE EVALUATION DOES NOT REQUIRE R.E.C. REVIEW

Appendix 2

IS IT A CLINICAL TRIAL ?
The algorithm and its endnotes will help you answer this question. Please start in column A and follow the instructions. Additional information is provided in the attached notes. If you have doubts about the answer to any of the questions contact the clinical trials unit at MHRA (0207) 084 2327. A If you answer yes to any of the questions below go to column B. If you answer no to all these questions, the activity is not a clinical trial. B If you answer no to the question below go to column C. If you answer yes to this question the activity is not a clinical trial. C If you answer yes to any of the questions below go to column D. If you answer no to all these questions the activity is not a clinical trial. D If you answer yes to any of the questions below go to column E. If you answer no to both these questions the activity is not a clinical trial. Why are you looking for those effects? To ascertain the efficacyvi of the medicine? To ascertain the safety of the medicine? E If you answer yes to any of the questions the activity is a clinical trial. If you answer no to all these questions the activity is not a clinical trial.

Is it a medicinal product?i Are you administering a substanceii to a human subject?

Is it not a medicinal product? Are you only administering any of the following substances? *Human whole blood; *Human blood cells; *Human plasma; *Tissues except a somatic cell therapy medicinal productiii; *A food productiv (including dietary supplements) not presented as a medicine; * A cosmetic productv * A medical device

What effects of the medicine are you looking for? To discover its clinical effects?

Is the substance presented as a medicine? i.e. for preventing or treating disease Does the substance function as a medicine?vii i.e. can it be administered, with a view to making a medical diagnosis, to restore, correct or modify physiological functions in human beings or is otherwise administered for a medicinal purpose? Is it an active substance in a pharmaceutical form? Is the substance an ingredient in the preparation of a combination of substances administered for a medicinal purpose? Is it being used for a medicinal purpose?

To discover its pharmacological effects?

To discover its pharmacodynamic effects?

How are you looking for those effects? Is the prescription of the medicine linked to the decision to include the patient in the study? Is the medicine prescribed in a manner outside the terms of the marketing authorisation? Does the protocol specify when the patient will take the medicine?

To identify its adverse reactions?

Is any diagnostic or monitoring procedure added to the patients usual therapeutic strategy?

To study its absorption, distribution, metabolism or excretion?

Will methods other than epidemiological methods be used to analyse the collected data?

IS IT A CLINICAL TRIAL?
Footnotes:
i

Regulation 2 of the "Medicines for Human Use (Clinical Trials) Regulations 2004 defines "Medicinal product". It includes the definition of "medicinal product" in Article 1.2 of Directive 2001/83/EC which applies for the purposes of the Directive (2001/20/EC). It also includes the definition contained in section 130 of the Medicines Act 1968 because the pre-Ist. May UK regime operated under the Act. It is possible that section 130 also applies to substances that are not medicinal products but are deemed to be medicinal products by orders made under sections 104 and 105 of the Act. Consequently the UK regime covered some products outside the EC definition. There is likely to be very few because the definition in section 130 largely overlaps with the EC definition and we are not aware of any products deemed to be medicinal products under sections 104 and 105 of the Act. "A guide to what is a medicinal product" (the MHRA Guidance note number 8) provides further guidance and is accessible on the MHRA website (htttp://www.mhra.gov.uk) Substance is any matter irrespective of origin e.g. human, animal, vegetable or chemical.

ii iii

Somatic cell therapy medicinal products use somatic living cells of human (or animal) origin, the biological characteristics of which have been substantially altered as a result of their manipulation to obtain a therapeutic, diagnostic or preventative effect (in humans) through metabolic, pharmacological and immunological means.

Any ingested product which is not a medicine is regarded as a food. A food is unlikely to be classified as a medicine unless it contains one or more ingredients generally regarded as medicinal and indicative of a medicinal purpose. The Cosmetic Directive 76/768/EC, as amended (implemented in the UK as the Cosmetic Products (Safety) Regulations 1996(S.I. 1996/2925) as amended) harmonises the requirements for cosmetics in the European Community. A "cosmetic product "means any substance or preparation intended for placing in contact with the various external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and mucous membranes of the oral cavity with the view exclusively or principally to cleaning them, perfuming them or protecting them in order to keep them in good condition, change their appearance or correct body odours.
vi v

iv

Efficacy is the concept of demonstrating scientifically whether and to what extent a medicine is capable of preventing or treating a disease and derives from EU pharmaceutical legislation.

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Appendix 3 Guidance on evidence of peer review of student projects for NRES form Question A45 of the NRES Research Ethics Committee Application Form asks for details of how the scientific quality of the research has been assessed. Applicants are asked to justify and describe the review process and outcome. For student projects, the guidance notes say that the proposal should have been reviewed at least by the supervisor, who should ensure that the student has identified a valid research question and that the research is suitably designed, taking into account the limitations of time and resources. It is not sufficient just to confirm that the supervisor has reviewed the proposal. Evidence of the review process is required, and details should therefore be provided of any concerns or criticisms raised by the supervisor on reading earlier drafts of the proposal, and how these were addressed by the student and resolved or rectified. Additional documentation such as report forms, action lists or notes from student/supervisor meetings may be enclosed with the application as supporting evidence of supervisory review. However, a complete record of the supervisory process is not required.

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Appendix 4 Useful Contacts Kent, Surrey and Sussex Office for Research Ethics Committees (OREC) Sandra Holley Manager Tel: 01323 638613 Email: Sandra.holley@corec.org.uk Brighton and Sussex University Hospitals NHS Trust Scott Harfield Research & Development Manager Tel: 01273 696955 ext7497 Email: scott.harfield@bsuh.nhs.uk The following NHS Trusts belong to the Sussex NHS Research Consortium. Useful information regarding approvals for NHS research within these Trusts is available on the Consortium web site at http://www.sxrc.nhs.uk/research_approval/approval.htm Membership of the Consortium changes from time to time and an up-to-date list can be found at http://www.sxrc.nhs.uk/about_us/consortium_members.htm Brighton and Hove City tPCT Natasha Darby Research & Development Officer Tel: 01273 295485 Email: natasha.darby@bhcpct.nhs.uk East Sussex Downs and Weald PCT Rubee Ramtuhul (Eastbourne Downs) Research & Development Officer Tel: 01323 417714 Email: rubee.ramtuhul@eastbournedownspct.nhs. uk Dr Cynthia Lyons (Sussex Downs & Weald) Research & Development Officer Tel: 01273 403594 (PA) Email: cynthia.lyons@sussexdownsandwealdpct.n hs.uk Hastings and Rother PCT Ruth Paine Research & Development Officer Tel: 01424 735627 Email: ruth.paine@bar-pct.nhs.uk Surrey PCT Dr Ruth Milton Research & Development Officer Tel: 01252 305700 Email: Ruth.Milton@gwpct.nhs.uk West Sussex tPCT Interim arrangements for R&D cover are currently based on the old PCTs, as below: Adur, Arun and Worthing tPCT Dr Farhang Tahzib Tel: 01903 708400 Email: Farhang.Tahzib@aaw.nhs.uk Crawley PCT Frances Martin Tel: 01293 572100 Ext. 184 Email: frances.martin@crawleypct.nhs.uk Horsham and Chanctonbury PCT Debera Robertson Tel: 01403 223295 Email: debera.robertson@hcpct.nhs.uk Mid Sussex PCT Dr Peter Hayward Tel: 01444 475713 Email: peter.hayward@mspct.nhs.uk Western Sussex PCT Dr Graham Watkinson Tel: 01243 815353 (PA) Email: graham.watkinson@wsx-pct.nhs.uk Royal West Sussex NHS Trust Lindsay Marchant Research & Development Officer Tel: 01243 788122 Ext. 2746 Email: lindsay.marchant@rws-tr.nhs.uk

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South Downs Health NHS Trust Hannah Howard Research & Development Officer Tel: 01273 696011 Ext. 3642 Email: hannah.howard@southdowns.nhs.uk South East Coast Ambulance Service NHS Trust Martin Lewis (Sussex Division) Tel: 01273 897869 Email: martin.lewis@secamb.nhs.uk). Rosemary Daly (Kent Division) Tel: 01622 740334 Email: rosemary.daly@secamb.nhs.uk). LRDO for the Surrey Division is to be confirmed. Sussex Partnership NHS Trust Hazel Whalley Research & Development Officer Tel: 01323 444117 Email:hazel.whalley@sussexpartnership.nhs .uk Worthing & Southlands NHS Trust John Sitzia Research & Development Officer Tel: 01903 285224 Email: john.sitzia@wash.nhs.uk

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