Research Governance

1. Research Governance Dr Lesley Hall Research Governance Manager Joint Research Office 12th November 2008

2. 2 Outline Differences between Research/Audit/Service Evaluation Research Governance � what is it? Regulations and legislation which impact on research Gaining approvals to carry out research

3. 3 Research/Audit/Service Evaluation Not all of the projects undertaken are research. If your study is an audit or service evaluation then it would NOT be classified as research However, often difficult to differentiate Most useful guidance provided by National Research Ethics Services (NRES) Guidance page �http://www.nres.npsa.nhs.uk/rec-community/guidance/#researchoraudit Go to �Research or Audit� and download �Defining Research Leaflet�

4. 4 Main differences Treatment Neither audit nor service evaluation uses a treatment without a firm basis of support in the clinical community Allocation Research may involve allocation to treatment groups, whereas audit and service evaluation does not Randomisation If randomisation is used, it is research

5. 5 Main differences NRES Guidance sets out key discriminates Intent Research - primary aim is to derive new knowledge (eg, through clearly defined questions with systematic and rigorous methods) � What should we be doing? Audit - measure levels of treatment or care by assessing services against standards with the aim of continuous improvement � Are we doing what we should be doing? Service Evaluation � What standard does this service achieve?

6. 6 Examples of differences

7. 7 Research Governance � what does it mean? When you have decided it is research you must then be aware of how the research must be governed � about reducing risks associated with research by: Ensuring scientific quality of the research through good design and review Addressing ethical issues (particularly proper informed consent) Ensuring safety of participants Maintaining confidentiality of participants Ensuring financial probity and appropriate use of NHS resources

8. 8 Main regulations and legislation Department of Health�s Research governance framework for health and social care 2nd Edition Sept 2005 EU Clinical Trials Directive implemented in the UK through the UK Medicines for Human Use (Clinical Trials) Regulations 2004 and GCP Amendment regulations 2006 EU Medical Devices Directives implemented in the UK through the Medical Devices Regulations 2002 (SI No 618) (2002) Human Tissue Act 2004 (implemented Sept 2006) Mental Capacity Act 2005 (partially implemented Apr 2007 to become law Oct 2007) Data Protection Act 1998 and more recently Freedom of Information Act 2000 Governance arrangements for NHS Research Ethics Committees - July 2001 (GAfREC)

9. 9 Main principles of DH�s Research Governance Framework (RGF) Applies to research in the NHS involving human participants (patients or staff), their organs, tissue or data/records The aim is to bring together general principles of good practice to ensure good quality research is undertaken that respects participants� rights, dignity and confidentiality. The host NHS organisation carries out random audits to ensure research is performed to RGF standards � particularly in relation to clear allocation of responsibilities and ensuring the research is well-monitored

10. 10 Before research can start research For all research in the NHS you require NHS Trust R&D permission at each site for the study � in accordance with Research Governance Framework For clinical trials of Investigational Medicinal Products (ctIMPs) there are specific requirements and approvals required by law

11. 11 Risk assessment and approvals For all projects NHS R&D departments are assessing risks on behalf of the Trust Organisational risk: Sponsorship Investigator and other research staff risk Patient safety (ethics, attention to patient confidentiality and data protection) Scientific risk Financial risk For ctIMPs EurdraCT registration and MHRA approval Adherence to legal framework and GCP regulations

12. 12 Organisational risk - Sponsorship under RGF Must have an identified Sponsor: All research in the NHS involving human participants (patients or staff), their organs, tissue or data MUST have a research Sponsor. Usually one Sponsor responsible for : Ensuring that arrangements are in place to deliver the research as proposed. The scientific quality of the research � through peer review Ensuring all necessary approvals have been obtained Allocating responsibilities for the management, monitoring and reporting of the research

13. Sponsorship examples Non-commercial research involving NHS patients � usually an NHS Trust acts as Research Sponsor Usually the main Trust where study is initiated Some Trusts/Uni have co-sponsorship arrangements where working in partnership University can act as Research Sponsor � eg, involving tissue samples held at in a university research tissue bank or healthy volunteer only study � so where there is no NHS Trust involvement For commercial research the Sponsor is usually the commercial organisation (need evidence of accepted sponsorship through clinical trial agreement) 13

14. 14 Investigators and other researchers - status under RGF The Chief Investigator is the person designated to take overall responsibility for the design, conduct and reporting of the study � they are accountable to their employer and through them to the Sponsor of the research For multi-centre studies it is common to have a Chief Investigator located at the main site and local Principle Investigators identified at local sites Honorary Research Contracts (HRCs) for non-NHS staff with direct contact and/or direct bearing on quality of care or letters of permission/access for those working with data or tissue A full HRC provides NHS indemnity � The Trust indemnifies for negligent harm under Clinical Negligence Scheme for Trusts (CNST) � to enable them to do so must carry out essential checks (CRB and Occupational Health)

15. 15 Patient safety - ethics Evidence of ethical review - Government Arrangements for NHS Research Ethics Committees (GAfREC) paragraph 3.1 states that ethical advice from the appropriate NHS REC is required for any research proposal involving: patients and users of the NHS. This includes all potential research participants recruited by virtue of the patient or user's past or present treatment by, or use of, the NHS. It includes NHS patients treated under contracts with private sector institutions individuals identified as potential research participants because of their status as relatives or carers of patients and users of the NHS, as defined above access to data, organs or other bodily material of past and present NHS patients fetal material and IVF involving NHS patients the recently dead in NHS premises the use of, or potential access to, NHS premises or facilities NHS staff - recruited as research participants by virtue of their professional role."

16. 16 Ethics documentation required NHS Ethics Committees - National Research Ethics Service (NRES � formerly COREC) Application form online � now has a section to be signed by the sponsor before submission Now have �main REC� for each study Before you can begin you must have a favourable opinion for the main site from the main REC If multi-centre study � must have �no objection at local level� (if Site Specific Assessment necessary) for all sites. This is sent to the main REC and distributed to the Chief Investigator.

17. 17 Patient safety � Data Protection/Caldicott Informed consent is key for use of data (although Section 60 of the Health and Social Care Act 2001 exemption via PIAG in some exceptional situations) If information is to be recorded on a new database in the Trust, the database must be registered and should be held on Trust server If patient identifiable information is used or transferred out of the Trust e.g. to University computers, then Caldicott Guardian approval must be obtained "All items of information which relate to an attribute of an individual should be treated as potentially capable of identifying patients and hence should be appropriately protected to safeguard confidentiality". (Caldicott Committee: Report on the review of patient-identifiable information, 1997)

18. 18 Scientific Risk Research Governance Framework states that all projects should be independently peer reviewed � this is the responsibility of Sponsor if large funder (eg, commercial company, large charity etc) would expect the project to have undergone rigorous peer review If own account R&D office would need to arrange an independent peer review. Must have a favourable peer review before R&D approval

19. 19 Financial Risk Projects must be fully costed � seek advice Eg, through a university Grants & Contracts department or a dedicated research facility For externally-funded, non-commercial research see the Attributing revenue costs of externally funded non-commercial research in the NHS (ARCO) guidelines Commercial projects would be expected to be fully costed with appropriate overheads and all necessary set-up fees (eg, R&D and Pharmacy, if applicable)

20. 20 Clinical Trials of Investigational Medicinal Products (ctIMPs) The EU Clinical Trials Directive (Medicines for Human Use regulations in the UK) includes all interventional clinical trials involving Investigational Medicinal Products (IMPs) for human use where the aim is to test the safety or efficacy of the product � (ctIMPs) Covers all kinds of medicinal products, including pharmaceutical and biological medicines, vaccines, herbal remedies and homeopathic products Also includes a pharmaceutical form of an active substances or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a way different from the authorised form, or when used in an unauthorised indication, or to gain further information about the authorised form

21. 21 Definition of a ctIMP Regulated in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) - official definition of a �medicinal product�: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings ["the first limb"] Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis ["the second limb"] (Source: Article 1 of Directive 2001/83/EC as amended)

22. 22 Permissions needed for ctIMP ctIMP must be registered with European clinical trials database to obtain unique EudraCT number to be used on all correspondence Must obtain a Clinical Trial Authorisation (CTA) from Medicines and Healthcare Products Regulatory Agency (MHRA) For ctIMPs � need to see evidence that study will be regularly monitored to ensure study is GCP compliant (pharmocovigilance � safety reporting of Adverse Events) For commercial studies � Commercial Sponsor arranges If non-commercial monitoring should be arranged through an accredited clinical trials unit

23. 23 Good Clinical Practice in ctIMPs (Amendment Regulations 2006) Commission Directive on Good Clinical Practice (GCP) 2006 - regulating that ctIMPs are conducted to GCP standards � MHRA carry out site inspections Summary of main GCP Responsibilities: Trial documentation - Master Trial Files � including responsibilities delegation logs Adequate resources (time, facilities, staff, training, potential to recruit) Recorded evidence of investigators qualifications (signed CV), GCP training etc Rights/well-being of trial subjects (ethical approval and medical care ensured) Must comply with protocol as set out in application or have amendments approved (MHRA and Ethics) � this constitutes a serious breach in GCP if not adhered to IMPs � stored, labelled and used only in accordance with protocol Data held and stored appropriately � changes dated and initialled (no tippex) Informed consent is essential - patient MUST sign and DATE (dates cannot be added afterwards) also MUST follow the original protocol and ethics approval � MUST show that all staff trained in obtaining informed consent Regular monitoring � establishing committees and evidence of decisions made (minutes) Progress reports to Ethics and MHRA (copy to sponsor) � yearly and end to trial Safety reporting � very specific for ctIMPs regarding reporting of Serious Adverse Events (guidance available regarding legal requirements) Records retention and archiving � patient confidentiality issues

24. Use Clinical Trials toolkit when setting up a ctIMP!Clinical Trials Toolkit - http://www.ct-toolkit.ac.uk/route_maps.cfm 24

25. 25 EU Medical Devices Directive What is a Medical Device? - The Medical Devices directive defines a medical devices as: Any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of: diagnosis, prevention, monitoring, treatment or alleviation of disease, diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, investigation, replacement or modification of the anatomy or of a physiological process, control of conception, and which does not achieve its principle intended action in or on the human body by pharmacological, immunological or metabolic means, but may be assisted in its function by such means.

26. 26 Permissions needed for Devices Devices are regulated in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) The devices legislation covers the placing on the market and putting into service medical devices This enables the device to obtain a CE mark � manufacturer's claim that the device satisfies the relevant Essential Requirements in the Directives and is fit for its intended purpose If using CE marked devices in research then no need to register with MHRA Clinical devices developed and used within an NHS setting only (eg, medical physics) do not fall under the regulations � CE mark not necessary unless placing on the market (looking for EN 60601-1 standard) GREY areas � does it cross-over into medicinal products legislation (eg, device administers a medicinal product)

27. 27 Human Tissue Act 2004 Implemented Sept 2006 � Regulated in the UK by The Human Tissue Authority (HTA) for the removal, storage, use and disposal of human bodies, organs and tissue from the living and deceased. What does the Act do? Identifies the range of activities for which a licence will be required Prohibits the conduct of certain activities without a licence Establishes penalties (including custodial sentences) Prohibits commercial dealing in human material

28. 28 Definition of relevant material Included: human bodies internal organs and tissues skin and bone stem cells created inside the human body embryonic stem cells�� non blood derived stem cells� umbilical cord blood stem cell bone marrow primary human cell cultures� Not included: Embryos outside the human body cultured cells which have divided outside the human body artificially created embryonic stem cells cell lines extracted DNA��� plasma extracted DNA

29. 29 Consent to use tissue The HT Act makes consent the fundamental principle Human Tissue Authority encourages informed and generic consent for use of tissue in research at the outset - allows tissue to be used for different research projects over an unspecified period of time without obtaining repeat consent for each and every research project Exceptions � use without consent: Human tissue already held in storage for research on the day before the Act came into effect Tissue which has been lawfully removed from the living for other purposes, e.g. any surplus (or �residual�) tissue taken with consent as normal clinical care and which is left over from these procedures (note: must seek ethical approval and be anonymised) Human tissue from the body of a person who died more than 100 years ago

30. 30 Overview of tissue use A licence is only required to store tissue Even where consent is not required � a licence to store tissue is required Even where consent is not required ethics approval is always required - examples: Project specific Research Tissue Bank - can apply for generic ethics approval therefore facilitating programmes of research without a need for individual project based ethics approval as long as within established parameters If transferring to or from a Research Tissue Bank then a Material Transfer Agreement � this clarifies issues of confidentiality, storage, handling and issues of liability Use the new data and tissue toolkit!

32. 32 Mental Capacity Act 2005 Becomes law Oct 2007 The Mental Capacity Act 2005 provides a statutory framework to empower and protect vulnerable people who are not able to make their own decisions. It makes it clear who can take decisions, in which situations, and how they should go about this. It enables people to plan ahead for a time when they may lose capacity.

33. 33 Five key principles of the MCA A presumption of capacity The right for individuals to be supported to make their own decisions That individuals must retain the right to make what might be seen as eccentric or unwise decisions Anything done for or on behalf of people without capacity must be in their best interests Least restrictive intervention of the person�s basic rights and freedoms

34. 34 Research and the MCA The Act also sets out clear parameters for research Research involving, or in relation to, a person lacking capacity may be lawfully carried out if an �appropriate body� (normally a Research Ethics Committee) agrees that the research is safe, relates to the person�s condition and cannot be done as effectively using people who have mental capacity. Carers or nominated third parties must be consulted and agree that the person would want to join an approved research project � �personal �consultee� (family member, carer, friend, attorney with Lasting Power of Attorney or court appointed deputy) or a �nominated consultee� where no personal consultee available (could be professional � eg, GP, member of care team as long as not connected to research)

35. 35 Approvals required before you can begin your research To recap� NHS Trust R&D at each site for the study Favourable ethical opinion for main and site specific assessment for additional sites Honorary Research Contracts/or permissions for non NHS staff Data protection/Caldicott approval MHRA approval for ctIMPs Appropriate arrangements for using or storing tissue Approval from appropriate REC regarding MCA Any other approvals Other certificates or approvals as appropriate (eg, GTAC � for gene therapy; ARSAC � radiation)

36. 36 When to apply for various approvals Confusing as to when to apply for certain approvals It is now a requirement of final R&D approval that there is evidence of other approvals before giving final R&D approval Ideally you should apply for ethics, MHRA, other approvals (eg Caldicott) at the same time as applying for R&D approval so the applications can be processed in parallel � you should NOT wait for R&D approval before applying for ethics, MHRA etc (integrated application process) You CANNOT begin your research in an NHS Trust without the final letter of approval from that organisation

37. 37 Useful websites NUTH Trust R&D application form � internet under �Directorates� � �Research & Development� http://www.newcastle-hospitals.org.uk/directorates/research-and-development - Trust intranet under �R� for �Research & Development� Department of Health � Research Governance Framework - http://www.dh.gov.uk/en/Policyandguidance/Researchanddevelopment/A-Z/Researchgovernance/index.htm NRES � for ethics applications and guidance http://www.nres.npsa.nhs.uk/index.htm MHRA for Medical Devices and Medicinal Productshttp://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=5 EudraCT website for registering a ctIMP http://eudract.emea.europa.eu/ Clinical Trials Toolkit � essential guide to ctIMPshttp://www.ct-toolkit.ac.uk/

38. 38 Useful websites NHS (ARCO) guidelines at http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4125280 NHS RD Forum www.rdforum.nhs.uk Human Tissue Authorityhttp://www.hta.gov.uk/ Mental Capacity Act information � Department of Healthhttp://www.dh.gov.uk/en/PublicationsAndStatistics/Bulletins/ChiefExecutiveBulletin/DH_4108436 INVOLVE (formerly Consumers in NHS Research) www.involve.org.uk National Research Register (NRR) www.doh.gov.uk/research/nrr.htm

39. 39 Contact details Dr Lesley HallResearch Governance ManagerJoint Research Office 4th Floor, Leazes WingRoyal Victoria InfirmaryQueen Victoria RoadNewcastle upon TyneNE1 4LPTrust R&D main office: 0191 2825959 or email Trust.R&D@nuth.nhs.uk