Research Governance

Dr Lesley Hall

Research Governance Manager

Newcastle Hospitals NHS Foundation Trust

Sept 17th 2007

17/09/072

Outline

Is what you are doing research? Research Governance – what does it mean? Research regulations and legislation

– Research Governance Framework– EU Directives (Medical Devices) and (Clinical Trials of

Medicinal Products - ctIMPs)– Human Tissue Act– Mental Capacity Act

Approvals required before beginning research Newcastle Trust R&D approvals system

17/09/073

Is what you are doing research?

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) – (formerly COREC) – go to: http://www.nres.npsa.nhs.uk/applicants/review/apply/research.htm at site entrance follow links:

– >Applicants > Apply > Research in the NHS …more info>> – Section headed ‘Is your project research?’ – Download

‘Defining Research Leaflet’

17/09/074

Defining Research

NRES Guidance sets out key discriminates– Intent – primary aim of research is to derive new knowledge (eg,

through clearly defined questions with systematic and rigorous methods) whereas audit and service evaluation measure levels of care by assessing services against standards (audit) or by asking what standard does this service achieve? (service evaluation)

– 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

17/09/076

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

Main research 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– EU Medical Devices Directives implemented in the UK through the

Medical Devices Regulations 2002 (SI No 618) (2002)– More recently:

Human Tissue Act 2004 (implemented Sept 2006) Mental Capacity Act 2005 (partially implemented Apr 2007 to

become law Oct 2007)

17/09/077

Research Governance Framework

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 patients’ rights, dignity and confidentiality. The main focus is on:

– Ethical implications of the research– The scientific quality of the research – Financial probity of the research – Clear allocation of responsibilities– Ensuring the research is well-monitored

The host NHS organisation must carry out random audits to ensure research is performed to RGF standards

17/09/078

Sponsorship under the RGF

All research in the NHS involving human participants (patients or staff), their organs, tissue or data MUST have a research Sponsor.

In most cases studies have only one Sponsor. Sponsor is not to be confused with Funder The sponsor is responsible for:

– Ensuring that arrangements are in place for the research team to access resources and support 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

17/09/079

Sponsorship in Newcastle

Main sponsorships arrangements are as follows:– Non-commercial research where NUTH Trust is the main site

and involves NUTH Trust patients, staff, facilities or premises the Sponsor is usually NUTH Trust

– Non-commercial research where NUTH Trust is an additional site then the Sponsor is usually arranged through the main site

– Non-commercial research involving tissue samples held in a Newcastle University tissue bank, using University staff and premises – Newcastle University is usually Sponsor

– For commercial research the Sponsor is usually the commercial organisation

17/09/0710

Other responsibilities under RGF

Investigators– The Chief Investigator is the 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

– In all cases where the NUTH Trust is involved there must be a ‘responsible person’ identified to accept responsibility for research governance issues in the Trust

17/09/0711

Researcher status under RGF

All researchers whose research involves direct contact with NHS patients and a direct bearing on their quality of care, must have either a substantive employment contact with the NHS or a Honorary Research Contract (HRC) issued by Trust HR departments subject to necessary CRB and Occ Health clearance

This provides NHS indemnity – The Trust indemnifies for negligent harm under Clinical Negligence Scheme for Trusts (CNST)

Other arrangements have recently been introduced for those researchers who do not have direct patient contract or bearing on quality of care where CRB and Occ Health checks are not necessary (check with Trust HR or University HR)

It is the Chief Investigator’s responsibility to ensure that all staff have either an HRC or the required letter setting out the researcher’s responsibilities and issues of confidentiality

17/09/0712

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.

17/09/0713

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 – which is a public representation of the manufacturer's claim that the device satisfies the relevant Essential Requirements in the Directives, is fit for its intended purpose and, where required, has been independently assessed by a Notified Body.

If using CE marked devices then no need to register with MHRA GREY areas – does it cross-over into medicinal products

legislation (eg, device administers a medicinal product)

17/09/0714

EU Clinical Trials Directive

The EU Clinical Trials Directive 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

17/09/0715

Definition of a ctIMP

Regulated in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) - official definition of a ‘medicinal product’:a) Any substance or combination of substances presented as

having properties for treating or preventing disease in human beings ["the first limb"]

b) 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)

17/09/0716

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)

Integrated application process – see Clinical Trials toolkit

Clinical Trials Toolkit - http://www.ct-toolkit.ac.uk/route_maps.cfm

17/09/0718

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

17/09/0719

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

17/09/0720

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

Grey areas (seek advice from MTA as codes of practice not fully established):

– Hair and nails– Plasma and serum – whole blood – if extracting DNA may require licence

17/09/0721

What do you need to use tissue?

Informed consent is the fundamental principle Consent can be for use in a specific research project if

samples are to be destroyed after use – needs ethical approval but a licence is not required

If stored need to have consent to store and be kept in a licensed tissue bank which has ethical approval

Samples can be used without consent but ethics must approve the research and samples must be anonymised

17/09/0722

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.

17/09/0723

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

17/09/0724

What does the MCA do?

The Act deals with the assessment of a person’s capacity and acts by carers of those who lack capacity

– The Act sets out a single clear test for assessing whether a person lacks capacity to take a particular decision at a particular time

– Best Interests - The Act provides a checklist of factors that decision-makers must work through in deciding what is in a person’s best interests (including written statements). Also, carers and family members gain a right to be consulted.

The Act deals with two situations where a designated decision-maker can act on behalf of someone who lacks capacity

– Creates a new form of power of attorney ‘Lasting powers of attorney (LPAs) –person can appoint an attorney to act on their behalf if they should lose capacity in the future (like the current Enduring Power of Attorney (EPA), but extends to allow an attorney to make health and welfare decisions)

– Court appointed deputies - The Act provides for a system of court appointed deputie to be able to take decisions on welfare, healthcare and financial matters as authorised by the Court but will not be able to refuse consent to life-sustaining treatment.

17/09/0725

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

– Transitional regulations will cover research started before the Act where the person originally had capacity to consent, but later lost capacity before the end of the project.

17/09/0726

Approvals required before you can begin your research

NHS Trust R&D at each site for the study Favourable ethical opinion for main and site specific

assessment for additional sites MHRA approval for ctIMPs Data protection/Caldicott approval Appropriate arrangements for using or storing tissue Honorary Research Contracts for non NHS staff

17/09/0727

Newcastle Trust R&D Approvals

For all projects we are assessing risks on behalf of the Trust – Patient safety (ethics, appropriate approvals eg.

MHRA, attention to patient confidentiality and data protection)

– Scientific risk– Financial risk – Investigator risk– Organisational risk: Sponsorship

17/09/0728

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."

17/09/0729

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 – if NUTH Trust sponsor call Trust R&D Department (RGF Manager or Res Op Manager can sign)

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.

Trust R&D must see evidence of a favourable opinion or ‘no objection at local level’ before we can finalise R&D approval

Any amendments to study or study protocol must be reported to the ethics committee and to Trust R&D

17/09/0730

Patient safety – Medical devices and medicinal products

For devices we are looking for CE marked details and other approvals (eg FDA) and information regarding previous use of the device

For ctIMPs – looking for MHRA Clinical Trials Authorisation information and EudraCT Number – must have MHRA approval before we can give full R&D Approval

Any amendments for ctIMPs – R&D must have evidence of MHRA & ethics approval to the amendments

17/09/0731

Patient safety – Data Protection/Caldicott

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 to be transferred out of the Trust e.g. to University computers, then Caldicott Guardian approval must be requested (and given)

We must have confirmation of approvals before we can give final R&D approval

17/09/0732

Scientific Risk

Research Governance Framework states that all projects should be independently peer reviewed – if large funder would expect the project to have

undergone rigorous peer review– If own account or other – the R&D office arrange the

peer review– Must have a favourable peer review before we can

give R&D approval

17/09/0733

Financial Risk

Projects must be fully costed – seek advice– Advice through Newcastle University Grants and Contracts

office if applicable– Projects being carried out in the Clinical Research Facility will

be costed there– For externally-funded, non-commerical research see the

Attributing revenue costs of externally funded non-commercial research in the NHS (ARCO) guidelines at http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4125280

– For commercial projects we have set up fees (£900 R&D Set up and £650 for Pharmacy set-up)

17/09/0734

Investigator risk

Trust R&D will check the status of all those involved in the research to ensure all have the required NHS employment contracts or Honorary Research Contracts where needed– If employed by the University of Newcastle apply

through Medical Faculty HR department (daniel.stow@newcastle.ac.uk)

– If employed by another organisation contact Trust R&D (Trust.R&D@nuth.nhs.uk) to arrange

17/09/0735

Organisational risk

If NUTH Trust is not sponsor will need to see evidence of accepted sponsorship

For ctIMPs – need to see evidence that study will be regularly monitored in accordance with GCP guidelines

– Commercial sponsor will usually organise this– If non-commercial (and NUTH Trust Sponsor) monitoring can

be arranged through the Newcastle Clinical Trials Unit (http://www.ncl.ac.uk/ihs/research/clinical)

Clinical Trial Agreement (CTAg) now common to set out sponsorship arrangements, insurance & indemnity issues etc – standard commercial and non-commercial agreements are now being used

17/09/0736

Making an application for Trust R&D Approval at Newcastle

Application form on internet (under ‘Directorates’ – ‘Research & Development’ and Trust intranet under Research & Development) with guidance notes as to what we need see - http://www.newcastle-hospitals.org.uk/directorates/research-and-development. To register a project and begin the approvals system we need:

– R&D registration form– Full (and final if possible) protocol including patient consent forms– Full breakdown of costs and funding streams– Copy of NRES application form – MHRA submission details if a ctIMP– Clinical Trial Agreements and other contracts as appropriate (eg,

commercial or non-commercial contract, Material Transfer Agreement arranged if tissue is to be transferred – R&D can arrange this)

17/09/0737

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 we have

evidence of other approvals before giving our final approval Ideally you should apply for ethics, MHRA, other approvals

(eg Caldicott) and R&D approval at the same time so that all these applications can be processed in parallel – you should NOT wait for R&D approval before applying for ethics, MHRA etc

At registration for Trust R&D approval we only need to see evidence that you have applied for these approvals – we will process your application awaiting final approvals

17/09/0738

Trust R&D Approvals Committee

We meet once a month – see Trust R&D website for deadlines for applications (2 weeks before the meeting) and dates that the Approvals Committee meets

Each project is risk assessed (representatives from finance, pharmacy, lab medicine, information governance are present)

Outcome of the meeting:– Recommend to approve– Recommend to approve subject to further

clarification of issues raised and/or final approvals from ethics/MHRA/Caldicott etc

– Recommend NOT to approve You CANNOT begin your research in the Trust without the final

letter of approval signed by the Trust CEO

17/09/0739

Useful websites

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 ctIMPs

http://www.ct-toolkit.ac.uk/ Human Tissue Authority

http://www.hta.gov.uk/ Mental Capacity Act information – Department of Health

http://www.dh.gov.uk/en/PublicationsAndStatistics/Bulletins/ChiefExecutiveBulletin/DH_4108436

17/09/0740

Contact details

Dr Lesley HallResearch Governance ManagerTrust R&D4th Floor, Leazes WingRoyal Victoria InfirmaryQueen Victoria RoadNewcastle upon TyneNE1 4LP

Trust R&D main office: 0191 2825959 or email Trust.R&D@nuth.nhs.uk