Research Guidelines Research Governance EU Directive on Clinical

Research Guidelines Research Governance EU Directive on Clinical Trials ICH-GCP: ØInformed Consent ØSafety & Adverse Events ØDocumentation - Audit

ICH definition - GCP "A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected" ICH E 6 1. 24

ICH-GCP • The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use • ICH-GCP - Good Clinical Practice guidelines agreed at the conference

The objectives of ICH GCP Guidelines • Developed with consideration of the current good clinical practices of the European Union, Japan & USA, plus those of Australia, Canada, the Nordic countries & World Health Organisation. • Provide a unified standard for the European Union, Japan & USA to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

Good Clinical Practice - GCP • What is GCP? “Ethical and scientific quality standards for designing, conducting, recording and reporting trials that involve participation of human subjects” • Why is it needed? To ensure that the RIGHTS, SAFETY and WELLBEING of the trial subjects are protected Ensure the CREDIBILITY of clinical trial data • Why has it developed into formal guidelines? Public disasters, serious fraud and abuse of human rights

ICH GCP Guidelines cover… Ethics Committee /IRB Clinical Trial Protocol & Amendments Investigator’s Brochure Sponsor Essential Documents for conduct of a trial

Responsibilities of the Investigator • • Randomization Compliance • Records Ethics • Reports Informed Consent • Resources Investigational drug • Safety reporting Qualifications • Unblinding Medical care of trial subjects Agreements

World Medical Association Declaration of Helsinki • Adopted by 18 th WMA Assembly, June 1964 (Helsinki, Finland) • Covers all “medical research” • Most recent amendment October 2000 changes include: Peer review of protocol, supervision of research, results to be made available, test against “gold standard”, access to best proven treatment at end of research.

Research Governance Framework

Scope of the Framework § Research by staff with Trust and Honorary Trust Contracts § Research involving patients, service users, care professionals, volunteers or their organs, tissues or data § Research funded by the NHS § Research using facilities funded by the NHS

Aims of the Framework § To promote a quality research culture § To promote excellence § To provide strong leadership for research § To implement standards: § set out in legislation and regulations § required by the Department of Health § established as good practice

Research Governance domains § Ethics § Science § Information § Health, Safety and Employment § Finance and Intellectual Property

Ethics - key points § Independent review of research involving patients, service users, care professionals, volunteers, or their organs, tissues or data § Consideration of the dignity, rights, safety and well being of participants § Informed consent § Data protection § Consumer involvement § Diversity of human culture § Avoidance of animal experiments

Science - key points § Peer review – commensurate with the scale of research § Regulation by the MHRA and MDA § Data retention to allow further analysis and support monitoring

Information - key points § Free access to information on research being conducted and research findings § Publication of results in a format understandable to the public § Making findings available to participants

Responsibilities of the Researcher § Developing proposals § Seeking ethical committee approval § Conducting research according to the agreed protocol § Ensuring participant welfare § Feeding back results to the participants

Responsibilities of the Sponsor § Assuring scientific quality (peer review) § Ensuring research ethics committee approval § Ensuring arrangements for the management and monitoring of research

Responsibilities of the Care Organisation § Ensuring that research using their patients, users, carers or staff meets the standards in the Research Governance Framework § Ensuring ethics committee approval § Retaining responsibility for research participants’ care

Sanctions “the assumption will be that there is full compliance (or else research is stopped)”

The EU Clinical Trials Directive 2001/20/EC The Medicines for Human Use (Clinical Trials) Regulations 2004

Aims of the EU Directive • To simplify and harmonise the administrative provisions governing clinical trials in the EU • To facilitate the internal market in medicinal products • To maintain appropriate protection for public health

Application of GCP ICH-GCP is to be the GCP standard (EU GCP Directive 2005) All drug trials will need: – an ICH-GCP compliant protocol – an investigator brochure – case report forms – a site file – to report SAEs

The regulations cover: • All medicinal products – medicinal by function or presented as treating or preventing disease in human beings (including health products) • All phases of trials - including Healthy Volunteer Trials • Trials sponsored by industry, government, charities, universities, NHS organisations • Trials recruiting participants after 1 st May 2004 – the regulations are RETROSPECTIVE • Devices are exempt if looking at mode of delivery (comparing devices) rather than dosage Further guidance is still awaited

EU Directive & Informed Consent • Standards currently adopted in the UK comply with the Directive • However, the Directive states that a “legal representative” may act for a trial subject that is not able to give informed consent Ø A formal mechanism to appoint a legal representative for incapacitated adults will be introduced

Indemnity/Compensation • Provision must be made for compensation for non-negligent harm for all trials e. g Ø The clinical negligence scheme for Trusts Ø University Public Liability Insurance Ø Specific Clinical Trials insurance • ABPI model indemnity agreements to used for industry sponsored trials

Licensing Authority Approval UK “competent authority” will be the Medicines and Health-care products Regularity Agency (MHRA) • Prior authorisation is required for all trials and substantial amendments • Consideration the MHRA within 30 days, extendable to 60 days • SAE reporting protocols • Report to the MHRA within 90 days of trials conclusion • If trial is terminated or ended prematurely notification required within 15 days

EU Directive & Ethics Committees • 60 day time limit for decisions • A single request for additional information • Approval or Rejection decisions • Approval to take place in parallel with licensing authority approval • Extended time limits for gene therapy, somatic cell therapy, medicinal products containing Genetically Modified Organisms and xenogenic cell therapy trials • 35 day time limit to review amendments • If trial is terminated or ended prematurely notification required within 15 days • Substantial amendments to be notified

Substantial Amendments are considered to be substantial if they are likely to impact on: • Subject safety • Scientific value of the trial • Conduct or management of the trial • Quality or safety of the IMP • Duration of the trial - anything other than minor administrative amendment

EU Directive & Competent Authority - Information to Support Approval Core information - Required by the Directive • Covering letter • EUDRACT form - register via MHRA • Protocol • Investigator Brochure • Investigational medicinal products dossier - Ph 1 trials • List of CA to which an application has been made • EC opinion if available Member State Specific Local information: consent forms, information sheets, recruitment, indemnity, manufacturing of IMPs

EU Directive & Good Manufacturing Practice and Investigational Medicinal Products • Manufacture or importation from countries outside the European Economic Area will require prior Licensing Authority authorisation • All products to be approved by a “Qualified Person” (QP) as compliant with GMP • Labelling requirements • Unlikely that Manufacturer’s licence and QP will be required to cover reconstitution and packing of IMPs by hospital Pharmacists

GCP and GMP Inspections • Inspections to be undertaken (by MHRA) of trial sites, manufacturing sites, laboratories used for analysis and sponsors premises • Charges to be levied, amount still to be determined • Inspections will be of two types: Ø Cyclical, systems based inspections of sponsors Ø Triggered inspections as required

Safety Reporting • PI to identify category • Complete Safety Report Form (s) • Forward as appropriate to Trust and Sponsor within 24 hrs • If SUSAR Sponsor to forward to REC, MHRA and relevant CA outside UK if applicable (EUDRAVIGILANCE database). • N. B. It is relevant to report events that may be related to placebo or reference drugs N. B. If SAE for non-CTIMP report within 15 days using non-CTIMP SAE form (COREC/UHL website)

Timelines for Sponsor further reporting • Fatal /life threatening report within 7 days to MHRA • ‘Other’ report within 15 days to MHRA • Further information to MHRA or/and REC within 8 days if requested • Annual Safety Report listing all SARs and SUSARs for the study on anniversary of CTA approval (PI responsibility)

The Medicines for Human Use (Clinical Trials Regulations) 2004 • Order came into force in the UK on 1 May 2004 following the EU Directive on Good Clinical Practice in clinical trials 2001/20/EC (The Clinical Trials Directive). • Clinical Trials Authorisation has now replaced the DDX / CTX

The MHRA have produced a short description of the (the UK order which implements the EU Directive) which aims to help those involved in the conduct of clinical trials to follow and understand the Regulations http: //medicines. mhra. gov. uk/ourwork/licensingmeds /types/ctdregs_shortdesc. pdf

GOOD CLINICAL PRACTICE Consent

What is Informed Consent? "Informed consent is a process by which a subject voluntarily confirms his or her willingness to participate in a particular clinical trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate” ICH 1. 28

Who can consent a subject? • A medically qualified person (usually) - however, Declaration of Helsinki states “physician” • UHL has a policy for Nurses & AHPs obtaining consenting for clinical trials – each study assessed and training package implemented as necessary. Not automatic right • Consent may be delegated to a sub investigator (needs to be documented) – must have be approved by LREC • The investigator retains overall responsibility • Consent must be documented in the medical notes

When should a subject be consented? • Prior to participation in a trial • Before ANY trial procedure - including the taking of blood to screen patients if it is not part of normal clinical practice or a questionnaire to access health etc

How should someone be consented? • The consent form must have been approved by the Ethics Committee • There should be no coercion to enter the trial • Non-technical language must be used • The information must be presented to the subject in the most appropriate way • The subject must have “ample” time to consider their decision

How should a consent form be completed? • Subject must sign & date the form (& preferably write their own name) • Original PIL & consent form - site file • Copies of PIL & consent form - Patient notes and to the patient • The consent form & patient information leaflet should always be kept together

GOOD CLINICAL PRACTICE Safety & Adverse Events

Safety Data collected in Clinical Trials • Adverse Events • Serious Adverse Events • Adverse Reactions • Suspected Unexpected Serious Adverse Reaction • Pregnancy • Lab data • Vital Signs • Project specific data

Adverse Event • Any untoward medical occurrence • Not necessarily causal relationship with treatment • Unfavourable /unintended sign ICH (1. 1)

Adverse Reaction Untoward or unintended response to IMP ICH (1. 2)

Suspected Unexpected Serious Adverse Reaction • Serious adverse reaction • Unexpected-not consistent with information already available in the protocol and the IB

SAE, SAR or SUSAR is SERIOUS and requires reporting if it: • Results in death • Is life threatening • Requires hospitalisation or prolongation of stay • Results in persistent or significant disability/incapacity • Consists of congenital anomaly or birth defect • Other

Continued • Results in death - Record the event that lead to death as the SAE - “Death” is the outcome • Life threatening - “The patient was, in the view of the investigator, at immediate risk of death from the event as it occurred. It does not include an event that, had it occurred in a more serious form, might have caused death”

Continued • Prolonged hospitalisation - Record diagnosis NOT procedure - Hospitalisation = in-patient admission - Not out-patient appointments or A & E visits • Disabling or incapacitating - Event which is disabling or incapacitating or causes a disruption of one’s ability to carry out normal life functions or daily activities

Continued • Congenital anomaly - Diagnosed in the offspring of a subject who received study drug • Other - Additional option given by some pharmaceutical companies - Event not covered by SAE categories but in the investigator’s opinion, should be considered serious

Pregnancy what and when to report • Protocol specific - report on SAE or pregnancy reporting form • All need reporting - don’t forget the female partners of men participating in the trial too!! • All need to be followed up - Length of follow-up depends on drug

GOOD CLINICAL PRACTICE Documentation & Audit

Essential Documents “Are those documents, which permit evaluation of the conduct of the trial and the quality of data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of GCP and with all regulatory requirements” ICH (8. 1)

Essential Documents which… • are audited by the regulatory authorities or sponsor company to confirm the validity of the data & integrity of the data collected • are contained in the files established at the beginning of the trial at sponsors office and investigators site Minimum list - see ICH section 8

Essential Documents - source data • Records should be accurate, complete, legible & timely ICH (4. 9. 1) • Data should be consistent with source documents (or discrepancies explained) ICH (4. 9. 2) • Any changes should be initialled, dated & explained • Document all deviations from protocol and explain ICH (4. 5. 3) • Document all dose/therapy modifications, visits and tests not conducted

What needs to be recorded in the patient notes? • Copy of signed and dated Consent Form and PIL • Title of the trial including the drug to be received • Study and patient number • Visit dates • Concomitant medicines taken • Any adverse events • A letter informing the GP that the patient has been enrolled in the clinical trial

Essential Documents continued • Essential documents should be retained for 2 yrs following last approval of marketing application in the ICH region (taken to be 15 yrs) ICH (4. 9. 5) • All records must be made available (direct access) for monitors, auditors & regulatory authorities ICH (4. 9. 7)

ICH definition - Audit "a systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)" ICH E 6 1. 6)

Common audit findings • Patients do not fulfil the entry criteria • Incomplete/incorrectly completed consent forms • Drug accountability inadequate • Hidden entry envelopes opened during study

Audit can be conducted to: • EU GCP Directive • EU Clinical Trials Directive • Protocol

Clinical Trial Audits • Sponsor Audits - Independent & separate from routine monitoring or quality control functions and evaluate trial conduct & compliance with the protocol, SOPs, GCP & applicable regulatory requirements • FDA Audits - In USA inspections occur without notice. In Europe, carried out with notice (about 14 days) • MHRA Audits – increasingly common and at short notice

Audit of the SITE FILE will check …. • Approvals & correspondence – Ethics approval, all correspondence to & from Ethics /Trust , MHRA notification • Laboratory – normal ranges, reports, procedures, etc • Documentation – protocol & amendments (signed), Information Leaflet & Consent, signed consent forms, Investigator Brochure, Indemnity, all correspondence between sponsor & investigator

Audit of the SITE FILE will check …. • Personnel – CVs of those working on the study, training records (such as GCP) • Drug – shipping records, drug receipt - but these may be in pharmacy • Patient details – screening / enrolment / identity logs, SAE reports

Audit of the PATIENT NOTES will check …. • Data verification –Case report forms, looking at data queries, lab results, ECGs, x-rays etc • Data verification patient notes – protocol details/number in the notes, date of birth, vital signs, all visit dates, concomitant medication & changes, medical examination, study specific procedures

An audit may also look at • Drug storage – accountability, temperature logs, security, dispensing, labelling, • Laboratories – procedures, handling samples, accreditation • Other study specific procedures

The Inspection Report • Contains details of all finding • Each finding labelled “Critical”, “Major”, “Minor” or “For Note” • Each finding is referenced to the particular regulation / guideline to which it is attributable • A reply to the report is required

Common Audit Findings • Patient or Investigator signature on consent form not dated • No version / date on consent form • Staff CVs not on file • Ethics Committee member list not up to date • Ethics Committee letter did not list all docs reviewed • Ethics Committee letter did not contain statement of GCP compliance • Drug not temperature monitored (was required) • Signatures not dated • Investigator failed to report SAEs

In summary • Legislation will affect us all - we all have to work to GCP and Research Governance guidelines • The legislation aims to improve standards and build public confidence • Ensure that: Ø The site file and filing is up to date – have a complete “paper trail” Ø The PIL & consent form in use are the most up to date and approved by LREC Ø People obtaining informed consent have been “approved” Write it down– if it’s not written down it didn’t happen

Remember…. . “ the assumption will be that there is full compliance (or else research is stopped)”

Useful Contacts in Research and Development at LGH • Office Manager - Nicky Turner 4109 • Programme Board Co-ordinators - Jill Horsley 8239 Gemini Davda 4614 Marlene Chapman 8246 • Clinical Trials Pharmacist – Claire Khalil 8241 • Clinical Trainer - Sarah Nicholson 8180