Research GuidelinesResearch Guidelines

Research GovernanceEU Directive on Clinical TrialsICH-GCP:

Informed ConsentSafety & Adverse EventsDocumentation - Audit

ICH definition - GCPICH 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 E6 1.24

ICH-GCPICH-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 The objectives of ICH GCP GuidelinesGCP 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 - Good Clinical Practice - GCPGCP• 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…ICH GCP Guidelines cover…

Ethics Committee/IRB

EssentialDocumentsfor conduct

of a trial

Clinical Trial Protocol &

Amendments

Investigator’sBrochure

SponsorInvestigator

Responsibilities of the Responsibilities of the InvestigatorInvestigator

• Agreements • Compliance • Ethics • Informed Consent • Investigational drug• Qualifications• Medical care of trial subjects

• Randomization• Records• Reports• Resources• Safety reporting• Unblinding

World Medical Association World Medical Association Declaration of HelsinkiDeclaration of Helsinki• Adopted by 18th 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 Research Governance FrameworkFramework

Scope of the FrameworkScope 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 FrameworkAims 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 Research Governance domainsdomains

Ethics

Science

Information

Health, Safety and Employment

Finance and Intellectual Property

Ethics - key pointsEthics - 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 pointsScience - 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 Information - key pointspoints

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 Responsibilities of the ResearcherResearcher

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 Responsibilities of the SponsorSponsor

Assuring scientific quality (peer review)

Ensuring research ethics committee

approval

Ensuring arrangements for the

management and monitoring of research

Responsibilities of Responsibilities of thetheCare OrganisationCare 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

SanctionsSanctions

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

The Medicines for The Medicines for Human Use (Clinical Human Use (Clinical Trials) Regulations Trials) Regulations

20042004

The EU Clinical Trials The EU Clinical Trials Directive 2001/20/ECDirective 2001/20/EC

Aims of the EU Aims of the EU DirectiveDirective

• 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 GCPApplication 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: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 1st 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 & EU Directive & Informed ConsentInformed 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

A formal mechanism to appoint a legal representative for incapacitated adults will be introduced

Indemnity/Indemnity/CompensationCompensation• Provision must be made for compensation

for non-negligent harm for all trials

e.g

The clinical negligence scheme for

Trusts

University Public Liability Insurance

Specific Clinical Trials insurance

• ABPI model indemnity agreements to

used for industry sponsored trials

Licensing Authority Licensing Authority ApprovalApprovalUK “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 EU Directive & Ethics CommitteesCommittees

• 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 Substantial AmendmentsAmendmentsAmendments 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 EU Directive & Competent Authority - Information to Authority - Information to Support ApprovalSupport ApprovalCore information - Required by the Directive• Covering letter• EUDRACT form - register via MHRA• Protocol• Investigator Brochure• Investigational medicinal products dossier - Ph1

trials• List of CA to which an application has been made• EC opinion if available

Member State SpecificLocal information: consent forms, information sheets,

recruitment, indemnity, manufacturing of IMPs

EU Directive & Good EU Directive & Good Manufacturing Practice and Manufacturing Practice and Investigational Medicinal Investigational Medicinal ProductsProducts

• 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 GCP and GMP InspectionsInspections

• 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:

Cyclical, systems based inspections of

sponsors

Triggered inspections as required

Safety ReportingSafety Reporting

• PI to identify category

• Complete Safety Report Form (s)

• Forward as appropriate to Trust and Sponsor

within 24hrs

• 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 for Timelines for Sponsor for further reportingfurther reporting

• Fatal /life threatening report within

7days 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 The Medicines for Human Use (Clinical Trials Use (Clinical Trials Regulations) 2004Regulations) 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?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 Who can consent a subject?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 When should a subject be consented?consented?

• Prior to participation in a trialPrior to participation in a trial

• Before Before ANYANY trial procedure - including trial procedure - including

the taking of blood to screen patients the taking of blood to screen patients

if it is not part of normal clinical if it is not part of normal clinical

practice or a questionnaire to access practice or a questionnaire to access

health etchealth etc

How should someone be How should someone be consented?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 How should a consent form be completed?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 Safety Data collected in Clinical Trialsin Clinical Trials

• Adverse Events

• Serious Adverse Events

• Adverse Reactions

• Suspected Unexpected Serious Adverse Reaction

• Pregnancy

• Lab data

• Vital Signs

• Project specific data

Adverse EventAdverse Event

• Any untoward medical occurrence

• Not necessarily causal relationship

with treatment

• Unfavourable /unintended sign

ICH (1.1)

Adverse ReactionAdverse Reaction

Untoward or unintended response to

IMP ICH (1.2)

Suspected Unexpected Suspected Unexpected Serious Adverse ReactionSerious Adverse Reaction

• Serious adverse reaction

• Unexpected-not consistent with

information already available in the

protocol and the IB

SAE,SAR or SUSAR is SAE,SAR or SUSAR is SERIOUS SERIOUS and requires reporting if it: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 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”

ContinuedContinued• 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

ContinuedContinued

• 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 - Pregnancy - what and whenwhat and when to report 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 DocumentsEssential 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 DocumentsEssential DocumentsDocuments 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 DocumentsEssential Documents - source data - 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 What needs to be recorded recorded in the patient notes?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 Essential Documents continuedcontinued

• Essential documents should be retained for 2

yrs following last approval of marketing

application in the ICH region (taken to be

15yrs) ICH (4.9.5)

• All records must be made available (direct

access) for monitors, auditors & regulatory

authorities ICH (4.9.7)

ICH definition - AuditICH 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 E6 1.6)

Common audit findingsCommon 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 Audit can be conducted to:conducted to:• EU GCP Directive

• EU Clinical Trials Directive

• Protocol

Clinical Trial AuditsClinical 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 Audit of the SITE FILE will check ….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 Audit of the SITE FILE will check ….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 Audit of the PATIENT NOTES will check …. 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 An audit may also look at- at-

• Drug storage – accountability,

temperature logs, security, dispensing,

labelling,

• Laboratories – procedures, handling

samples, accreditation

• Other study specific procedures

The Inspection ReportThe 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 Common Audit FindingsFindings• 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 summaryIn 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: The site file and filing is up to date – have a

complete “paper trail”The PIL & consent form in use are the most

up to date and approved by LRECPeople obtaining informed consent have

been “approved”

Write it down– if it’s not written down it didn’t happen

Remember…..Remember…..

“ the assumption will be that there is

full compliance (or else research is

stopped)”

Useful Contacts in Useful Contacts in Research and Research and Development at LGHDevelopment 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