“good clinical practice” murraycrcgcp.pdf · good clinical practice (gcp) •“gcp is an...

“Good Clinical Practice”Patrick Murray, MD, FASN, FRCPI

Professor, University College Dublin,Mater Misericordiae University Hospital,

Dublin, Irelandpatrick.murray@ucd.ie

CRCClinical

ResearchCentre

Dublin Academic Medical Centre

www.ucd.ie/crc/

Good Clinical Practice (GCP)

• “GCP is an international ethical & scientificquality standard for…..– Designing,– Conducting,– Recording,– Reporting

• ……trials that involve the participation of humansubjects”

ICH-GCP: Lecture Outline

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities (see S. O’N)• Investigator Responsibilities• Patient Safety

ICH-GCP History• 1964 Declaration of Helsinki• 1974 Belmont report• 1977 USA GCP (FDA)• 1987 France GCP; Germany- conduct of clinical trials; Ireland Clinical

Trials Act (1990)• 1989 Nordic GCP• 1991 European GCP• 1996 ICH (International Conference on Harmonisation) – GCP: EU,

Nordic countries, Japan, USA, Australia, Canada, WHO• 2004 EU Clinical Trials Directive

– www.eortc.org/Services/Doc/clinical-EU-directive-04-April-01.pdf– Trial Registration- https://eudract.emea.europa.eu/– Irish Medicines Board: www.imb.ie/EN/Medicines/Clinical-Trials.aspx– IMB Medicines Listing-

www.imb.ie/EN/Medicines/HumanMedicines/HumanMedicinesListing.aspx

Declaration of Helsinki• Gold standard ethical guidance document for all research

conducted in human subjects– www.wma.net/e/policy/b3.htm

• First version published in 1964 by the World MedicalAssociation

• Use is mandatory if you wish to publish in ICJME (InternationalCommittee of Medical Journal Editors) publications

• 2008 update published (2000 prior version), with 2 importantadditions:– 1) Pre-registration of clinical trials

• www.clinicaltrials.gov; WHO registrye (www.who.int/ictrp/en/); others• European Clinical trials must also have a registered Eudra CT number

– https://eudract.emea.europa.eu/– 2) Post-study access by study subjects to interventions identified as

beneficial in the study or access to other appropriate care or benefitsshould be described in the protocol

ICH-GCP: Lecture Outline

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities• Investigator Responsibilities• Patient Safety

ICH-GCP Purpose

• “Compliance with this standard provides publicassurance that the rights, safety and well-being oftrial subjects are protected, consistent with theprinciples that have their origin in the Declarationof Helsinki”– www.ich.org/LOB/media/MEDIA482.pdf

ICH-GCP Principles

• “Clinical trials should be conducted in accordancewith the ethical principles that have their origin inthe Declaration of Helsinki, and that areconsistent with GCP and the applicable regulatoryrequirement(s)”

ICH-GCP Principles

• “Before a trial is initiated, forseeable risks andinconveniences should be weighed against theanticipated benefit for the individual trial subjectand society. A trial should be initiated andcontinued only if the anticipated benefits justifythe risks”

ICH-GCP Principles

• “The rights, safety, and well-being of the trialsubject are the most important considerations andshould prevail over interests of science andsociety ”

ICH-GCP Principles

• “The available nonclinical and clinicalinformation on an investigational product shouldbe adequate to support the proposed trial”

ICH-GCP Principles

• “Clinical trials should be scientifically sound, anddescribed in a clear, detailed protocol”

ICH-GCP Principles

• “A trial should be conducted in compliance withthe protocol that has received prior independentethics committee approval”

ICH-GCP Principles

• “The medical care given to, and medical decisionsmade on behalf of, subjects should always be theresponsibility of a qualified physician or, whenappropriate, of a qualified dentist”

ICH-GCP Principles

• “Each individual involved in a trial should bequalified by education, training, and experience toperform his or her respective task(s)”

ICH-GCP Principles

• “Freely informed consent should be obtained fromevery subject prior to clinical trial participation”

ICH-GCP Principles

• “All clinical trial information should be recorded,handled, and stored in a way that allows itsaccurate reporting, interpretation and verification”

ICH-GCP Principles

• “The confidentiality of records that could identifysubjects should be protected, respecting theprivacy and confidentiality rules in accordancewith the regulatory requirement(s)”

ICH-GCP Principles

• “Investigational products should be manufactured,handled, and stored in accordance with goodmanufacturing practice (GMP). They should beused in accordance with the approved protocol”

ICH-GCP Principles

• “Systems with procedures that assure the qualityof every aspect of the trial should beimplemented”– [Standard Operating Procedures: SOPs]

ICH-GCP: Lecture Outline

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities: see S. O’

Neill• Investigator Responsibilities• Patient Safety

ICH-GCP: Lecture Outline

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities• Investigator Responsibilities• Patient Safety

Investigator Responsibilities

• Qualified investigator• Familiar with product and protocol• Comply with GMP and other regulatory

requirements• Demonstrate potential for suitable recruitment• Maintain list of delegated duties and associated

individuals, and ensure that all are appropriatelyqualified and informed

• Written IEC approval before commencing trial

Investigator Responsibilities: Informed Consent

• Comply with ethical principles (Declaration of Helsinki)• All subjects should be fully informed• Neither the investigator, nor the trial staff, should coerce

or unduly influence a subject to participate or to continueto participate in a trial

• Prior to a subject’s participation in a trial, the writteninformed consent form should be signed and personallydated by the subject or the subject’s legally accptedrepresentative, and by the person who conducted theinformed consent discussion. A copy should be receivedby the subject

Investigator Responsibilities: During Trial• Conduct the trial in compliance with the protocol (signed to

confirm)• Permit monitoring and auditing by sponsor and inspection by

appropriate regulatory authorities• A qualified physician who is an investigator or sub-investigator

should be responsible for all trial-related medical decisions• It is recommended that the investigator inform the subject’s

primary physician• Although a subject is not obliged to give his/her reason(s) for

withdrawing prematurely from a trial, the investigator shouldmake a reasonable effort to ascertain the reason(s)

• The investigator is responsible for drug accountability at thetrial site

• The investigator should document and explain any protocolviolations or deviations, or if blinding is broken

Investigator Responsibilities: Records & Reports

• Ensure the accuracy, completeness, legibility andtimeliness of the data reported to the sponsor inthe case report forms (CRFs)

• All data on CRFs from source documents shouldbe consistent

• Should make available for direct access allrequested trial-related records

• All SAEs should be reported immediately to thesponsor

Investigator Responsibilities: Post-Trial

• Upon completion of the trial, the investigatorshould inform the institution (where applicable)

• The investigator should provide the InstitutionalEthics Committee (IEC) with a summary of thetrial’s outcome, and the regulatory authoritieswith any reports required

• Essential documents should be retained for atleast 2 years post licence approval

ICH-GCP: Lecture Outline

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities• Investigator Responsibilities• Patient Safety

Patient Safety• Adverse Event (AE) Definitions & Investigator

Responsibilities for Safety Reporting– Adverse Event (AE): any untoward medical

occurrence in a patient or clinical investigation subjectwho has taken a pharmaceutical product (and whichdoes not necessarily have causal relationship with thistreatment)

• All AEs must be recorded in the case report form, even ifthe event is commonly observed

• Laboratory abnormalities may also be classified as AEs– Adverse Reaction (AR): an adverse event with a

reasonable causal relationship with treatment

Patient Safety• Adverse Event (AE) Definitions & Investigator

Responsibilities for Safety Reporting– Serious Adverse Event (SAE): any untoward medical

occurrence in a patient or clinical investigation subject that atany dose results in:

• Death• Is life threatening• Requires patient hospitalisation, or prolongation of existing

hospitalisation• Results in persistent or significant disability• Is a congenital anomaly/birth defect

– Report all SAEs to Sponsor (Company, Other) immediately(<24 hours), and to regulatory agencies (IMB, EMEA)within 7 days

Patient Safety• Adverse Event (AE) Definitions & Investigator

Responsibilities for Safety Reporting– Serious Adverse Reaction (SAR): a serious adverse

event with a reasonable causal relationship withtreatment

– Suspected Serious Adverse Reaction (SSAR)– Suspected Unexpected Serious Adverse Reaction

(SUSAR)

Adverse Event Classificiation

AE

SAR

AR

SAE

Unexpected Expected

Life-Threatening/Death

Congenital anomalyHospitalisationDisability

From: ICRINGCP CourseSyllabus,April, 2009

Summary: ICH-GCP

• ICH-GCP History• ICH-GCP Principles• Ethics Committee Responsibilities (see S.

O’Neill)• Investigator Responsibilities• Patient Safety