Clinical trials with reference Clinical trials with reference to GCP Guidelinesto GCP Guidelines

Certificate course in Research Ethics Review Certificate course in Research Ethics Review (CCRER)(CCRER)

2525thth April 2008 April 2008Priyadarshani Galappatthy Priyadarshani Galappatthy MD,MRCP MD,MRCP

Department of PharmacologyDepartment of Pharmacology

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OverviewOverview

Definition and phases of clinical trialsDefinition and phases of clinical trials Principles of GCP guidelinesPrinciples of GCP guidelines Responsibilities, functions, procedures Responsibilities, functions, procedures

for ERC/IRB in GCP guidelinesfor ERC/IRB in GCP guidelines Monitoring and auditing Monitoring and auditing Documents for clinical trialsDocuments for clinical trials Approvals for a clinical trial in SLApprovals for a clinical trial in SL

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Clinical ResearchClinical Research

Broad definition:Broad definition:• Medical research in human subjectsMedical research in human subjects

Narrow definition:Narrow definition:• The gamut of activities related to testing The gamut of activities related to testing

and development of diagnostic, and development of diagnostic, prophylactic, therapeutic and cosmetic prophylactic, therapeutic and cosmetic modalities in human subjectsmodalities in human subjects

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Clinical Research in Clinical Research in Drug DevelopmentDrug Development

Defines efficacy, safety, PK, PD, PE – hence Defines efficacy, safety, PK, PD, PE – hence transforms a chemical substance to a drugtransforms a chemical substance to a drug

Involves multiple stakeholdersInvolves multiple stakeholders Every aspect is subject to regulatory reviewEvery aspect is subject to regulatory review Governed by specific laws, rights, & legal Governed by specific laws, rights, & legal

implicationsimplications Involves risks and benefits for patientsInvolves risks and benefits for patients Holds ethical implications and penaltiesHolds ethical implications and penalties Has liabilities for investigators and ethics Has liabilities for investigators and ethics

committeescommittees

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Phases of Clinical Research (1)Phases of Clinical Research (1) Phase 0Phase 0

Very early human dosing Very early human dosing Helps determine critical pharmacokinetic Helps determine critical pharmacokinetic

factorsfactors Increasingly used for early decision-makingIncreasingly used for early decision-making

Phase 1Phase 1 Series of healthy volunteer studiesSeries of healthy volunteer studies Terminology often used for all volunteer Terminology often used for all volunteer

studiesstudies Establishes safety, PK, and healthy PD in Establishes safety, PK, and healthy PD in

humanshumans Conducted in specialized unitsConducted in specialized units

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Phases of Clinical Research (2)Phases of Clinical Research (2) Phase 2Phase 2

• Proof of concept (PoC) and dose range finding Proof of concept (PoC) and dose range finding (DRF) studies in patients(DRF) studies in patients

• Successful PoC transforms valueSuccessful PoC transforms value Phase 3Phase 3

• Definitive studies to confirm efficacy & safetyDefinitive studies to confirm efficacy & safety• Establishes level of less frequent side-effectsEstablishes level of less frequent side-effects• Often unaffordable for smaller companiesOften unaffordable for smaller companies

Phase 4Phase 4• Post marketing surveillance (PMS) Post marketing surveillance (PMS) • Establishes long-term benefit risk ratioEstablishes long-term benefit risk ratio• Establishes place in therapyEstablishes place in therapy

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How to ensure clinical trials are How to ensure clinical trials are conducted ethically and according conducted ethically and according

to regulatory requirements ?to regulatory requirements ?

GuidelinesGuidelines BenchmarksBenchmarks

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Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles in the Declaration of Helsinki, and that the clinical trial data are credible.

Guideline was developed with consideration of the current good clinical practices of the European Union, Japan, United States, Australia, Canada, the Nordic countries and the WHO.

GCP: The Code of ConductGCP: The Code of Conduct

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ICH GCP OrganizationICH GCP Organization

Glossary and PrinciplesGlossary and Principles ResponsibilitiesResponsibilities

• ERC/IRB ERC/IRB • InvestigatorsInvestigators• SponsorSponsor

Trial protocol and protocol amendmentsTrial protocol and protocol amendments Investigators’ brochureInvestigators’ brochure Document inventory and locationDocument inventory and location

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Essential Elements of GCPEssential Elements of GCP

Autonomy and informed consentAutonomy and informed consent Ethical oversightEthical oversight Benefit-risk evaluationBenefit-risk evaluation Documentation and monitoringDocumentation and monitoring Drug product integrity & accountabilityDrug product integrity & accountability Fidelity of dataFidelity of data Qualified and trained staffQualified and trained staff Audits & InspectionsAudits & Inspections

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Autonomy & Informed ConsentAutonomy & Informed Consent

Enshrined as Respect for Persons - One of Enshrined as Respect for Persons - One of the 3 Basic Ethical Principles in the the 3 Basic Ethical Principles in the Belmont Report of 1979 and in the Basic Belmont Report of 1979 and in the Basic Principles of the Declaration of Helsinki.Principles of the Declaration of Helsinki.

Requires the documentation of consent:Requires the documentation of consent:• Involves a consent procedure, materials, Involves a consent procedure, materials,

discussiondiscussion• Written where possible, else witnessedWritten where possible, else witnessed• Includes autonomy to refuse and withdrawIncludes autonomy to refuse and withdraw• A healthy refusal rate is expectedA healthy refusal rate is expected

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Ethical OversightEthical Oversight

Aspects pertaining to the Ethical Aspects pertaining to the Ethical Review committee/ Institutional Review committee/ Institutional review Board (ERC/IRB) in GCP review Board (ERC/IRB) in GCP guidelinesguidelines

ResponsibilitiesResponsibilities Composition, functions and Composition, functions and

operationsoperations ProceduresProcedures

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Responsibilities of IRB/IEC (1) Safeguard the rights, safety, and well-being of all

trial subjects. Special attention paid to vulnerable subjects. The IRB/IEC should obtain the following documents:

• trial protocol/amendments, • written informed consent forms consent form updates, • subject recruitment procedures (e.g. advertisements), • written information to be provided to subjects, • Investigator's Brochure (IB), • available safety information, • information about payments and compensation to subjects, • the investigator’s current curriculum vitae and/or other

documentation evidencing qualifications, • any other documents that the IRB/IEC may need to fulfil its

responsibilities.

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Responsibilities of ERC/IRB (2)Responsibilities of ERC/IRB (2) Consider the qualifications of the

investigator/s Conduct continuing review of each ongoing

trial, at least once per year. If the protocol indicates that prior consent

of the trial subject is not possible, the IRB/IEC should determine that the protocol addresses ethical concerns and meets regulatory requirements

Review amount and method of payment to subjects to assure that coercion or undue influence on the subjects is prevented.

Ensure that information regarding payment to subjects, is in the informed consent form

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Responsibilities of ERC/IRB- (3)Responsibilities of ERC/IRB- (3)

The IRB/IEC should review a proposed clinical trial within a reasonable time

Document IRB/ERC views in writing, identifying the trial, the documents reviewed and the dates for the following • approval/favourable opinion • modifications required prior to its

approval/favourable opinion • disapproval / negative opinion• termination/suspension of any prior

approval/favourable opinion.

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Composition, Functions and Operations of ERC (1)

Consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial.

It is recommended that the IRB/IEC should include: • At least five members. • At least one member whose primary area of interest is in a

non-scientific area. • At least one member who is independent of the

institution/trial site. A list of IRB/IEC members and their qualifications

should be maintained. An IRB/IEC may invite non-members with expertise

in special areas for assistance

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Composition, Functions and Operations of ERC (2)

The IRB/IEC should function according to written operating procedures

Maintain written records of its activities and minutes Comply with GCP and regulatory requirements. Make decisions at meetings at which a quorum, as

stipulated in operating procedures, is present. Only members who participate in the IRB/IEC review

and discussion should vote/provide their opinion and/or advise.

The investigator may provide information on the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.

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Procedures in ERC/IRB (1) Document in writing, and follow its

procedures, including • composition and the authority under

which it is established. • Schedule, notify conducting its meetings. • Conduct initial and continuing review of

trials. • Provide expedited review and approval of

amendments/revisions in ongoing trials that have the approval of the IRB/IEC.

• Specify that no subject should be admitted to a trial before the IRB/IEC issues its written approval of the trial.

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Procedures in ERC/IRB- (2)• Specify that the investigator should promptly

report to the IRB/IEC: Deviations from, or changes of, the protocol. Changes increasing the risk to subjects and/or affecting

significantly the conduct of the trial All adverse drug reactions (ADRs) that are both serious

and unexpected. New information that may affect adversely the safety

of the subjects or the conduct of the trial.

• Ensure that the IRB/IEC promptly notify in writing the investigator/institution concerning:

Its trial-related decisions/opinions. The reasons for its decisions/opinions. Procedures for appeal of its decisions/opinions.

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Qualified & Trained StaffQualified & Trained Staff Applies to:Applies to:

• Investigators and other site staffInvestigators and other site staff• Monitors, auditors, and sponsor’s administrative staffMonitors, auditors, and sponsor’s administrative staff• Statisticians and data managersStatisticians and data managers• Independent data monitoring committeeIndependent data monitoring committee

CVs of investigators, co-investigators, and CVs of investigators, co-investigators, and sponsor’s staff must be on filesponsor’s staff must be on file

Investigators & site staff should be trained on Investigators & site staff should be trained on protocol & procedures through investigators’ protocol & procedures through investigators’ meetings and site initiation meetingsmeetings and site initiation meetings

Training files of sponsors’ staff to be maintainedTraining files of sponsors’ staff to be maintained

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Benefit-risk EvaluationBenefit-risk Evaluation

Applies to: Sponsor, regulatory authority, Applies to: Sponsor, regulatory authority, investigators, ethics committeesinvestigators, ethics committees

Based on: Prior information available to Based on: Prior information available to sponsor, data submitted to regulatory sponsor, data submitted to regulatory authority, investigators brochure, authority, investigators brochure, emerging safety reportsemerging safety reports

Currently a qualitative exercise – outcome Currently a qualitative exercise – outcome may vary based on the evaluator’s may vary based on the evaluator’s perspective and individual sensitivitiesperspective and individual sensitivities

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Safety Reporting

All serious adverse events (SAEs) should be reported immediately to the sponsor

The investigator should also comply with the applicable regulatory requirements related to the reporting of unexpected serious adverse drug reactions to the regulatory authorities and the IRB/IEC.

Adverse events and/or laboratory abnormalities identified should be reported within the time periods specified in the protocol.

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Documentation and MonitoringDocumentation and Monitoring

The long-term nature of clinical The long-term nature of clinical developmentdevelopment

Sponsor’s responsibilities:Sponsor’s responsibilities:• Securing direct access for sponsor and Securing direct access for sponsor and

regulatorsregulators• Monitoring and audits to verify protection of Monitoring and audits to verify protection of

subjects’ rights, data accuracy, and compliance subjects’ rights, data accuracy, and compliance to protocol, GCP, & regulationsto protocol, GCP, & regulations

Direct access monitoringDirect access monitoring• Source data verification, consent verification,Source data verification, consent verification,

drug accountability, training & information, drug accountability, training & information, communication of deviations through communication of deviations through monitoring reportsmonitoring reports

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Monitoring

The purposes of trial monitoring are to verify that: • The rights and well-being of human subjects

are protected. • The reported trial data are accurate, complete,

and verifiable from source documents. • The conduct of the trial is in compliance with

the currently approved protocol /amendments, with GCP, and with the applicable regulatory requirements.

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Product Integrity & AccountabilityProduct Integrity & Accountability

Manufacturing & packaging under GMPManufacturing & packaging under GMP Appropriate labelingAppropriate labeling Transport under appropriate conditionsTransport under appropriate conditions Secure and appropriate storageSecure and appropriate storage Accountability of dispensing and returnsAccountability of dispensing and returns Compliance monitoringCompliance monitoring

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Audits & InspectionsAudits & Inspections

DefinitionDefinition Auditors and inspectorsAuditors and inspectors The audit/inspection processThe audit/inspection process

• NotificationNotification• Presentation of credentialsPresentation of credentials• Hospitality and accessHospitality and access• Audit report, observations, & corrective Audit report, observations, & corrective

action planaction plan• Termination and notification of terminationTermination and notification of termination

Regulatory access to audit reportsRegulatory access to audit reports

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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, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirements.

If or when sponsors perform audits, as part of implementing quality assurance, they should consider: • Purpose • Selection and Qualification of Auditors

The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.

The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

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Quality Assurance and Quality Control

The sponsor is responsible for implementing and maintaining quality assurance with written SOPs to ensure that trials are conducted, data are generated, documented and reported in compliance with the protocol, GCP, and regulatory requirements.

A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor.

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Contract Research Organization (CRO)

The CRO should implement quality assurance and quality control.

Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.

All references to a sponsor in GCP guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions

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Essential documents for conduct of Essential documents for conduct of a clinical trial –(1)a clinical trial –(1)

Before starting trial - 20Before starting trial - 20 During clinical conduct - 25During clinical conduct - 25 After completion/termination - 8After completion/termination - 8

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Essential documents for conduct of Essential documents for conduct of a clinical trial –(2)a clinical trial –(2)

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Essential documents for conduct of Essential documents for conduct of a clinical trial – (3)a clinical trial – (3)

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Essential documents for conduct of a Essential documents for conduct of a clinical trial – (4)clinical trial – (4)

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GCP: The Code of ConductGCP: The Code of Conduct

A A standardstandard for the design, conduct, for the design, conduct, performance, monitoring, auditing, performance, monitoring, auditing, recording, analyses, and reporting recording, analyses, and reporting of clinical trials that provides of clinical trials that provides assuranceassurance that the data and that the data and reported reported results are credible and results are credible and accurateaccurate, and that the , and that the rights, rights, integrity, and confidentiality of trial integrity, and confidentiality of trial subjects are protectedsubjects are protected..

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Approvals for a clinical trial in SLApprovals for a clinical trial in SL

ERC/IRBERC/IRB Hospital authorities/ERCHospital authorities/ERC Drug regulatory authority – for Drug regulatory authority – for

registration and import of trial drugregistration and import of trial drug Sri Lanka Clinical trials registrySri Lanka Clinical trials registry

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