Transcript Clinical Research & GCP

Clinical trials with reference
to GCP Guidelines
Certificate course in Research Ethics Review
(CCRER)
25th April 2008
Priyadarshani Galappatthy MD,MRCP
Department of Pharmacology
Overview
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Definition and phases of clinical trials
Principles of GCP guidelines
Responsibilities, functions, procedures
for ERC/IRB in GCP guidelines
Monitoring and auditing
Documents for clinical trials
Approvals for a clinical trial in SL
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Clinical Research
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Broad definition:
• Medical research in human subjects
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Narrow definition:
• The gamut of activities related to testing
and development of diagnostic,
prophylactic, therapeutic and cosmetic
modalities in human subjects
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Clinical Research in
Drug Development
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Defines efficacy, safety, PK, PD, PE – hence
transforms a chemical substance to a drug
Involves multiple stakeholders
Every aspect is subject to regulatory review
Governed by specific laws, rights, & legal
implications
Involves risks and benefits for patients
Holds ethical implications and penalties
Has liabilities for investigators and ethics
committees
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Phases of Clinical Research (1)
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Phase 0
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Very early human dosing
Helps determine critical pharmacokinetic
factors
Increasingly used for early decision-making
Phase 1
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Series of healthy volunteer studies
Terminology often used for all volunteer
studies
Establishes safety, PK, and healthy PD in
humans
Conducted in specialized units
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Phases of Clinical Research (2)
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Phase 2
• Proof of concept (PoC) and dose range finding
(DRF) studies in patients
• Successful PoC transforms value
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Phase 3
• Definitive studies to confirm efficacy & safety
• Establishes level of less frequent side-effects
• Often unaffordable for smaller companies
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Phase 4
• Post marketing surveillance (PMS)
• Establishes long-term benefit risk ratio
• Establishes place in therapy
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How to ensure clinical trials are
conducted ethically and according
to regulatory requirements ?
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Guidelines
Benchmarks
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GCP: The Code of Conduct
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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.
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ICH GCP Organization
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Glossary and Principles
Responsibilities
• ERC/IRB
• Investigators
• Sponsor
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Trial protocol and protocol amendments
Investigators’ brochure
Document inventory and location
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Essential Elements of GCP
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Autonomy and informed consent
Ethical oversight
Benefit-risk evaluation
Documentation and monitoring
Drug product integrity & accountability
Fidelity of data
Qualified and trained staff
Audits & Inspections
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Autonomy & Informed Consent
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Enshrined as Respect for Persons - One of
the 3 Basic Ethical Principles in the
Belmont Report of 1979 and in the Basic
Principles of the Declaration of Helsinki.
Requires the documentation of consent:
• Involves a consent procedure, materials,
discussion
• Written where possible, else witnessed
• Includes autonomy to refuse and withdraw
• A healthy refusal rate is expected
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Ethical Oversight
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Aspects pertaining to the Ethical
Review committee/ Institutional
review Board (ERC/IRB) in GCP
guidelines
Responsibilities
Composition, functions and
operations
Procedures
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Responsibilities of IRB/IEC (1)
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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:
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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)
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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)
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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)
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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.
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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)
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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)
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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:
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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:
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Its trial-related decisions/opinions.
The reasons for its decisions/opinions.
Procedures for appeal of its decisions/opinions.
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Qualified & Trained Staff
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Applies to:
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Investigators and other site staff
Monitors, auditors, and sponsor’s administrative staff
Statisticians and data managers
Independent data monitoring committee
CVs of investigators, co-investigators, and
sponsor’s staff must be on file
Investigators & site staff should be trained on
protocol & procedures through investigators’
meetings and site initiation meetings
Training files of sponsors’ staff to be maintained
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Benefit-risk Evaluation
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Applies to: Sponsor, regulatory authority,
investigators, ethics committees
Based on: Prior information available to
sponsor, data submitted to regulatory
authority, investigators brochure,
emerging safety reports
Currently a qualitative exercise – outcome
may vary based on the evaluator’s
perspective and individual sensitivities
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Safety Reporting
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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 Monitoring
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The long-term nature of clinical
development
Sponsor’s responsibilities:
• Securing direct access for sponsor and
regulators
• Monitoring and audits to verify protection of
subjects’ rights, data accuracy, and compliance
to protocol, GCP, & regulations
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Direct access monitoring
• Source data verification, consent verification,
drug accountability, training & information,
communication of deviations through
monitoring 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 & Accountability
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Manufacturing & packaging under GMP
Appropriate labeling
Transport under appropriate conditions
Secure and appropriate storage
Accountability of dispensing and returns
Compliance monitoring
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Audits & Inspections
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Definition
Auditors and inspectors
The audit/inspection process
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Notification
Presentation of credentials
Hospitality and access
Audit report, observations, & corrective
action plan
• Termination and notification of termination
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Regulatory access to audit reports
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Audit
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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
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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
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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)
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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
a clinical trial –(1)
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Before starting trial - 20
During clinical conduct - 25
After completion/termination - 8
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Essential documents for conduct of
a clinical trial –(2)
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Essential documents for conduct of
a clinical trial – (3)
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Essential documents for conduct of a
clinical trial – (4)
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GCP: The Code of Conduct
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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.
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Approvals for a clinical trial in SL
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ERC/IRB
Hospital authorities/ERC
Drug regulatory authority – for
registration and import of trial drug
Sri Lanka Clinical trials registry
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