Transcript American Society of Clinical Oncology

Clinical Trial Ethical
Considerations
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Disclosures
None
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Overall Message
• The protection of the rights, safety, and well being
of the individual trial participant is the paramount
issue of human clinical trials.
• The investigator’s duty is solely to the patient’s or
volunteer’s protection.
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Objectives
• Learn the history of modern clinical trial ethics
• Understand the principles of Good Clinical Practice
(GCP)
• Review the elements of Informed Consent
• Review the mechanisms for Investigational Agent
availability off clinical trial
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Oath of Hippocrates
• Hippocrates, physician from island of Cos, Greece
• 4th century, BC
• “ I will prescribe regimens for the good of my
patients according to my ability and my judgment
and never do harm to anyone.”
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History of Modern Human Trial
Ethics: Post World War II
• Nuremberg Code of 1947
– Developed in aftermath of War Crimes Trials
– Established standards for conducting ethical and
humane research with human participants
• Declaration of Geneva 1948
• Defined the physician’s ethical duties
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Good Clinical Practice (GCP)
• Adopted term that defines clinical trial standards
including:
– Design
– Conduct
– Analysis
– Reporting
• Not a single document but encompasses all
government regulations and other accepted trial
practice standards
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Good Clinical Practice (GCP)
• Shared responsibility for GCP compliance
– Trial Sponsor
– Individual Investigator
– Institution
• GCP rigorous standards assure
– Trial participant’s rights, integrity, and confidentiality are
protected
– Study results are credible and accurate
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Ethical considerations
• Declaration of Helsinki
• International Conference on Harmonization Good
Clinical Practice
• Informed consent process
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History of Modern Human Trial
Ethics: Helsinki
• Declaration of Helsinki 1964
– World Medical Association
– International agreement of human clinical trial ethical
conduct
– Guidelines for physicians conducting biomedical
research involving human subjects
• Establishes the rights of trial participants
• Defines subject full informed consent requirements
– Revisions 1975, 1989, 1996, 2000, 2008
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Helsinki Principles
• The Helsinki Declaration is morally binding on
physicians.
• The Helsinki Principles override national or local
laws or regulations if the Declaration provides
higher standards.
• Investigators must abide by local regulations and
Helsinki Principles.
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Helsinki Principles
• Respect for the individual
• The individual’s right to self-determination and to
make informed decisions
• The investigator’s duty is solely to the patient or
volunteer
• The welfare of the study subject always takes
precedence over the interests of science and
society
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Helsinki Principles
• Individuals and groups with increased vulnerability
require special vigilance.
• Consent by surrogates (such as parent or spouse)
is allowed if the surrogate is acting in the subject’s
best interest.
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Helsinki Principles: Research
Operations
• The research must be based upon:
– a thorough knowledge of the scientific background
– a careful assessment of risks and benefits
– a reasonable likelihood of benefit to the population
under study
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Helsinki Principles: Study Conduct
• Research should be conducted:
– By appropriately trained investigators
– Using an approved protocol
– Subject to independent ethical review and oversight by
a properly convened committee
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Helsinki Principles: Study Conduct
Issues
• If new information changes the potential risks and
benefits, then the study may need to be stopped.
• The public should have access to information on
the trial.
• The results of the trial should be published.
• After the trial is complete, the interests of the
subjects are still part of the ethics of the trial.
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Other ethical guidelines
• Council of International Organizations of Medical
Sciences ([email protected])
• International Conference on Harmonization Good
Clinical Practice (GCP) (www.ich.org)
• Individual national regulations
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History of Modern Human Trial
Ethics: ICH
• International Conference on Harmonization (ICH)
1990
• Joint initiative of Industry, Academia, Ministries of
Health from US, EU, Japan
• Observers: WHO, Health Canada
• Defined minimal standards for development and
registration of investigational products including
drugs focusing on safety, quality and efficacy
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History of Modern Human Trial
Ethics: ICH
• Recognizes international standards for conduct of
human clinical trials
• Implemented in 1996
• Current Version: ICH Good Clinical Practice (GCP)
Guidance E6
• Trials conducted under ICH GCP have global
acceptance of trial data for pharmaceutical
international marketing applications
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ICH guideline on Good Clinical
Practice (GCP)
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ICH.E6(R1) document (www.ich.org)
Principles of GCP
Ethics committee
Investigator
Sponsor
Essential documents: protocol, investigators’s
brochure, etc
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GCP Ethical Principles
• Trials should be conducted in accordance with
ethical principles which have their origin in the
Declaration of Helsinki.
• A trial should be initiated and continued only if the
anticipated benefits to the trial subjects and society
outweigh the risks.
• The rights, safety, and well-being of the trial
subjects outweigh interests of science and society.
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GCP Ethical Principles
• The available preclinical and clinical data on a new
product must be adequate to support the proposed
trial.
• The protocol must have received approval by an
independent ethics committee.
• Each trial subject must freely give informed
consent before trial participation.
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Informed Consent Process
• The goal of the informed consent process is to
provide individuals with sufficient information so
that they can make informed choices about
whether to participate in clinical research.
• The process includes ongoing dialogue between
the patient and the research team, the informed
consent document, and other educational
materials.
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Elements of Informed Consent
Documents
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Purpose of the study
Risks
Benefits
Alternatives
Confidentiality
Readability
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NCI Informed Consent Template
• US National Cancer Institute (NCI) has developed
a template for informed consent consistent with US
regulations.
• Format: questions and answers
– Why is this study being done?
– How many people will take part in the study?
– What will happen if I take part in this research study?
(before, during, and after)
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NCI Informed Consent Template
• Format: questions and answers
– How long will I be in the study?
– Can I stop being in the study?
– What side effects or risks can I expect from being in the
study?
– Are their benefits to taking part in the study?
– What other choices do I have if I do not take part in the
study?
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NCI Informed Consent Template
• Format: questions and answers
– What are the costs of taking part in the study?
– What happens if I am injured because I took part in the
study?
– What are my rights if I take part in the study?
– Will my medical information be kept private?
– Who can answer my questions about the study?
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History of Modern Human Trial
Ethics: United States
• Code of Federal Regulations (CFR)
• CFR Title 21 Chapter 1 (1938): Rules for Food and
Drug Administration (FDA)
– Good Clinical Practice (GCP) addressed
• Title 45 CFR 46: Department of Health & Human
Services (1974)
– Guidelines for conduct of human research
– Incorporates Helsinki Declaration principles
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Trial Site Standard Operating
Procedures (SOP)
• Detailed written instructions to achieve uniformity
of specific trial conduct functions
• Assure compliance with complex GCP guidelines
• Often required by trial sponsor
• Provide a mechanism for consistency of
performance and patient rights protection in event
of personnel or leadership change
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Trial Site SOP
• Elements
– Direct daily activity process flow
– Define staff responsibilities
– Guide the audit process
– Serve as training tools for new staff
• Commercially available templates that are
adaptable to a specific site
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Sample of Suggested SOP Topics
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Adverse event reporting
Managing clinical study supplies
Data management
Informed consent
Drug accountability and storage
Regulatory documentation
Close out study activities
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Investigational Drug Availability
after Trial
• There is no regulation that mandates
investigational drug availability out side of a clinical
trial
• Most sponsors will provide continued use of an
investigational drug at completion of a study until
commercially available
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Investigational Drug Availability
after Trial
• US FDA Expanded Access Program
– Drugs with “significant” activity before FDA approval
– Sponsor must apply to FDA and supply agent
– Individual patient Investigational New Drug (IND)
application (patient history, proposed treatment,
manufacturer information, informed consent approved
by local IRB, investigator qualifications, FDA Form 1571
with treating physician as sponsor)
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Investigational Drug Availability
after Trial
• US NCI as sponsor
– Treatment Referral Center protocols
• Clinical evidence supports drug should be made available
• Protocol at NCI designated Cancer Centers
– Special Exemption Process
• Similar to FDA single patient IND
• Specifically used for a patient who previously received the
agent on trial with benefit and is no longer able to receive
through a trial.
– Examples: ATRA and Arsenic Trioxide for APL,
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Clinical Trial Ethical Summary
• Protection of the individual participant’s rights and
safety is the prime obligation of a clinical trial
• The investigator’s prime duty is to protect the study
participant
• International consensus has clearly defined Good
Clinical Practice
• Proper informed consent is essential for participant
protection
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Prepared by
Stephen S. Grubbs, M.D.
Delaware Christiana Care CCOP
Newark, Delaware
Special Thanks
Edward L. Trimble, MD, MPH
National Cancer Institute, USA
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