clinical trial ethical considerations

ICTW Punta del Este, Uruguay

Clinical Trial Ethical Considerations


Disclosures

None


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.


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


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.”


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


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


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


Ethical considerations

• Declaration of Helsinki• International Conference on Harmonization

Good Clinical Practice• Informed consent process


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


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.


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


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.


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


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


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.


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


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


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


ICH guideline on Good Clinical Practice (GCP)• ICH.E6(R1) document (www.ich.org)• Principles of GCP• Ethics committee• Investigator• Sponsor• Essential documents: protocol,

investigators’s brochure, etc


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.


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.


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.


Elements of Informed Consent Documents• Purpose of the study• Risks• Benefits• Alternatives• Confidentiality• Readability


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)


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?


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?


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


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


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


Sample of Suggested SOP Topics• Adverse event reporting• Managing clinical study supplies• Data management• Informed consent• Drug accountability and storage• Regulatory documentation• Close out study activities


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


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)


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,


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


Prepared byStephen S. Grubbs, M.D.

Delaware Christiana Care CCOPNewark, Delaware

Special ThanksEdward L. Trimble, MD, MPH

National Cancer Institute, USA