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@example.com) • 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 by Stephen S. Grubbs, M.D. Delaware Christiana Care CCOP Newark, Delaware Special Thanks Edward L. Trimble, MD, MPH National Cancer Institute, USA