1. Clinical Trial Ethical Considerations
Dear Colleagues, I hope that you had a nice lunch and that you will be able to stay awake during the time when normal human physiology suggests that a siesta would be more appropriate than attending closely to a lecture. During this talk I would like to address some of the ethical considerations surrounding cancer clinical trials.

2. Disclosures None

3. 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.

4. 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

5. 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.”
From the earliest times of history, doctors recognized the importance of ethical treatment. The most famous statement comes from the Oath of Hippocrates, who was a Greek physician from the island of Cos in the Ionian Sea. This statement, dated to the 4th century BC, reads: “I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm to anyone”.

6. 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

7. 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

8. 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

9. Ethical considerations
Declaration of Helsinki
International Conference on Harmonization Good Clinical Practice
Informed consent process
During this talk on ethical considerations, I will discuss the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice, and the informed consent process.

10. 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

11. 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.
The Helsinki Declaration is morally binding upon physicians. The Helsinki Principles take precedence over national or local laws and regulations if the Declaration provides higher standards. Clinical investigators must abdie by local regulations and the Helsinki Principles.

12. 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
The Helsinki Principles are based upon respect for the individual. Each individual has a right to self-determination and to make informed decisions. The duty of the investigator is solely to the patient or volunteer. Although there is always a need for scientific research, the welfare of the study subject always takes precedence over the interests of science and society.

13. 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.
The principles acknowledge that some individuals and groups require special vigilance, such as in cases of incomptence, mental or physicial incapability of giving consent, or young age. Consent by surrogates, such as a parent or spouse, is allowed if that person is acting in the subject’s best interest

14. 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
According to the Helsinki principles, the research must be based upon a thorough knowledge of the scientific background and a careful assessment of the risks and benefits. In addition, there must be a reasonable likelihood of benefit to the population under study.

15. 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
Research must be conducted by investigators with the appropriate training, who use an approved trial protocol. The research must be subject to independent ethical review and oversight by a properly convened committee.

16. 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 Helsinki principles state that new information which changes the potential risks and benefits to a trial should be evaluated. In some cases, a study may need to be stopped. The public should have access to information about the trial. The results of trials should be published. After a trial is complete, the interests of the subjects are still part of the ethics of the trial.

17. Other ethical guidelines
Council of International Organizations of Medical Sciences
International Conference on Harmonization Good Clinical Practice (GCP) (
Individual national regulations
As you know, human beings generally dislike universal consensus. Other ethical guidelines have been developed by the Council of International Organizations of Medical Sciences and the International Conference on Harmonization, as well as by individual nations. The guidelines which are most commonly cited are the Helsinki Principles and Good Clinical Practice (GCP).

18. 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

19. 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

20. ICH guideline on Good Clinical Practice (GCP)
ICH.E6(R1) document (
Principles of GCP
Ethics committee
Investigator
Sponsor
Essential documents: protocol, investigators’s brochure, etc
The ICH document “guideline on good clinical practice” can be downloaded from the ICH website. It includes principles of GCP and extensive descriptions of the responsibilities of the ethics committee, the investigator, the trial sponsor, and the essential documents, such as the protocol and the investigator’s brochure.

21. 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.
The ethical principles found in GCP are similar to the Helsinki Principles. For example, it says that the benefits must outweigh the risks. The rights and safety of the trial subjects outweigh the interests of science and society.

22. 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.
As with the Helsinki principles, the available scientific data must be adequate to support the rationale for the trial. An independent ethics committee must approve the trial before it opens and monitor the trial once it is open. Each trial subject must freely give informed consent before trial participation.

23. 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.
Informed consent is a process which extends beyond the informed consent document. The goal is to provide individuals with the information they need to 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.

24. Elements of Informed Consent Documents
Purpose of the study
Risks
Benefits
Alternatives
Confidentiality
Readability
Informed consent documents should include discussion of the purpose of the study, risks and benefits to participants, alternatives to the study and the confidentiality of patient records. In addition, the document should be written at an 8th grade or lower reading level. Individual countries may have regulations or laws which specific the content of the informed consent document.

25. 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)
The NCI has developed a template for informed consent in cancer trials which is consistent with US regulations. It uses the format of questions and answers. The questions include: 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 the study treatment?

26. 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?
Other questions include: 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?
Will my medical costs be kept private?

27. 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?

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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)

34. 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,

35. 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

36. Delaware Christiana Care CCOP National Cancer Institute, USA
Prepared by
Stephen S. Grubbs, M.D.
Delaware Christiana Care CCOP
Newark, Delaware
Special Thanks
Edward L. Trimble, MD, MPH
National Cancer Institute, USA