1. Principles of Ethics & DoH
Aditi Sawardekar

2. What is clinical research and why is it important?
Involves humans
Provides access to advances in patient care (latest drugs, new devices, new processes of care)

3. What is a clinical trial?
Prospective study in humans
Compares at least 2 interventions
One is experimental treatment
One serves as “control”
Ideal design:
Randomized subject assignment
Double-blinded (double-masked)

4. What are the phases of drug development?
Phase 1 (Maximum Tolerated Dose, PK)
Phase 2 (biologic effect, rate of AEs)
Phase 3 (comparative efficacy, safety)
Phase 4 (post-marketing studies in special groups, e.g. children)

5. Consensus documents, ethics and Clinical Research
Primum Non Nocere = First do no harm (Hippocrates Epidemics)
Nuremberg Code
Declaration of Helsinki (International Conference on Harmonisation)
Belmont Report
Hippocrates Epidemics: collections of medical writings by Hippocrates talks about the Hippocratic oath

6. Ethics is defined as …
The Discipline of describing Behavior, Practices, Thinking & Moral values generally agreed to be acceptable in the Society

7. Historical Perspective
Nuremberg War Tribunal (1947):
Criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity.
Horrifying procedures were conducted for research purposes on thousands of concentration camp prisoners without their informed consent.

8. Syphilis Study in Tuskegee
As part of a research project conducted by the U.S. Public Health Service,
600 low-income African-American males, 400 of whom were infected with Syphilis, were monitored for 40 years.
Free medical examinations, participants were not told about the disease
Even though a proven cure (Penicillin) became available in the s, the study continued until 1972 with participants being denied treatment.
Some cases, when participants were diagnosed as having Syphilis by other physicians, researchers intervened to prevent treatment.
Many participants died of Syphilis during the study.
The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment

9. Thalidomide Tragedy
Thalidomide was used in the 1950s to combat unpleasant symptoms associated with pregnancy.
At the time it was being used it was not usually disclosed to patients that the drug was investigational and still in the testing phase of the Regulatory Process.
After women in Europe, Canada, and the U.S. were treated with the drug it was discovered that the drug had teratogenic effects, causing severe deformities in the fetus.
Thalidomide was soon banned worldwide.
Unfortunately, approximately 12,000 babies were born with severe deformities due to thalidomide
Used as sleeping pills & in morning Sickness in 1st Trimester
The deformity called Phocomelia (seal like limbs)

10. Response To Research Abuses
Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and led to the formulation of the Nuremburg Code (1948).
The Thalidomide Disaster led to the adoption of the "Kefauver Harris Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications.
The Declaration of Helsinki drafted by the World Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today.
The National Research Act (1974) passed primarily in response to the Syphilis study, codified the requirement that human participants in research must be protected and set the stage for the issuance of the Belmont Report.

11. National Research Act (1974)
Due to the publicity from the Syphilis Study, the National Research Act of 1974 was passed.
The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.
Commission spoke about the ethical principles that should be the basis for Research in Human subjects (Biomedical Research) & developing guidelines to ensure Research is conducted ethically
Commission spoke about the ethical principles that should be the basis for Research in Human subjects & developing guidelines to ensure researd is conducted ethically

12. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
Carrying out its charge, the Commission prepared the Belmont Report in 1979.
The Belmont Report is a statement of basic ethical principles and guidelines that provide “an analytical framework to guide the resolution of the ethical problems arising from research with human subjects.”
The framework of the Belmont Report is presented in three discussion topics.
Solving problems that arise taking into consideration the ethical aspect

13. BELMONT REPORT

14. Basic Ethical Principles
Respect for Persons
Individuals should be treated as autonomous agents
Individuals with diminished autonomy are entitled to protections
Beneficence
Do not harm
Maximum possible benefits and minimize potential harms
Justice
Fair distribution of burdens and benefits of Research
Autonomous: Independent
Diminished Autonomy: Less/No autonomy: Vulnerable subjects: E.g. Children

15. Autonomy (Respect For Person)
Treat individuals as autonomous persons; allow individuals to choose for themselves
Persons with limited autonomy need additional protection, even to the point of excluding them from activities that may harm them. The extent of protection should depend upon the risk of harm, and the likelihood of benefit.
The judgment that any individual lacks autonomy should be periodically re-evaluated.

16. Beneficience
The IRB should determine whether the risks to subjects are reasonable in relation to anticipated benefits
Obligations of beneficence affect both the researcher and society –
Investigators are required to give forethought on maximization of benefits and reduction of risk that may be involved in the research
Society should recognize the longer term benefits and risk; that may result from the improvement of knowledge, and from the development of novel medical, psychological, and social processes and procedures

17. Justice Treat people fairly
Do not exploit those who are readily available or malleable
Fair distribution of the risks and the benefits of research based upon the problem/issue under investigation
Malleable: Flexible
No discrimination to be done on the basis of Caste, Race, Social, economic background of an individual

18. Application of General Principles
Consideration of the three general principles in the conduct of research lead to the consideration of:
Informed Consent Process
Risk/Benefits Assessment
Selection of Research Participants

19. IRB Members should consider the following…

20. Application Of Autonomy
Informed Consent Process
Information - Does the consent form provide all the information necessary for the individual to make a reasoned decision?
Comprehension - Is the consent form crafted in language understandable to the potential participant?
Voluntariness - Does the consent form and clearly indicate that participation in the research is voluntary?
What additional protections can be in place to protect those with limited autonomy?

21. Application of Beneficience
Assessment of Risks and Benefits
Risk refers to the probability of harm; when considering risk, one should consider both the probability and the severity of the envisioned harm; while the term, benefit refers to something that promotes health, well-being, or welfare.
What are the risks of harm to the participants (consider physical, psychological, social, and economic harms)? Are the risks justified? Can they be minimized?
Can the research design be improved to minimize risk and maximize benefit?
What are the benefits (to the participant; to society)?

22. Application Of Justice
Selection of Subjects
Is the potential subject pool appropriate for the research?
Is it appropriate to involve vulnerable populations (e.g., economically disadvantaged; limited cognitive capacity) in the research or are they being enrolled because it is convenient or because they are easily manipulated as a result of their situation?
Are the recruitment procedures fair and impartial?
Are the inclusion and exclusion criteria fair and appropriate?

23. The Belmont Report
Although never officially adopted or endorsed by Congress the Belmont Report has served as an ethical framework for protecting human subjects for over 25 years.
Endorsed: Sanctioned

24. THE DECLARATION OF HELSINKI (DoH)

25. World Medical Assembly (WMA)
International organization representing physicians
Created in 1947
Individual physicians can also join the WMA as associate members
Aims at promoting high standards of medical ethics
Provides ethical guidance to physicians through Declarations & Statements
The General Assembly of WMA meets annually. It is the decision-making body of the WMA
General Assembly: General Body Meeting

26. Declaration Of Helsinki (DoH)
DoH remains the foundation of Ethical reference for global medical research.
Not a guideline or set of rules
DoH is a set of principles defines standards
Principles have been incorporated into law in some countries.
Always included as an appendix to Research Contract Documents
Principles: Values

27. Declaration Of Helsinki (DoH)
DOH states the ethical principles to be respected by physicians when carrying out medical research, involving human subjects/ human material, as identifiable human data.
The DoH is not legally binding.
It has a recognized moral value & is widely accepted.
DoH was first drafted in 1964 by WMA

28. Declaration Of Helsinki (DoH)
Made by the physicians for the physicians Role of physician above that of the Investigator

29. Declaration Of Helsinki (DoH)
DoH has undergone several amendments. Last version adopted in Oct 2000 in Edinburgh.
Helsinki, Finland 1964
Tokyo, Japan 1975
Venice, Italy 1983
Hong Kong 1989
South Africa 1996
Edinburgh, Scotland, 2000

30. Declaration Of Helsinki (DoH)
3 Sections, 32 Paragraphs.
Sections are:
Introduction
Basic principles for medical research
Additional principles for medical research combined with medical care

31. Introduction “The health of my patient will be my first consideration”
Medical progress is based on research which must rest in part on experimentation involving human subjects.
Considerations related to the well-being of the human subject should take precedence over the interests of science and society.
Progress of medicine depends on Research Conducted on Human subjects

32. Introduction
Medical Research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures
Medical research is focus to Ethical standards is for promoting Respect & Protection of Human & their Rights.
Main aim of ethical standards in Medical Research is to promote Respect & Protection of Human & their rights

33. Introduction
Research investigators should be aware of ethical, legal, regulatory requirements for research on human subjects in their countries & international applications. No national, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in DoH.
Research investigators should knw the legar, ethical & regulatory req within their country as well as other countries & the need for protecting the human subjects preceeds all of them as seth forth by DoH

34. Basic Principles
It is the duty of the physician to protect the life, health privacy & dignity of the human subject
Medical research involving human subjects must not manipulate the data & maintain the scientific principles
Effects observed in Animals used for research & on Environment should also be considered
Effects observed in animals & on Environment should also be considered
conform to generally accepted scientific principles: Stick to Scientific Principles

35. Basic Principles
Each experimental procedure must be described in a protocol
Research protocol must contain a statement of ethical aspects
Medical research must be conducted by scientifically qualified persons supervised by a clinically competent medical person

36. Basic Principles
Predictable risks & burdens should be weighed against foreseeable benefits for the subject
Physicians should cease any investigation if risks outweigh potential benefits
Medical research is only justified if there is a reasonable likelihood that a population will benefit

37. Basic Principles Subjects must be volunteers & informed participants.
Rights of the research subjects to safeguard their physical & mental integrity & privacy must be respected.
Each potential subject must be adequately informed and his/her freely given consent obtained, in writing.

38. Basic Principles
For legally incompetent subject, investigator must obtain consent from a legally authorized representative.
Where a legally incompetent subject is able to give assent to decisions about participating in research, that consent should be obtained in addition.
Assent: by child
Consent: by Parents
legally incompetent subject: Subject unable to consent

39. Basic Principles
Subjects in a dependent relationship with the researcher should be consented by an independent physician
If research is intended on subjects who cannot consent (Vulnerable subjects), it must be justified to & approved by the review committee
Results of all trials conducted according to these principles must be accurately published or otherwise made available
(Vulnerable subjects)

40. Additional Principles
Medical Research combined with medical care
Responsibility as a an “Investigator”
Data valid & as per ethical standards
Responsibility as a “Physician”
Incase of Adverse events need to take the responsibility

41. Additional Principles
The benefits, risks, burdens & effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic & therapeutic methods. This does not exclude the use of placebo, in studies where no proven prophylactic, diagnostic/therapeutic method exists.
Comparator should be the best drug available for treating the indication.
If no method yet available placebo may be used

42. Additional Principles
At study conclusion, every patient entered into the study should be assured of access to the best proven prophylactic & therapeutic methods identified by the study.
The physician should fully inform the patient which aspects of the care are related to the research. The refusal to participate in a study must never interfere with the patient-physician relationship.

43. Additional Principles
Incase the proven treatment is ineffective, Physician with the Informed consent may use the unproven or new treatment if his judgment offer hope to save life.
Incase the proven treatment is ineffective. Physician with the Informed consent may use the unproven or new treatment if his judgement offer hope to save life.

44. DoH, October 2000 Version
Controversial version, on issue of use of Placebo in Clinical
research.
All previous versions state “Best Proven Treatment” should be given to the control group.
In absence of proven treatment, placebo can be used.
Version 2000, point 29, states “Best Current Treatment” should be given; i.e. Placebo can be used only when no proven treatment is available.

45. DoH, Clarification to 2000 Version
Specified conditions to be fulfilled for the use of the Placebo:
Where the placebo is necessary (for methodological reasons) to determine efficacy or safety of a new method/treatment.
Where the trial investigates minor condition without risk of serious or irreversible harm for the patient

46. Used By…………. Physicians CT subjects Researchers Governments
Regulatory Authorities
Health Care providers
Pharmaceutical manufacturers

47. Thank You!!!!!!!!!!!