PRINCIPLES OF ETHICS & DoH

Aditi Sawardekar

What is clinical research and why is it important?

• Involves humans

• Provides access to advances in patient care (latest drugs, new devices, new processesof care)

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)

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)

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

Ethics is defined as …

• The Discipline of describing Behavior, Practices, Thinking & Moral values generally agreed to be acceptable in the Society

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.

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 1950s, 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

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

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.

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

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.

BELMONT REPORT

Basic Ethical PrinciplesRespect 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

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.

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

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

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

IRB Members should consider the following…

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?

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)?

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?

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.

THE DECLARATION OF HELSINKI (DoH)

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

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

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

Declaration Of Helsinki (DoH)

Made by the physicians for the physicians

Role of physician above that of the Investigator

Declaration Of Helsinki (DoH)DoH has undergone several amendments. Last

version adopted in Oct 2000 in Edinburgh.Helsinki, Finland 1964Tokyo, Japan 1975Venice, Italy 1983Hong Kong 1989South Africa 1996Edinburgh, Scotland, 2000

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

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.

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.

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.

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

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

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

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.

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.

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

Additional PrinciplesMedical 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

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.

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.

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.

DoH, October 2000 VersionControversial 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.

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

Used By…………. Physicians

CT subjects

Researchers

Governments

Regulatory Authorities

Health Care providers

Pharmaceutical manufacturers

THANK YOU!!!!!!!!!!!