History to Evolution of Regulations and Guidelines

DR RAGHAVENDRA RAO M

SENIOR SCIENTIST &HEAD, CLINICAL RESEARCH

HEALTHCARE GLOBAL ENTERPRISES LTD.

BANGALORE

MORAL DOCTRINE AS ETHICS : RELIGION

Hinduism- Vedas and Upanishads

Buddhism – Panchasila

Jainism – “Ethical Realism”

Christianity- Biblical scriptures “Virtous vs. Sin”

Islam – Quran tenets “Command the good and forbid the evil" in all spheres of life

Sikh- Virtuous living, -prudence, dutifulness, temperance, tolerance

Concept of Dharma [ca.1750–500 BCE]In Hinduism, dharma signifies behaviors that are considered to be in accord with rta, the order that makes life and universe possible

dharma means ‘right way of living’ and ‘path of righteousness’

In certain contexts, dharma designates human behaviours considered necessary for order of things in the universe, principles that prevent chaos, behaviours and action necessary to all life in nature, society, family Community as well as at the individual level

Dharma encompasses ideas such as duty, rights, character, vocation, religion, customs and all behaviour considered appropriate, correct or morally upright.

ETHICS

Moral, Ethical & Legal aspects

Internal - Moral code of conduct

Guidelines

Political decision - Code of Ethics

Legislation by State - External

30th century BC - Siddha

10th Century BC – 200 AD : Caraka Samhita (written code)

Hammurabi 1 - 2nd Century AD

4th Century BC : Hippocratic Oath

DO NO HARM

Primum non nocere

Ayurveda

Siddha

Unani

Information may be aquired for benefit of patients

Concept of living in harmony with Nature

Encompassed Tenets from Vedas and UpanishadsRig veda, Atharvaveda, Bhrihadaranyaka Uanishad.

Tenets from Islam

Early history :Babylonian Civilization 1728 BC- 24 BCBook of Daniel

A passage in the Old Testament even describes a clinical trial. Thefirst chapter of the Book of Daniel describes what happens afterNebuchadnezzar, king of Babylon, conquered Israel

Hammurabhi codified ethics, law and criminality

Going back in history ….Greek philosopher

“It is not cruel to inflict on a few criminals

sufferings which may benefit multitudes of

innocent people through all centuries”

…….. Celsus

Bioethics History – Western Sphere1657 - Just moral propriety in medicine

1740 – 1804 – Thomas Percival : First Code of medical ethics

18th Century – John Gregory (medical humanism)

1846 – AMA code, 1st national code

1865 – Claude Bernard’s ‘Experimental medicine’

1897 – Code of Medical Ethics, AMA 1927 - Fritz Jahr, in an article on "bioethical imperative, discussed the scientific use of animals and plants

1947 – AMA adoption of Percival code

1960s - “Bioethics’ word coined

1970 - American biochemist Van Renseelaer Potter added ‘biosphere’ thus included ecology to the meaning

1972 – Reich : The Encyclopedia of Bioethics

German Code of conduct/ Ethical Guidelines for physicians/ Researchers

1898 - German Ethics of Science & Medicine

1933 - Guidelines by Reich Government

NAZI CONCENTRATION CAMP

ICMR

Nuremberg Trial70 medical experiments

7000 deaths

23 stood trial in NUREMBERG under allied forces

7 hanged 5 life imprisonment, 15 guilty

Several escaped

Nuremberg code 1947 Laid down ten principles for HUMAN EXPERIMENTATION

Nuremberg code includes such principles as

1. Informed consent

2. Absence of coercion;

3. Properly formulated scientific experimentation;

4. Beneficence towards experiment participants.

Declaration of Geneva 1948Physicians Oath

Declaration of a physician's dedication to the humanitarian goals of medicine

Adopted Modern Version of Hippocratic Oath

Nuremberg Code WWII 1947

Declaration of Helsinki 1964

Nazi War Crimes 1939-45

Tuskegee SyphillisStudy 1932-74

Thalidomide Study1957-1962

Belmont Report 1972

CIOMS 1982

Radiation Exp US Govt1944-74

UN Decl of Human Rights 1948

NIH First IRB 1953

FDA CFR 21 1980

Wilbrook Study 1963-66

Milestones in Ethical Development

Thalidomide StudyNon barbiturate sedative

2.5 million tablets sold

207 pregnant women

Phacomelia

1962 FDA tightened restrictions on its usage

Laid down guidelines to for clinical research in medical practice

Need for a clear experimental protocol

“Absolute consent” to “Exemption in some cases”

To be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence

What to submit for review

Wilbrook State School for mentally retarded -1956-1970

CRITICISM

It is morally wrong to perform an experiment on either a normal or a mentally retarded child when no benefit can result for that child.

The institutionalized should not be used for human experimentation.

Experimentation on children, even with parental informed consent, is illegal unless it is in the interests of the child.

According to one report, parents were told that the only way their child could be admitted to Willowbrook is through the hepatitis unit.

The intention of the experiment was never the immunization of the children. That was merely an expected consequence. A moral purpose is required to justify an experiment.

Every patient has a right to be treated decently by physicians--i.e., every physician has an obligation first and foremost to the patient. The patient's right supercedes every consideration about what would benefit humanity.

DEFENSE :KRUGMAN

There was no additional risk for the subjects. Under the normal conditions at the institution the subjects would have been exposed to the same strains of hepatitis.

Experimental subjects had a lowered risk of complications since they were housed in a special unit where there was little danger of exposure to other diseases.

Experimental subjects had the chance of benefiting from immunization.

Experimental subjects were obtained only with informed consent from parents.

Milestones in Ethical Development1993 Public exposure of U.S. human radiation experiments

1993 NIH Revitalization Act mandating inclusion of women and minorities in research

1993 NIH Office of Research on Women’s Health

15 of 23 guilty, 7 hanged, 5 life sentences

Ethics of Clinical Trials: Protection of ParticipantsThe BELMONT REPORT

3 ethical principles guide clinical research:

Respect for Persons: Treatment of person as autonomous

Beneficence: Issue re: potential conflict between good of society vs. individual

Justice: Treatment of all fairly & all equally share benefits & risks

The Belmont Report is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (DHHS)

Henry Beecher, NEJM, 1966

Landmark Article on U.S. Abuses

American medical research project conducted by the U.S. Public Health Service from 1932 to 1972,

examined the natural course of untreated syphilis in African-American men.

28 deaths, 100 cases of disability, 19 cases of congenital syphilis

"What was done cannot be undone, but we can end the silence ...

We can stop turning our heads away.

We can look at you in the eye, and finally say, on behalf of the American people, what the United States government did was shameful and I am sorry."

$ 9 b compensation

Ethical Principles and Guidelines for the Protection of Human

Subjects of Research

The National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research

April 18, 1979

Autonomy

Beneficence

Non-maleficence

Justice

Ethical Principles in Modern Medicine

Principle Application

Respect for persons

Individuals should be treated as autonomous agents

Persons with diminished autonomy are entitled to protection.

Informed consent

Subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them

The consent process must include three elements:

information,

Comprehension, and

voluntariness.

Beneficence

Human subjects should not be harmed

Research should maximize possible benefits and minimize possible harms.

Assessment of risks and benefits

The nature and scope of risks and benefits must be assessed in a systematic manner

Justice

The benefits and risks of research must be distributed fairly.

Selection of subjects

There must be fair procedures and outcomes in the selection of research subjects

1947 : Nuremberg Code

1948 : Universal Declaration of Human

Rights Geneva

1956 : Code of Medical Ethics, MCI

1964 : WHA, Helsinki Declaration

Codes of Medical Ethics / Guidelines

1945 : Nuremberg Code

1964 : Helsinki Declaration

1979 : Belmont Report,USA

1980 : ICMR’s Policy Statement,

1993 -95 : Genetics, Human tissue, Xeno -transplantation (Nuffield

Council, UK)

1982, 1991, 1993 : The WHO / CIOMS guidelines

1996 : ICH GCP Guidelines

2001 : NBAC Report (US)

2002 : Revised CIOMS & Nuffield Council Guidelines

2013 : Last Revised Helsinki Declaration (7th version)

“A systemic study of the moral dimensions - including moral vision,decisions, conduct and policies of the life sciences and healthcare, employing a variety of ethical methodologies in an inter-disciplinary setting”

The Encyclopedia of Bioethics - Warren Reich

Bioethics is a multidisciplinary study of ◦ Philosophical

◦ Ethical

◦ Social

◦ Legal

◦ Economic

◦ Medical

◦ Anthropological

◦ Religious

◦ Environmental

and other related issues arising from◦ biological sciences and technologies, and their applications in human society and

the biosphere.

Greatest good for greatest number

(means to an end)

Utilitarianism(Teleontology)

Always act right or do good

(means are ends in themselves)

Kantianism

(Deontology)

Relation to Consequences

Less capacity to consent, to healthcare & more gullible and trusting

Dependency, obligation, inducements

disease/condition mentally ill

age uneducated

poor employee

studentsinstitutionalised

military prisoners

tribals/ migrants

Not well-represented in clinical or market studies

women children

Violation of Ethical Norms during & after release of ethical guidelines, 2000

Pig Heart Transplantation

John Hopkins – RCC Collaboration

VEGF trial in a private hospital in Delhi

Genetics Research on vulnerable population (tribals) funded by NIH, EU & published in American Journal without Indian Collaborator or Govt. consent

Erythromycin trial for contraception

A Private, "One-Man" Clinic

In 2003, letrozole, an anticancer drug,

was tested in more than 430 young

women at a dozen private clinics to

find out whether it promoted ovulation

NEJM 2005

Research in Bhopal

• Captive participants - Tribal minor girls in Hostel• Circular by Dy Director, Tribal Welfare Department authorising Warden/ Head

of school gave consent for residents• Misconcept – public immunisation program, vaccine free of cost• Parents gave consent for non-residents but ignorant about consequences• No institutional ethics committee review

Over the past 7 years - 73 clinical trials including 3,300 patients (1,833 children)

Ethics Committee Chairperson states EC has lost control – BBC News

30th BC : Siddha Code of Conduct

10th BC : Charaka Samhita

-2 AD

1956 : Code of Medical Ethics, MCI

1980 : Policy Statement on Ethical Considerations involved inResearch on Human Subjects

2000 : Delhi Medical Council Regulations

2000 : Revised ICMR guidelines ‘Ethical guidelines for

Biomedical Research on Human Subjects’

2001 : Indian GCP Guidelines

2002 : Indian Medical Council Amendment

2005 : Revised Schedule Y

2006 : Second revised ICMR guidelines ‘Ethical Guidelines for

Biomedical Research on Human Participants’

2007 : Guidelines for Stem Cell Research & Therapy

2008 Draft GM Food Guidelines

2013 : National Guidelines on Stem Cell Research

Ethics Committee

Informed consent

Clinical trials

Research on children, mentally disadvantaged, those with diminished autonomy

Traditional Medicine

Publications

The Bill

THE BIOMEDICAL RESEARCH ON HUMAN

PARTICIPATION (PROMOTION AND

REGULATION) BILL, 2007

Title different ? 2013

Contents modified

Essentiality

Voluntariness, informed consent and community agreement (ECs shall decide about waiver)

Non-exploitation

Privacy and confidentiality

Precaution and risk minimisation

Professional competence

Accountability and transparency

Maximisation of the public interest

Institutional arrangements

Public domain

Totality of responsibility

Compliance

Clinical Trials of Drugs, Devices, Vaccines, Diagnostic agents,Herbal Drugs

Epidemiological Studies

Human Genetics Research

Transplantation Research including Fetal tissue and Xeno-transplantation

Assisted Reproductive Technologies

2002 - Indian Medical Council Act amendment

2005 - Drugs & Cosmetics Act amendment : Schedule Y

45 CFR 46 and all of its subparts (A,B,C,D)

45 CFR 46, subpart A (Common Rule)

21 CFR 50 and 21 CFR 56

CIOMS International Ethical Guidelines

ICH-GCP-E6 Sections 1 through 4

Canadian Tri-Council Policy

Indian Council of Medical Research

Other (please submit copy to OHRP with this Assurance)

Guidelines

◦ Ethical - ICMR 1980, 2000, 2006◦ Indian GCP, 2001◦ Guidelines for Stem Cell Research & Therapy, 2007◦ Ethical Practices in Studies involving Animals - INSA,CPCSEA◦ Guidelines for Gene Therapy by DBT◦ Policy Statement for Genetics and Genomics by DBT◦ National Biotech Strategy Guidelines – DBT◦ Ethical Guidelines for Social Science Research in Health (CEHAT)

Acts

◦ Drugs & Cosmetics Act, 1940, Revised Schedule Y, 2005◦ Environment Protection Act , 1986◦ Ethical Guidelines - ? Bill 2014 for legislation◦ Notifications from CDSCO

Health Ministry’s Screening Committee - MTA

ICMR

Clinical Trial Registry of India

Supreme Court Judgment 3.1. 2013

Systems for proper conduct & monitoring of clinical trials

Constitution of committees by MoH

◦ To develop systems

◦ Expert Committee for AEs/ ADRs

◦ Technical Committee

◦ Apex Committee

Recent Notifications2013 onwards – increased regulation

Notification

◦ 30.1.2013 – Rule 122 DAB; GSR 53(E) on compensation◦ 01.2.2013 – Rule 122 DAC; GSR 63 (E): Permission for clinical

trials◦ 08.2.2013 – Rule 122 DD; GSR 72(E): Ethics committee

registration◦ 07.6.2013 – AV consent; order on 19.11.2013◦ 30.8.2013 – Sponsor to furnish details of fees, financial support

& payment in kind◦ 24.4.2014 – Draft compensation formula for research related

non- death injury◦ 3.7.2014 – 14 orders from CDSCO based on RRC’s report

2015 – Draft Amendment of Drugs & Cosmetics Act

Ranjit Roy Chaudhury Report 2013

Accreditation – Outsourcing by National Council of

Accreditation – Quality Council of India?

◦ Investigators

◦ Sites

◦ Ethics Committees – Role of FERCI

Accreditation - Need

Improve knowledge and practice of research ethics amongvarious health research stakeholders

To strengthen human research protection programs

To promote standard for quality

To encourage institutional commitment to scientificallyand ethically sound research with continuousimprovement

Accreditation AgenciesSIDCER – Strategic Initiative for the Development of Capacity for Ethics Review

AAHRPP - Association for the Accreditation of Human Research Protection Program

Voluntary Recognition/ Accreditation for a period of 3 years

“The responsibility of our ethical decisions are entirely

ours and can be shifted onto nobody else; neither to

God, nor to nature, nor to society, nor to history….

Whatever authority we accept, it is we who accept it.

We only deceive ourselves if we do not realize this

simple point.”

Karl Popper

Thank You