History of Evolution of Ethical Guidelines and Regulations for Clinical Research

Dr. Sudha Ramalingam MD PGD(Bioethics)Registrar-Research

Professor, Community MedicinePSG Center for Research and Bioethics

PSG Institute of Medical Sciences and ResearchCoimbatore

psgbioethics@gmail.com

Scope

• History of Clinical Research

• Evolution of Bioethics

• Evolution of Codes &Guidelines

International

National

• Present scenario

History of Clinical Trials

•Oldest reference to clinical trial•Old testament •Book of Daniels • After Nebuchadnezzar conquered Israel10 days trial of pulses Vs meat

Collier R. Legumes, lemons and streptomycin: A short history of the clinical trial. CMAJ. 2009;180:23–24

Moses Maimonides (1135-1204), the Jewishphysician, philosopher, and Rabbi of Cairo,“physicians should seek to help individualpatients, and should not use them merely as a

way of learning new facts”

• Louis Pasteur (1822-1895)

• Rabies Vaccination

• Cognizant of ethical implications

• Vaccinated a 9 yr old only after he wasconvinced the boy would die otherwise.

•Walter Reed (1851-1902)•Sought volunteers to allow themselves bittenby mosquito •$100 for volunteers & additional $100 for those who developed yellow fever

Cancer Clinical Trials: Experimental Treatments & How They Can Help You by Robert Finn, copyright 1999, published by O'Reilly & Associates, Inc.

Bioethics History – Western Sphere

• 1657 - 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

“A systemic study of the moral dimensions- including moral vision, decisions, conductand policies of the life sciences and healthcare, employing a variety of ethicalmethodologies in an inter-disciplinarysetting”

The Encyclopedia of Bioethics - Warren Reich

Bioethics

Philosophical Ethical Social

Legal Religious

Economic Environmental

Medical Anthropological

Issues related to biological

sciences

Evolution of Codes of Medical Ethics

HISTORY

ICMR

Twin Studies in Auschwitz

Dr. Josef Mengele

15 of 23 guilty, 7 hanged, 5 life sentences

10 Principles

• Termination of study

• Informed Consent

• 1947 : Nuremberg Code

• 1948 : Universal Declaration of Human Rights Geneva

• 1956 : Code of Medical Ethics, MCI

• 1964 : WHA, Helsinki Declaration

• Need for a clear experimental protocol

• To be submitted for consideration, comment,guidance, and where appropriate, approval to aspecially appointed ethical review committee, whichmust be independent of the investigator, the sponsoror any other kind of undue influence

• What to submit for review

Henry Beecher, NEJM, 1966

Landmark Article on U.S. Abuses

Injection of Live cancer cells in elderly

without consent

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

Remembering Tuskegee

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

Basic Ethical Principles

Respect to Persons Informed Consent

Beneficence Risk Benefit

Analysis

Justice Fair selection of

Subjects

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)

Susan Reverby

Infecting with STD microbesSing Sing Penitentiary, NY, USIndiana PrisonersGuatemala people next

Marta Orellana, 74, a victim of the US syphilis trial when she was nine. 'They never gave me a chance to say no,' she says. Photograph: Rory Carroll for the Guardian

www.bioethics.gov

John C. Cutler,former deputy director of the Pan American Sanitary Bureau

Archivo General de Centro América Office of US Presidential

Commission for the Study of

Bioethical Issues

125,000 pages of documents, including 12,000 pages of Dr. Cutler's own papers that he donated to Pitt in 1990.

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

1999-2000 :Banned drugs (M4N)were used on oral cancer patients

Brought to limelight by a patient named Mr Gopalan

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 1956 : Code of Medical Ethics, MCI 1980 : Policy Statement on Ethical Considerations involved in

Research 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, Diagnosticagents, Herbal Drugs

• Epidemiological Studies

• Human Genetics Research

• Transplantation Research including Fetal tissue andXeno- transplantation

• Assisted Reproductive Technologies

• 2002 - Indian Medical Council Act amendment

• 2005 - Drugs & Cosmetics Act amendment :Schedule Y

• 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

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 Notifications• 2013 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 byNational Council of Accreditation –Quality Council of India?

– Investigators– Sites– Ethics Committees – Role of

FERCI

Accreditation - Need

• Improve knowledge and practice of researchethics among various health research stakeholders

• To strengthen human research protectionprograms

• To promote standard for quality

• To encourage institutional commitment toscientifically and ethically sound research withcontinuous improvement

Accreditation Agencies

• SIDCER – 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