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
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
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