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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