Evolution ofRegulatory Guidelines
Dr. Padmaja UdaykumarProfessor & Head
Department of Pharmacology Fr Muller Medical College, Mangalore
• Historical ethical principles• Definition of bioethics• Importance of knowing evolution of research
ethics• Ethical guidelines relating to global events• The Indian events
Through this session, we look at
Why know evolution?
• Makes it interesting• Easier to understand• Learn from past events/mistakes
Principles of Indian Systems of Medicine
• Ayurveda
• Siddha
• Unani
Information may be acquired for benefit of patients
Ethics
• Endless quest to determine what is right and what is wrong
• Difficult to escape dealing with it
Origin of “Bioethics” is relatively new – traced back to 2nd half of the 20th century.
Early history------
• Book of DanielA passage in the Old Testament even describes a clinicaltrial. The first chapter of the Book of Daniel describeswhat happens after Nebuchadnezzar, king of Babylon,conquered Israel
• "Moses Maimonides (1135-1204)
Jewish physician, philosopher, & Rabbi ofCairo, taught that physicians should seek tohelp individual patients, and should not usethem merely as a way of learning new facts
“May I never see in the patient anything buta fellow creature in pain”
Bioethics History – Western Sphere
• 1803 – Thomas Percival : First Code of medical ethics• 18th Century – John Gregory (medical humanism)• 1865 – Claude Bernard’s ‘Experimental medicine’• 1897 – Code of Medical Ethics, AMA
• 1927 - Fritz Jahr, a German Theologian - coined the term ‘bioethics’ - argued for an ethical approach to issues concerning human beings & environment in an article "bioethical imperative”
• 1947 – AMA adoption of Percival code• 1970 - American biochemist Van Potter added
‘biosphere’ - thus included ecology to the meaning
• 1972 – Warren Reich : The Encyclopedia of Bioethics
“A study of the moral dimensions -including moral vision, decisions, conduct andpolicies of the life sciences and health care,employing a variety of ethicalmethodologies in an inter-disciplinarysetting”
The Encyclopedia of Bioethics -Warren Reich
Bioethics is a multidisciplinary study of – Philosophical– Ethical– Social– Legal– Economic– Medical– Anthropological– Religious– Environmental & other related issues
- arising from biological sciences and technologies, and their applications in human society and the biosphere.
What do you think ….?
“It is not cruel to inflict on a few criminals, sufferings
which may benefit multitudes of innocent people
through all centuries” ….. Celsius
"The goal of science is to produce new knowledge. If, during unethically conducted experiments, one valid scientific fact is produced, should that information be used as it has been, referenced in the literature or just discarded?“
-Jay Katz and Robert S. Pozos
• 30th century BC - Siddha• Babylon 1750 BC - Code of Hammurabi • 1st century BC - Charaka Samhita• 5th century BC - Shushruta Samhita• 4th Century BC - Hippocratic Oath
DO NO HARM
Primum non nocere
• Prior to 1960s – ethics – hands of physicians
• By 1960 – wide range of new ethical problems due to advances in medicine & biology
• Grew beyond boundaries of the word
Tuskegee syphilis study • By US public health service • To study the natural course of untreated
syphilis in rural African-American men• 1932 – 1972 • 600 men recruited• Free health care, meals & burial insurance from
govt• Treated for bad blood
• Penicillin with held• Prevented access to it • 1970 – Peter Buxton – US PHS interviewer -
whistle blower• 1972 - went to the press • Nation-wide uproar• Study withdrawn
399 syphilitics + 201 disease -free,28 deaths, 100 died of disability & complications, 40 wives
infected, 19 children 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
Aftermath
• 1974 – National research act • 1979 – Belmont report• Office for Human Research Practices (OHRP) -
to oversee clinical trials established • Federal laws & regulations requiring IRBs for
protection of human subjects
Following World War II –------Holocaust & related Nazi medical abuses →
changes in international law.
• Experiments on twins• Hypothermia, high altitude experiments• Bone muscle nerve transplantation• Sea water experiments• Head injury experiments• Malaria experiments
Twin Studies in Auschwitz
Dr. Josef Mengele
15 of 23 guilty, 7 hanged, 5 life sentences
Susan Reverby
Infecting with STD microbesSing Sing Penitentiary, NY, USIndiana Prisoners
Gautemala people next
John C. Cutler,former deputy director of the Pan American Sanitary Bureau
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
• 1947 Nuremberg Code
• 1948 Universal Declaration of Human Rights Geneva
• 1956 Code of Medical Ethics, MCI
• 1964 Declaration of Helsinki
• 1979 Belmont Report
Formulated by the Western allies
10 Principles
• Informed Consent
• Prior animal experiments
• Risk of death - avoid
• Termination of study
Why research ethics was still violated?
• Nuremberg’s Trial and Codes thought just as a lesson to teach the Nazi War Criminals
• Integrity of researchers
• Lack of oversight – IRB, Monitoring
• Pressure of reputation and fund
• Need for a clear experimental protocol
• 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
Henry Beecher, NEJM, 1966
Landmark Article on U.S. Abuses
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
Respect for persons
Beneficence
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 opportunity to choose what shall or shall not happen to them include three elements:
information comprehension voluntariness
Beneficence Do not harm Research should maximize possible benefits & minimize possible harms
Assessment of the nature and scope of risks and benefits 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 subjects
Codes of Medical Ethics / Guidelines
• 1980 : ICMR’s Policy Statement
• 1982, 1991,1993 : The WHO / CIOMS guidelines • 1993 -95 : Genetics, Human tissue, Xeno transplantation
(Nuffield Council, UK)• 1996 : ICH GCP Guidelines• 2001 : NBAC Report (US)• 2002 : Revised CIOMS & Nuffield Council
Guidelines • 2013 : Revised Helsinki Declaration (7th version)
Violation of Ethical Norms during & after release of ethical guidelines, 2000
• VEGF trial in a private hospital in Delhi• John Hopkins – RCC Collaboration• 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 - 2004
• Captive participants - Tribal minor girls (14,091) 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• 7 girls died
Over 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 : ICMR guidelines- Policy Statement on Ethical
Considerations involved in Research on HumanSubjects
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 BillTHE BIOMEDICAL
RESEARCH ON HUMAN PARTICIPATION
(PROMOTION AND REGULATION) BILL, 2007
Title different ? 2013
Contents modified
• 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, 2000)
• 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
Recent Notifications• 2013 onwards – increased regulation
• Notifications – 30.1.2013 – Rule 122 DAB; GSR 53(E) on compensation– 01.2.2013 – Rule 122 DAC; GSR 63 (E): Permission for trials– 08.2.2013 – Rule 122 DD; GSR 72(E): E C registration– 07.6.2013 – AV consent; order on 19.11.2013– 30.8.2013 – Sponsor to furnish details of fees & finances– 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
ICMR
Supreme Court Judgment - 3.1. 2013
• System for proper conduct & monitoring of clinical trials
• Constitution of committees by MoH
– To develop systems– Expert Committee for
AEs/ ADRs– Technical Committee– Apex Committee
Ranjit Roy Chaudhury Report 2013
• Accreditation – Outsourcing byNational Council of Accreditation –Quality Council of India?
– Investigators– Sites– Ethics Committees – Role of
FERCI
Forum for Ethics Review Committees in India (FERCI) 2002
• National chapter of Forum for Ethics review committees in Asia – Pacific (FERCAP), a WHO initiative
• Operates in collaboration with WHO, ICMR, CDSCO, SIDCER
Objectives
• To improve understanding and implementation of ethical review
• To assist adoption of SOPs for ethical review• To assist ECs in India to get accredited with
international agencies• To improve communication between ECs
Accreditation - Need
• To promote standard for quality
• Improve knowledge and practice of researchethics among various health researchstakeholders
• To strengthen human research protectionprograms
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 areentirely ours and can be shifted onto nobody else;neither to God, nor to nature, nor to society, nor tohistory….
Whatever authority we accept, it is we who acceptit. We only deceive ourselves if we do not realizethis simple point.”
Karl Popper
Thank You