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