ETHICS IN RESEARCH

Dr. Shaikh Ubedulla Iqbal, Mamata Medical College, Khammam. (A.P.)

Ethics is defined as
The discipline of describing behavior, practices, thinking and moral values generally agreed to be acceptable to society
OR

Ethics correct behaviour dictated internally by ones own moral integrity .

Guidelines & Law

Guidelines Norms for correct behaviour laid but not forced.

Law Correct behaviour governed externally or enforced by State .

Historical
perspectives on

human research

THE NUREMBERG DOCTORS TRIAL OF 1946

The Nazi regime exploited human beings by forcing them to participate in research without consent. The mortality rate of these war time research studies was typically 25 - 30%. The Nuremberg Trials were heard from 12/46 to 8/47

Defendants (20 were physicians) were charged with murder, torture and other atrocities committed in the name of medical science.

American soldiers stand guard the Nuremberg prison

Defendants rise as the Judge enters

Judges discussing the case

The Jewish Chronic Disease Hospital Study

Studies begun in 1963 at New York City's Jewish Chronic Disease Hospital to develop information on the nature of the human transplant rejection process. Studies involved the injection of live cancer cells into patients who were hospitalized with various chronic debilitating diseases. Previous studies had indicated that healthy persons reject cancer cell implants promptly. Patients with widespread cancer also reject homographs, however, rejection is delayed substantially when compared with healthy subjects.

The Willowbrook Study

From 1963 through 1966, studies were carried out at the Willowbrook State School, a New York State institution for "mentally defective persons." These studies were designed to gain an understanding of the natural history of infectious hepatitis and subsequently to test the effects of gamma globulin in preventing or ameliorating the disease. The subjects, all children, were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations.

Dr. Saul Krugman

The Willowbrook State School

The Milgram Study

The study was on obedience and humans response to authority. The subjects were deceived as to the nature of the study and were told it was a teacher/ learner experiment. The teachers were told to give the subject an electrical shock for missed answers.

60% of the teachers were persuaded to give shocks up to the highest level, even after the subject (acting the part) appeared to lose consciousness.
At the study debriefing many of the teachers justified their actions by saying they were only following instructions. The role of deception in human subject research continues to be debated even today.

Dr. Stanley milgram

Thalidomide Disaster 1962

Julie-Jean George

Professional tennis instructor Butch Lumpkin Tawana Williams

In 1957, a West German pharmaceutical manufacturer introduced a new sedative, thalidomide, which alleviated the symptoms of morning sickness in women during the first trimester of pregnancy.
In 1962, by which time the drug had been sold in 46 countries, it became clear that thalidomide damaged the fetus, causing stillbirth or, most prevalently, phocomelia (Greek for "seal limb"). Thousands of newborn babies were found to have truncated limbs that resemble flippers.

Tuskegee Syphilis Study

1932 to 1972

The study involved 600 black men--399 with syphilis and 201 who did not have the disease
1932, the Public Health Service, working with the Tuskegee Institute, began a study in Macon County, Alabama, to record the natural history of syphilis in hopes of justifying treatment programs for blacks. It was called the "Tuskegee Study of Untreated Syphilis in the Negro Male."

President Clinton's Statement May 16, 1997

REMARKS BY THE PRESIDENT IN APOLOGY FOR STUDY DONE IN TUSKEGEE

The Beecher Article

Beecher HK. Ethics and clinical research. The New England Journal of Medicine, 1966, 274: 13541360. Cited serious ethical problems including inappropriate risk exposure, questionable scientific design and no documentation of consent in 22 research studies. This lead to the 1982 Council for the International Organization of Medical Sciences (CIOMS) guidelines: the International Ethics Guidelines of Biomedical Research Involving Human Subjects.

Henry K. Beecher 1904-1976

Unethical Treatment of Human SubjectGene Transfer Trial (1999)

Carried out at University of Pennsylvania. Jesse Gelsinger, an 18 yr. old with mild ornithine transcarbamylase deficiency .

Gene-therapy study to determine safety, not efficacy; consent incomplete

Parents inadequately advised about risks 4 days after therapy, patient brain-dead 17 Sep 99

Johns Hopkins Tragedy (2001)

Normal volunteers inhaled hexamethonium as pulmonary vasodilator; large literature on toxicity (in older publications) Shortly thereafter, volunteer #3, 24 years old died of respiratory failure 2 June 2001 An FDA Warning Letter to Dr. Alkis Togias of the Johns Hopkins University Asthma & Allergy Center (March 31, 2003).

Ellen Roche Volunteer #3 An employee of Johns Hopkins.

Milestone documents of ethical guidelines for protection of human Volunteer

THE NUREMBERG CODE

1. The voluntary consent of the human subject is absolutely essential. 2. The experiment should be such as to yield fruitful results for the good of society.

3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that that death or disabling injury will occur.

THE NUREMBERG CODE

6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided.

8. The experiment should be conducted only by scientifically qualified persons.

9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage

DECLARATION OF HELSINKI (1964)

Developed by the World Medical Association(1964).

After several revisions it now consists of 32 paragraphs. Specify the ethical principles associated with conducting medical research studies of human subjects.
The principles have influenced legislation and regulations worldwide.

DECLARATION OF HELSINKI (1964)

Significant principles include Informed consent must be given. There should be prior research from animal studies.

The risks of participating in a trial should be justified by the possible benefits.

Research should be conducted by qualified health professionals. Physical and mental harm should be avoided.

THE BELMONT REPORT (1979)

Ethical Principles and Guidelines for Research Involving Human Subjects A. Boundaries Between Practice and Research B. Basic Ethical Principles 1. Respect for Persons 2. Beneficence 3. Justice C. Applications 1. Informed Consent 2. Assessment of Risk and Benefits 3. Selection of Subjects

Principle: Respect for Persons

"Individual autonomy Informed consent
full information full comprehension voluntary
without coercion

Protect individuals with reduced capacity to exercise autonomy

Principle: Beneficence
"Do no harm" - "Do benefit

Assessment of risks [harms] and benefits

Minimize harms to participants Use least harmful methods to achieve the scientific end Favorable Benefit-to-Risk comparison
maximize Benefit:-to-Risk ratio maximize benefits to participants and society

Principle: Justice
"Treat individuals fairly Selection of subjects / participants
Equitable distribution of research harms and benefits
Equitable selection of subjects / participants within a population Equitable selection of population

FDA AND ICH GUIDELINES

U.S. Federal Regulations

Directly derived from the ethical principles of the Belmont Report

Adopted in 1991 by 17 federal departments and agencies, hence the name the Common Rule

Governs research that is conducted or supported by these federal agencies

U.S. Federal Regulations

Title 45 Code of Federal Regulation 46 (45 CFR 46) Protection of Human Subjects and consists of 4 parts:

Subpart A - Basic DHHS Policy for the Protection of Human Research Subjects
Subpart B - Additional DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization Subpart C - Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D - Additional DHHS Protections for Children Involved as Subjects in Research.

U.S. Federal Regulations

The Food and Drug Administration (FDA) has a separate set of regulations governing human subjects research

21 CFR 56 governing IRBs 21 CFR 50 governing Informed Consent

The basic requirements for IRBs and for Informed Consent are congruent between the two sets of regulations. Differences center on differences in applicability. The Common Rule is based on federal funding of research. FDA regulations are based primarily on use of FDA regulated products:- drugs, devices, or biologics.

ICH
Q-

What is ICH? 1. International Harmonization.

Conference

of

2. It is a joint initiative involving regulators & industry as equal partners in the scientific & technical discussions of the testing procedures which are required to ensure and assess the safety, quality & efficacy of medicines.

ICH
Structure Three countries, USA, Japan and EU, with their 6 founding member parties (EU, EFPIA, MHLW, JPMA, FDA and PhRMA)
Observers (WHO, EFTA, Canada) - Non-

voting members. IFPMA representative

ICH operates via the ICH Steering

Committee, i.e. 6 parties & IFPMA.

ICH
Finalized Guidelines: Efficacy (E1 to E12) GCP=E6 (1996) Quality (Q1 to Q6)

Safety (S1 to S7 & M3)

Multidisciplinary (M1, M2, M4)

ICH-GCP (E 6)
Table of Contents - 8 sections 1. Glossary 2. The Principles of ICH-GCP 3. Institutional Review Board/Independent Ethics Committee (IRB/IEC) 4. Investigator 5. Sponsor 6. Clinical Trial Protocol & Protocol Amendment(s) 7. Investigators Brochure 8. Essential Documents for Conduct of a Clinical Trial

ICH-GCP
Q How does the ICH-GCP ensure ethical research? By laying down guidelines to be followed by:
IEC/IRB Investigator Sponsor

INDIAN SCENARIO OF ETHICAL GUIDELINES IN HUMAN RESEARCH

Why Are More Trials Being Done in Developing Countries?

Larger pool of sick people Less red tape & oversight People sign up faster because of lack of alternatives Use of placebos--easier to show treatment effect Research personnel are paid less Research in India is 50 60% less expensive than in the US Other estimates are that trials in a first-rate centre in India are 1/10 the cost of trials in a second-rate centre in the US

Growing Level of Research in Developing Countries

>

Strength India
Heterogeneous Population >1.2 billon Different Ethnic Groups Endogamous tribal population (conserved gene pool)

350 Medical Colleges > 400Research Institutes > 500 Universities 11,500 hospitals and 14,000 diagnostic laboratories 100 R&D labs in the public sector & 200 in Govt. Sector

1.5 lac sub-centres, 23,000 primary health centres, 4000 community health centres 1,600 urban family welfare centres 3 million graduates, 700,000 post graduates and 1500 PhDs in biosciences and engineering Employment for 15,000 scientists exists in Indian Biotech itself. 5000 harnessed Potential for hiring 50,000 professionals over 5 years in the Contract Research

SYMBIOSIS, PUNE

12th January, 2008

Ethical Approval - Developing & Developed Countries

Percent of respondents Developing Developed countries countries
Ethics committee in institution Review body in institution 58.9 94

41.4

75

Contemporary Clinical Trials 2007;28:677-83

Recent Violation of Ethical Norms after release of revised ethical guidelines

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. Anti-cancer drug letrozole as fertility agent without DCGIs clearance off label use. Studies in bhopal gas victims

Other Trials with Ethical Problems

Organizations involved range from local companies to large multinationals

Ethical Guidelines for Biomedical Research

The Bill
THE BIOMEDICAL RESEARCH ON HUMAN SUBJECTS (REGULATION CONTROL AND SAFEGUARDS) BILL, 2005

The Biomedical and Health research on Human Participants ( ethical, legal and social issues)Bill, 2010

ICMR - GUIDELINES
Ethical Guidelines for Biomedical Research on Human Subjects

ICMR 2000

Compiled by Central Ethics Committee on Human Research

ICMR GUIDELINES
Background: Nuremberg Code 1947

Universal Declaration of Human Rights (General Assembly of UN) 1948

International Covenant on Civil & Political Rights 1966

CIOMS
Declaration of Helsinki 1964 ICMR 1980 WHO & CIOMS 1982 ICH GCP 1996

ICMR - 2000

ICMR GUIDELINES
General Statement

1. Purpose (directed towards increase of knowledge) 2. Conduct (with dignity & well-being)
3. Evaluation (at all stage of research)

ICMR - GUIDELINES
Contents:General Principles on Ethical Consideration Ethical Review Procedures General Ethical Issues Specific Principles for Clinical evaluation of

Drugs/Devices/Diagnostics/Vaccines/Herbals
Specific Principles for Epidemiological Studies Specific Principles on Human Genetic Research Specific Principles for Research in Transplantation including Fetal Tissue Transplant Specific Principles on Assisted Reproductive Technologies.

GCP-INDIA
GOOD CLINICAL PRACTICE (GCP) An international ethical and scientific quality standard for designing, conducting and reporting clinical trials that involve the participation of human subjects. Provides public assurance that rights, safety & well-being of trial subjects are protected, consistent with Declaration of Helsinki and that the clinical data are credible.

GCP-INDIA
Formulated by an Expert Committee, set up by Central Drugs Standard Control Organization (CDSCO), with clinical experts

Relies on ICMR Guidelines

GCP-INDIA
Introduction Hippocratic Oath-Do no harm to the patients GCP is an elaborate set of guidelines that address a physicians ethical & scientific responsibilities while involved in biomedical research. GCP is a set of guidelines for biomedical studies involving human subjects. GCP guidelines seek to establish 2 cardinal principles: Protection of the rights of human subjects & Authenticity of biomedical data

GCP-INDIA
7 topics covered in Indian GCP: 1. Definitions 2. Pre-requisites for the study 3. Responsibilities (Sponsor, Monitor, Investigator) 4. Record keeping & Data handling 5. Quality Assurance 6. Statistics 7. Special Concerns

GCP - INDIA
Appendices:1. DoH 2. Schedule Y 3. Format for Submission of Preclinical & Clinical data for rDNA based vaccines, diagnostics & other biologicals. 4. Investigators Brochure 5. Essential Documents

Government Initiatives
The Bill THE BIOMEDICAL RESEARCH ON HUMAN SUBJECTS (REGULATION CONTROL AND SAFEGUARDS) BILL, 2005 The Biomedical and Health research on Human Participants ( ethical, legal and social issues)Bill,2010

SCOPE
Promote and regulate biomedical and behavioural research on human subjects to ensure safety and well being of the research subjects. Necessity to control and monitor the application of new technologies eg. stem cell research, therapeutic cloning, ART, Genomics etc.

To restrict unscrupulous clinical trials on unsuspecting patients.

Provide legislative power to the ICMR Ethical Guidelines formulated under the Chairmanship of Justice Shri M. N. Venkatachaliah, former Chief Justice and Chairman of National Human Rights Commission of India . Setting up of a National Biomedical Research Authority.

Chapters in the Bill

Chapter I - Short title, extent & commencement, and definitions Chapter II - Provision for the establishment of the Biomedical Research on Human Subjects Regulatory Authority Chapter III - Functions of Authority Chapter IV Provisions for finance, accounts & audit of the authority Chapter V Issue of licenses, fees, cancellation & renewal of licenses Chapter VI Ethics review Committees, National ethics committee Chapter VII Conditions for Subject participation : special groups, women & children, vulnerable groups Chapter VIII Clinical Research

Chapters in the Bill (Contd.)

Chapter IX Research in Epidemiology Chapters X Research in Human genetics & Genomics Chapter XI Research in Assisted Reproductive Technology Chapters XII Research in Transplantation of Human Organs & Tissues Chapters XIII Offences Chapters XIV Control by Central Government Chapters XV - Miscellaneous

Rules & Regulations to be placed before the Parliament: SCHEDULES IN THE BILL
Schedule A - General Principles for conducting biomedical research on human subjects Schedule B - Guidelines for research in clinical evaluation of drugs, vaccines, devices, diagnostic and herbal remedies (includes principles of Drugs & Cosmetics Act & Indian GCP guidelines) Schedule C - Guidelines for research on human subjects in epidemiological studies Schedule D - Guidelines for research in human genetics and genomics (includes genetics and genomics guidelines of DBT as one common code)

Schedule E - Guidelines for research in assisted reproductive technology

Schedule F - Guidelines for research in transplantation of human organs and tissues

CURRENT STATUS
Draft legislation ready for placing before the Parliament for notification after vetting by the Law department

Wide Public Consultation

Regional and National Debates Will provide legal support to the ethical guidelines Implementation

Government Initiatives (FERCI)

Initiatives toward regulating Indian Ethics Committees relevant to Indian ethos.

The ICMR has collaborated with the Forum for Ethics Review Committees of Asia Pacific (FERCAP) to develop SOPs for ECs.
The Forum for Ethics Review Committee in India (FERCI) has been set up under FERCAP with some members from the bioethics cell in the organizing committee of FERCI. FERCI organized the First National Conference on Research Ethics at the Tata Memorial Hospital, in November 2011. This national conference was a pioneering step toward improving the functioning of ECs in India and getting them together. FERCI, along with WHO and SIDCER(Strategic Initiative for Developing Capacity in Ethical Review ), plans to work on the capacity building of ECs in India and impart accreditations to them.

FERCI - The Indian Chapter of FERCAP

Issues facing India

Ethical Review- Rather unknown & rudimentary in general, poor
monitoring

Informed Consent- Inherent difficulties- illiteracy, too many

languages, lack of time to explain

Bioethics education- Not in the curriculum Community consultation- Product availability/access new concepts

Awareness- Patients/ subjects are not aware of their rights, Doctor/

scientist not aware of obligations

Diversity - of population, religions, castes , practice of different

system of medicines