Ethics in Clinical research

DR. L S DESHMUKH

DM (Neonatology)

deshmukhls@yahoo.com

Disclaimer

• Contents are drawn from various

sources.

• I am not authority / Expert on the topic

• No conflict of Interest

• Constructive criticism is welcome

Outline of presentation

• What is Ethics ?

• Why ethics in clinical trials- historical perspective

• principles of ethics

• Case studies

• Complexities of doing research in India

• Challenges

• The way forward

What is Ethics?

• The word 'ethics' is derived from the

Greek word, ethos, which means

custom or character.

• Ethics is the systematic study of

values, so as to decide what is right

and what is wrong.

Deontology/Kantian Ethics

• Requires that we treat people as ends

and never simply as means or as

subjects, and never simply as objects.

Text (Desjardins, 2006)

Photo (Buller, 2004)

Ethics

• Ethics is a subject that deals with values,

principles, beliefs, and opinions

• Not a natural science but a creation of the

human mind, open to the influence of time,

place, and situation

• A framework to determine what is right and

wrong regarding human action, character, and

behavior

• comes from within, unlike law which regulates

the external behavior

The first step in the evolution of

ethics is a sense of solidarity with

other human beings.— Albert Sweiter

Research

• Human subject research is a systematic

investigation that can be either research or

clinically oriented and involves the use of

human subjects in any capacity.

Moral problem in clinical research

• The goal of clinical research is generation

of useful knowledge about human health

and illness

• Benefit to participants is not the purpose

of research (although it does occur)

• People are the means to developing

useful knowledge; and are thus at risk of

exploitation

Ethics of Clinical Research

• Ethical requirements in clinical

research :

– minimize the possibility of exploitation;

– ensure that the rights and welfare of

subjects are respected

History

“Those who do not learn from history are

doomed to repeat it.” George Santayana

1. The Nuremberg Code (1947)

2. The Declaration of Helsinki (1964)

3. U.S. Code of Federal Regulations (1974)

4. The National Research Act and The IRB

System (1974)

5. The Belmont Report (1979)

6. ICMR Guidelines (2000,2006)

History

Nuremberg code

Nazi Experiments

1945-1947- The Nuremberg Trial

Children in concentration camps

who had been used for medical experiments

Thalidomide - phocomelia

1945-1947- The Nuremberg Trial

Photograph of an injury caused by a phosporous

experiment conducted at Ravensbruek in 1941

1945-1947- The Nuremberg Trial

A Romani (Gypsy) victim to make seawater potable.

Dachau concentration camp, Germany, 1944

1945-1947- The Nuremberg Trial

Bodies and parts of bodies of people

subjected to medical experiments

1945-1947- The Nuremberg Trial

High Altitude Experiments

1945-1947- The Nuremberg Trial

Female Jewish victim

1945-1947- The Nuremberg Trial

A victim immersed in icy water at the Dachau

concentration camp. Germany, 1942

1945-1947- The Nuremberg Trial

Execution of Jews by Nazis

1945-1947- The Nuremberg Trial

Nazi Camp Bunks

1945-1947- The Nuremberg Trial

Nuremberg holocaust

1945-1947- The Nuremberg Trial

23 Physicians in Dock During the Trial

1945-1947- The Nuremberg Trial

Court Room Scene-N-trial 1945

1945-1947- The Nuremberg Trial

Doctor Hoven testifying in his own defense

during the N-Trial

1945-1947- The Nuremberg Trial

Nazi-era doctor Heinrich Gross,

who was accused of killing

children

29

Nuremberg Trials

• Nazi Experiments

– experimental starvation

- induced gangrene

– low barometric pressure

– induced hypothermia

– induced burns and wounds

Nuremberg Trials

• Characteristics

– conducted without consent of participants

– caused unnecessary pain, suffering and death

– absence of benefits for the participants

– lack of adequate scientific rationale

Nuremberg Code

• The Nuremberg Code is a set of

research ethics principles for human

experimentation set as a result of the

Subsequent Nuremberg Trials at the end

of the Second World War.

• The ten points of the Nuremberg Code

• "the voluntary consent of the human subject

is absolutely essential"

The Declaration of Helsinki

• 1964 - Adopted by the 18th World Medical Assembly (latest version 2008)

• A notable change from the Nuremberg Code was a relaxation of the conditions of consent

• obtain consent 'if at all possible‘

• introduced the concept of oversight by an 'independent committee” Or ethics committees

The Declaration of Helsinki

• "all protocols must be submitted to an ethics

committee for review, which must be

independent of the investigator, the sponsor or

any other kind of undue influence".

Belmont Report

Tuskegee Syphilis Study

• cited as "arguably the most infamous biomedical

research study in U.S. history”

Tuskegee Syphilis Study

• "399 black men thought to have syphilis were

recruited and followed to determine the course

of the disease (what would happen to them).

• Penicillin was known to be an effective

treatment for syphilis by about 1947.

• The subjects were not informed of what was

being studied or of the treatment alternatives

available.

Belmont Report

• National Research Act/Belmont Report

1979

• The report established three tenents of

ethical research,

respect for persons,

beneficence and

justice

India has strong Ethics guidelines for clinical research

Every clinical trial program should be reviewed by an

ethics committee

– Initial review of proposed research protocols

– Regular monitoring of compliance to ethics guidelines

– Can be constituted by the institute where research is done

– Independent

– multi-disciplinary

– multi-sectorial

Ethics Guidelines in India

National Guidelines for

Accreditation, Supervision &

regulation of ART Clinics in

India, 2005

Draft

ICMR DBT Guidelines for

Stem Cell Research and

Therapy, 2006

Good Clnical Practices (GCP)

For Clinical Research In India

• Developed by Central Drugs Standard Control

Organisation (CDSCO)

• Components :

- Pre-requisites for the study

- Responsibilities

- Record Keeping and Data Handling

- Quality Assurance

- Statistics

Why Ethics in Clinical Research?

• Clinical Trials are an experiment

• With investigational products

• On human beings as participants

• With some additional complexities in

Indian context

Three basic principles

• Justice

• Respect for Persons

• Beneficence and non-malaficence

- maximize benefits

- minimize harms and wrongs

- do no harm

Core Principles of Clinical Trial Ethics

Principals of Ethical Research - Components

Essential Elements of Ethical Research

Balance of Risks and Benefits

• Minimize risks to subjects

• Maximize benefits to individual subjects

and to society

• Benefits should be proportional to or

outweigh risks.

Non-maleficence and Beneficence

Test on human beings only if

absolutely essential

Does all current research

certify that the drug is safe?

Essentiality

Provide remuneration to test subjects

Inform subjects about all potential side

effects and risks

Ensure ample compensation for accidental

injury

Insurance, Rehabilitation, Life-long support

Non-Exploitation

Inform subjects about the extent to which

personal info would be disclosed

Do not divulge identity and records of test

subjects as far as possible

Do not Provide information which will

allow identity to be guessed

Privacy & Confidentiality

Design the study such that risks

to the subjects is minimized

Ensure there are no adverse side

effects

Precaution

Balancing principles

• Balancing the need for a rigorous design

with the obligation to maximize benefits

and minimize harms

– Equipoise

– Randomization

– Choice of control

– Example: Randomized Controlled Trials

Choice of control

• “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”

(Helsinki 2000)

Clinical Equipoise ?

• “Genuine uncertainty within the

scientific community...” about the

comparative merits of intervention ‘A’

and ‘B’ (Freedman, 1987)

Professional Competence

All personnel involved in trials

should be trained and qualified

A strong sense of ethics essential

for personnel

Competence

No aspect of the study should be hidden Except

for privacy reasons

Prior disclosure of all conflicts of interest

Maintain permanent records of all research data

and notes

Fix responsibility for the study and its outcomes

Burden of Proof is always with those who

conduct the trial

Transparency & Accountability

Benefits of research should be equally distributed

Research on genetics should not lead to racial

inequalities

Do not conduct research on economically weak

sections to create advantage for those that are better off

Avoid implicit coercion

Do not enroll people at a disadvantage in the study

- Prisoners / Students / Subordinates/Employees

Ensure complete freedom of choice when they are

enrolled

Distributive Justice

Distributive justice

- the local study populations will not

significantly benefit from the research if the

new therapies will not be affordable to

them, although they are taking a higher

proportion of the risk.

Distributive justice is violated

Patient rights

• Use in the country after approval

- drug is marketed only in the affluent

countries

- insist on drug would be released in

India also at a price that is reasonable

Patient rights

Vulnerability of patients in a trial

• money paid

• health care to the family

• free medicines at the hospital

• Free diagnostic tests

• counter to the cardinal principle of autonomy

• not be compelled or unfairly enticed to participate

• truly a free choice?

Patient rights

Patients enrolled in clinical trials when

trials are closed

• numbers are completed because of

recruitment of patients in other countries

• important to ensure that all persons in the

trial receive their drugs

• should be a built-in safeguard when

approving a clinical trial

Patient rights

Access to drugs

- Participants cannot afford the Drug

• should be able to obtain at a reduced price or entirely free.

Information

• No information is ever provided about the outcome

• Must be provided not only to the participants of the trials but also to the community.

Patient rights

Use of the placebo

• unethical to give a placebo to a group of

patients when there is a drug available to

cure

• no role for a placebo in conditions for

which there is already an effective drug

• e.g. evaluation of new drugs for diabetes Chaudhury R R , ICMR

Single-dose perinatal nevirapine plus standard zidovudine to

prevent mother-to-child transmission of HIV-1 in Thailand

• The study was designed to test the superiority of

nevirapine-nevirapine regimen over the placebo-

placebo regimen

• Critics: Use of placebo unethical

• Supporters: Poor countries can anyway never

afford the expensive AZT regimen and the

shorter treatments were needed

• argued for “local standard of care”, In this case it

was “absence of care”New Engl Jr Med 2004; 351: 217-28.

Pregnant/Nursing Women

Only for research to better the health of

pregnant/nursing women, foetus or infants

Ensure that there is no risk to foetus or infant

Special Groups

Children

Only trials for drugs to improve child health

Only conduct trials on children after phase 3 clinical

trials on adults

Exception: drugs for diseases only affecting children

Consent from parents and/or legal guardians

Consent from child in the case of mature minors and

adolescents

Except where parents have given consent and there is

no other medical alternative to the tested therapy

Special Groups

Research Involving Children (1977);

The Belmont Report (1979)

Respect for Children

Declaration of Helsinki (2000)

• Obtain informed consent from parent

• If child capable, obtain assent

The National Commission (1977, 1979)

• Parental Permission (but within limits)

Protect child’s health and safety (i.e., beneficence)

• Child Assent (not as a right, but a benefit)

Nurture child’s moral growth and developing autonomy

Two Pillars of Ethics

• Informed Consent Process

• Institutional Ethics Committees

Informed consent

Informed Consent

Subjects should consent to participate in the

study

Subjects should be fully informed about the

objectives of the study

Subjects have the right to withdraw at any point

during study

No refund of remuneration should be demanded on early

withdrawal

Informed consent

Informed consent- Indian situation

• Getting informed consent difficult in developing countries

• 30% each consented after full or partial disclosure

• Significant gender difference with fewer females consenting to participate (P=0.043)

• Understanding of consent poor

B Gitanjali et al JPGM 2003; 49: 109-113.

ETHICS COMMITEE

Independent review of clinical research

ensures the public that investigator biases

have not distorted the approach, that ethical

requirements have been fulfilled, and that

subjects will not be exploited.

Minimize conflict of interest

Public Accountability

Ethics committee members

1. Chair person, preferably from outside the

institution

2. 1-2 basic medical scientists

3. 1-2 clinicians from various institutes

4. One legal expert or retired judge

5. One social scientist

6. One philosopher or ethicist

7. One lay person from community

8. Member secretary

Criteria for IEC Review

• Risks … are minimized.

• Risks are justified by anticipated benefits,

• Subjects will be selected and treated fairly

• Informed consent is adequate

Reporting ethical processes in Indian journals

• Research articles of 2006 published in Indian Pediatr

and Ind J Peds analyzed

• N = 132, 98 studies prospective

• 39 (29.53%) reported ethical approval

• 46/98 (46.94%) mentioned informed consent from

parents or guardians

• 54/98 (55.1%) studies enrolled children, 8 (14.81%)

mentioned assent

• 4 (7.41%) studies reported ethics committee

approval, Informed consent and assentBavdekar SB & Gogtay NJ.

WHO-ICMR study on status of Ethics

Committees in India

• Many institutions do not have IECs

• Many do not have written SOPs

• Paucity of trained personnel to work for EC

• Lack of training facilities for EC members

• Variability in quality of ethical review

• No regulation/ registration/ accreditation

• Lack of time for monitoring

Medical research in India

• unrelated to the country’s major health

problems.

• “little influence” on health care delivery.

• scant regard for standard ethical guidelines

• problem in defining local priorities

Clinical Trials Registry of India

• launched in July 2007

• editors of 12 Indian biomedical journal

• encourages the registration of all clinical

trials

• meant to bring transparency

• publication of a trial only if it has been

previously registered.

• no legal requirement to register a trial

Clinical Trials

• Phase I - Human Pharmacology

• Phase II - Therapeutic exploratory trials

• Phase III - Therapeutic confirmatory

trials

• Phase IV - Post Marketing Trials

Trials in India - Concerns

• Lack of formal training in bioethics and research methodology

• heavy burden of clinical duties

• sub-optimal administrative support

• a lack of regulation of private trials

• Variation in requirements for informed consent

• Lack of proper ethics review.

Trials in India - Concerns

• quality of clinical research,

• timelines for regulatory approval,

• deficiencies in the functioning of the

ethics committees

• an unethical approach to the

recruitment of trial subjects

Trials in India - Concerns

Limited awareness amongst investigators

-Do all studies require EC clearance?

-What documents need to be submitted?

-Can EC look at scientific aspects as well?

-Requirements for Regulatory clearances

Gardasil Trial - India

• HPV vaccine trial (AP & Gujrat ) 2010

• marketed in India by MSD Pharmaceuticals Pvt

Ltd.

• four deaths and complications among 120 girls

• The vaccine has been approved for adult women

aged 27, without any trials on them.

• No Phase III trials in adults before use in children

• scientific logic and ethical guidelines violated at

each step

Trials in India - Concerns

Unethical and dubious ?

• trials to develop a contraceptive vaccine

• cervical dysplasia (a pre-cancerous

condition) untreated to study the progress of

the disease

• trials on quinacrine sterilisation

• trial of ‘anti-cancer’ cure conducted in

Calcutta in 2000.

Trials in India – Preferred Destination?

• a technically competent workforce

• patient availability,

• low costs

• a friendly drug-control system.

Trials in India- The benefits

• participation by Indian researchers and

clinicians

• platform for carrying out clinical trials

• creating expertise

• increasing job opportunities

• bringing resources into the country.

( ? 2.2 billion US dollars by 2015 )

Challenges - 1

• Research Ethics: A new specialty

• Informed Consent: Several inherent difficulties

-Illiteracy, too many languages, lack of time for health

professionals to explain

• Bioethics education: Not in the curriculum

• Boom in clinical research has not been matched by

regulatory reform and ethical practices

Challenges- 2

Group 1 No major feasibility issues. Singapore

Capable of hosting Hong Kong

GCP trials

Group 2 Minor barriers that can be Taiwan

easily overcome. Thailand

Group 3 Significant feasibility China, Japan

issues But solutions India, Malaysia

can be found. Philippines

Group 4 Major barriers. Very difficult Indonesia,

to conduct studies in the Korea, Vietnam

near term. Myanamar

Proceedings of DIA International Symposium Taipei,

Taiwan October 2-3, 1998

Challenges- 4

Ethics Committees

• No funds allocated to EC

• Space crunch: Documentation and archiving

difficult

• Infrequent Meetings

• Limited resources for monitoring studies

• Not all research studies undergo review

Complexities in Indian context

• Developing country

• Socio-economic considerations

• Healthcare availability and access

• Literacy and education status

• Conflicts of interest

• “Guinea pig” perception

• Questions about clinical trials in India

• Acceptability of Indian data

• Issues of post trial access

Pluses

• By 2010, it is estimated that a fifth of all

global studies will be done in India

Why?

-Rx naïve patients

-Highly skilled GCP trained investigators ?

-Excellent technological infrastructure

-Lower costs of drug development

-Fast regulatory approvals ?The Lancet 2007; 369: 1233

Pharma: Assets (?ethics)

• Pharmaceutical company assets may exceed many nations’ Gross Domestic Product

– The current global drug market is $520 billion

• Governments and officials kowtow to the power and money

• “Democracy” transforms into Corporate Feudalism

• Science turned into a marketing tool

| www.plosmedicine.org June 2007 | Volume 4 | Issue 6 | e184

The way forward

Regulations

• Ethical Guidelines into Law (like US)

• Training in ethics at UG & OG level

• Involvement of UG students in

observational Research

Power of the People

• Democracy only works with Civil Society’s

full engagement

• The hegemony of Greed must be stopped

• Can NGOs/Civil Society conduct our own

clinical studies?

• Non-violence in the face of violence

• Engage and involve stakeholders

Life has become complex

RReellii ggiioonn MMoorraa lliittyy EEtthh iiccss LL aaww

TTaabb ooooss TTrraaddii ttiioonnss CCuusstt oommss

Ethics has always been in the gray zone

– 256 shades of Gray

Resources

• The Helsinki Declaration reflects international values. http://www.wma.net/e/

• The Nuremburg Code: http://www.nihtraining.com/ohsrsite/guidelines/nuremberg.html

• Belmont Report: http://ohsr.od.nih.gov/guidelines/belmont.html

• Council for International Organizations of Medical Sciences http://www.cioms.ch/

• Indian GCP for clinical trials http://cdsco.nic.in/html/GCP.htm

• Indian biomedical research ethics guidelines available at: ICMR Ethical Guidelines for Biomedical Research