a clinician' perspective

1. Ethics in Clinical research
DR. L S DESHMUKH
DM (Neonatology)
deshmukhls@yahoo.com

2. Disclaimer
• Contents are drawn from various
sources.
• I am not authority / Expert on the topic
• No conflict of Interest
• Constructive criticism is welcome

3. 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

4. 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.

5. 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)

6. 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

7. The first step in the evolution of
ethics is a sense of solidarity with
other human beings.
— Albert Sweiter

8. 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.

9. 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

10. Ethics of Clinical Research
• Ethical requirements in clinical
research :
– minimize the possibility of exploitation;
– ensure that the rights and welfare of
subjects are respected

11. History
“Those who do not learn from history are
doomed to repeat it.” George Santayana

12. 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

13. Nuremberg code
Nazi Experiments

14. 1945-1947- The Nuremberg Trial
Children in concentration camps
who had been used for medical experiments

15. Thalidomide - phocomelia

16. 1945-1947- The Nuremberg Trial
Photograph of an injury caused by a phosporous
experiment conducted at Ravensbruek in 1941

17. 1945-1947- The Nuremberg Trial
A Romani (Gypsy) victim to make seawater potable.
Dachau concentration camp, Germany, 1944

18. 1945-1947- The Nuremberg Trial
Bodies and parts of bodies of people
subjected to medical experiments

19. 1945-1947- The Nuremberg Trial
High Altitude Experiments

20. 1945-1947- The Nuremberg Trial
Female Jewish victim

21. 1945-1947- The Nuremberg Trial
A victim immersed in icy water at the Dachau
concentration camp. Germany, 1942

22. 1945-1947- The Nuremberg Trial
Execution of Jews by Nazis

23. 1945-1947- The Nuremberg Trial
Nazi Camp Bunks

24. 1945-1947- The Nuremberg Trial
Nuremberg holocaust

25. 1945-1947- The Nuremberg Trial
23 Physicians in Dock During the Trial

26. 1945-1947- The Nuremberg Trial
Court Room Scene-N-trial 1945

27. 1945-1947- The Nuremberg Trial
Doctor Hoven testifying in his own defense
during the N-Trial

28. 1945-1947- The Nuremberg Trial
Nazi-era doctor Heinrich Gross,
who was accused of killing
children

29. 29
Nuremberg Trials
• Nazi Experiments
– experimental starvation
- induced gangrene
– low barometric pressure
– induced hypothermia
– induced burns and wounds

30. 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

31. 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"

32. 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

33. 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".

34. Belmont Report

35. Tuskegee Syphilis Study
• cited as "arguably the most infamous biomedical
research study in U.S. history”

36. 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.

37. Belmont Report
• National Research Act/Belmont Report
1979
• The report established three tenents of
ethical research,
 respect for persons,
 beneficence and
 justice

38.  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

40. National Guidelines for
Accreditation, Supervision &
regulation of ART Clinics in
India, 2005
Draft
ICMR DBT Guidelines for
Stem Cell Research and
Therapy, 2006

41. 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

42. 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

43. 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

44. Principals of Ethical
Research - Components

45. 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

46.  Test on human beings only if
absolutely essential
 Does all current research
certify that the drug is safe?
Essentiality

47.  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

48.  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

49.  Design the study such that risks
to the subjects is minimized
 Ensure there are no adverse side
effects
Precaution

50. 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

51. 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)

52. Clinical Equipoise ?
• “Genuine uncertainty within the
scientific community...” about the
comparative merits of intervention ‘A’
and ‘B’
(Freedman, 1987)

53.  Professional Competence
 All personnel involved in trials
should be trained and qualified
 A strong sense of ethics essential
for personnel
Competence

54.  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

55.  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

56. 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

57. 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

58. 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?

59. 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

60. 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.

61. 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

62. 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.

63.  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

64.  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

65. 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

66. Two Pillars of Ethics
• Informed Consent Process
• Institutional Ethics Committees

67. Informed consent

69.  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

70. 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.

71. 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

72. 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

73. Criteria for IEC Review
• Risks … are minimized.
• Risks are justified by anticipated benefits,
• Subjects will be selected and treated fairly
• Informed consent is adequate

74. 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 assent
Bavdekar SB & Gogtay NJ.

75. 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

76. 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

77. 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

78. Clinical Trials
• Phase I - Human Pharmacology
• Phase II - Therapeutic exploratory trials
• Phase III - Therapeutic confirmatory
trials
• Phase IV - Post Marketing Trials

79. 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.

80. 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

81. 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

82. 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

83. 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.

84. Trials in India – Preferred Destination?
• a technically competent workforce
• patient availability,
• low costs
• a friendly drug-control system.

85. 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 )

86. 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

87. 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

88. 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

89. 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

90. 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

91. 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

92. The way forward

93. Regulations
• Ethical Guidelines into Law (like US)
• Training in ethics at UG & OG level
• Involvement of UG students in
observational Research

94. 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

95. 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

96. 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