describes the ethical issues to be followed during carrying out a research.

1. Ethical issues in Medical
Research
Dr.Triveni. A Kale
M.D.S Periodontics-
Professor - P.G Guide.
MGVs KBH Dental college and hospital, nasik
Faculty Research Methodology.(˘MUHS- Nasik)
Faculty MET(MUHS-Nasik)
Reviewer: MUHS journal for Health.
Assistant editor : journal of periodontal practise.

2. Learning objectives
To understand
• History
• Nuremberg Code
• Declaration of
Helsinki
• Belmont Report
• IRB
• Levels of review
• Resources
2

3. The first step in the evolution of ethics is
a sense of solidarity
with other human beings.
— Albert Sweiter
3

4. What is health research?
 A biomedical activity that entails systematic
collection and analysis of data with the
intention to generate new knowledge in which
humans are exposed to new interventions.

5. Practice Vs Research
 Medical practice – best known methods /
medicines should be used while treating.
 Research – Unproven and risky new
interventions are used.
Is this justifiable?
By following certain guiding
principles that can protect
the participants

6. Medical Ethics
The study of a moral ideals, rules and codes of
conduct that govern behavior of medical
professionals. (Grenz & Smith, 2003)
Is there any difference between ethics and
morals?
 Ethics - Greek word; moral - Latin word for the
same idea.
 Strictly, ‘ethics’ refers to a set of principles,
whereas ‘morals’ refers to individual behavior and
often has emotional component.

9. An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Prisoner in a compression chamber

10. Immersing people in ice water
With the intent of
discovering
means to prevent and
treat
hypothermia.
• 280 to 300 victims
• One study forced
subjects to
endure a tank of ice
water for up
to five hours.

11. History of Human Subject Research
• First documented trials in 1700’s
– Vaccination trials
– Researchers and family members as subjects
• Generally, human subject studies carefully
scrutinized
– Consent of subject key
– Generally high regard for medical profession
11

12. Nature of Nazi Experiments
• Decompression
• Hypothermia
• Sterilization
• Euthanasia agents
• Wounds and burns
• Starvation
• Typhus and typhoid
12

13. Incisions made by
medical personnel
that were purposely
infected with bacteria,
dirt, and slices of
glass
History & Background GCP

14. In 1946, an American
military tribunal opened
criminal proceedings
against 23 leading German
physicians : Doctors' Trial
• Sixteen of the doctors were
found guilty
• Seven were sentenced to
death
• Development of
the Nuremberg
Code of medical ethics
THE DOCTORS TRIAL

15. First Code
• Nuremberg Code, a set of 10 guidelines
for the ethical treatment of human
participants in research. 1949

16. 16

21. US public health service examined the
natural course of untreated syphilis in Black
American men
The subjects, all impoverished
sharecroppers from Macon county, Albama
Unknowing participants in the study : they
were not told that they had syphilis nor were
they offered effective treatment.
Tuskegee Study “Bad Blood” 1932-1972

23. Tuskegee Study “Bad Blood”
1932-1972
28 deaths
100 cases of disability
19 cases of congenital Syphilis

24. Unehical study in the world.
400 Afro american syphilis patient monitored for 40 years.
Given free medical checkup, But not told about their disease
Penicillin – Drug of choice , But Not used.
No consent.
Patients----------Research Specimens,---- many died
In 1973 U S health department stop the study.
The national research act was passed in the U.S and created
National Commission which drafted the Belmont Report.
Tuskegee Study (syphilis) →
(1932-1972 )

25. In 1948 the Universal Declaration of Human
Rights (December 10th 1948) was also adopted
and expressed the concern about rights of
human beings involved in medical experiments.
Universal Declaration of Human Rights

26. Injected live cancer
cells
Patients were not
told,
Physicians…not
consulted
‘They are going to
die anyways’
2
Jewish Chronic Disease
Study
1963

27. Subjects ( volunteers )were terminally sick
patients treated with obvious disrespect and
exposed to significant risks of harm.
Elderly patients who had some disability were
injected with live cancer cells in circumstances
in which it was unclear whether con-sent was
sought
Jewish Chronic Disease Study 1963

30. Beecher Article
Problems
• Lack of informed consent / withholding info
• Coersion / undue pressure on volunteers
• Use/exploitation of vulnerable population
• Withholding available treatments
• Deception
• Risks outweigh benefits
30

31. Declaration of Helsinki
• Nuremberg code: Limited effect in US
– Medical profession already “knew better”
– No real law enacted
• World Medical Association developed code of
research ethics (1964)
– Focused more on research with therapeutic intent
– Journal editors required this code be followed
– Birth of institutional review boards (IRBs)
31

32. 32

33. Willowbrook Hepatitis Study
• 1956 study to determine
– natural history of viral hepatitis
– Inoculation against hepatitis
• Children at institution for mentally retarded
deliberately infected with mild form of
hepatitis
– Lack of full disclosure of risks
– Possible coersion
– Use of vulnerable population
33

34. The Belmont Report
25 years later
•National Research Act. 1974
•The Belmont Report, 1979

35. Belmont Report
• Required reading for anyone involved in
human subject research
• Identified 3 basic principles
1. Respect for persons
2. Beneficence
3. Justice
• Each should have equal moral force when
determining merits of research
35

36. The Belmont Report 1979
( 1) Individuals should consent to participate
in studies and those who cannot give their
consent, such as children, people with
diminished abilities, and prisoners, need to
be protected.
( 2) The researcher not harm the
participants, minimize risks, and maximize
possible benefits.
( 3) fairness in procedures for selecting
participants.

37. The Belmont Report - 3 Ethical Principles
• Principle of respect for persons
– Individual autonomy
– Protection of individuals with reduced autonomy
• Principle of beneficence
– Requires a risk benefit assessment be made
– Maximize benefits and minimize harms
• Principle of justice
– Equitable distribution of research costs and benefits
37

38. 1. Respect for Persons / Autonomy
• Treat individuals as autonomous human
beings
– Let them choose for themselves
• Provide extra protection for those with limited
autonomy
– Limited mental capacity
– Lack of freedom or influence of others
• Informed Consent / Respect of Privacy
38

39. 2. Beneficence / Concern for Welfare
• Minimize harms & maximize benefits
– Best possible research design to maximize
benefits / minimize harms
– Need favorable risk-benefit ratio
– Capable researchers to perform procedures
– Consideration of the impact on physical,
mental, and spiritual health, as well as
participants’ physical, economic and social
circumstances
39

40. 3. Justice
– Fairness in selection of subjects
– Avoid exploitation of vulnerable
populations
– Avoid under-protection & overprotection
40

41. How to Apply the 3 Principles
• Autonomy - Informed consent
– Information Comprehension Voluntariness
• Beneficence – determination of the risk and benefits
– Peer review – risks are justified
– Investigator – study design
– Subject – the determination to participate
• Justice
– Selection of subjects described by the researcher
– Reviewed during the peer review process
– Determined to be equitable
41

48. Benefits vs Risks
• Benefits: positive value of advantage of being in
study
– Could be direct effect to individual
– Could be more of a societal benefit
• Risks: outcomes that potentially harm the
subject
– Must assess magnitude and probability
– Easy to quantify physical risk
– Harder to assess social, legal, financial,
psychological 48

51. Pillars of Protection for
Human Subjects Research
• Consent
• Peer Review
• Research Integrity
– Duty to protect subjects
– Carry out studies per protocol
– Communicate with subjects
– Report findings honestly
• Conflict of Interest
54

52. Core principles of ICH-GCP

55. Waiver of Consent
 Not more than minimal risk
 Participant and Researcher do not
come into contact (left over samples,
data analysis in retrospective studies)
 Emergency situation

57. Informed Consent Form with Participant/
Patient Information Sheet

59. Elements of ICF – Part 2
 Explains participation is voluntary.
 Can withdraw from study at any time
without loss of routine patient care.
 Voluntarily agree to participate in the
study after knowing the risks and benefits
 Signatures of participant & witness. (At
least one should be a signature)

62. Voluntary Participation
Participants may feel coerced to participate
or perceive that they have limited choice.

63. Justified Deception
• The deception must be justified in terms of
some significant benefit that outweighs the
risk to the participants. The researcher
must consider all alternatives to deception
and must justify the rejection of any
alternative procedures.

64. Debriefing
The final point is that deceived participants
must receive a debriefing that provides a full
description of the true purpose of the study,
including the use and purpose of deception,
after the study is completed.

65. Confidentiality
The ethical guidelines require that
researchers ensure the confidentiality of
their research participants.
Ensuring that participants’ records are kept
anonymous.

69. The Institutional Review Board
Each institution or agency is required to
establish a committee called an Institutional
Review Board ( IRB), which is composed of
both scientists and nonscientists.

70. What is an IRB?
• Committee of at least 5 members
– Varied professions / expertise
– Obtain special competencies from outside
consultants
– Sensitive to community attitudes
– Sensitive to vulnerable populations
• Trained in institutional regulations, standards
of professional conduct
73

74. What Does an IRB do?
• Approve, disapprove, or modify current human
subjects research
• Conduct continuing reviews
• Observe, monitor, audit
• Suspend or terminate approval
• What constitutes human subjects research?
77

76. According to rule 122DD of the recent amendments of
Schedule Y – “No ethics committee shall review and
accord its approval to a clinical trial protocol without
prior registration with the licensing authority.”
The registration unless it is suspended or cancelled
shall be valid for a period of three years from the date
of issue.
7
Registration of EC

80. HOW ETHICS COMMITTEE PROTECTS ETHICS…
A. Reviewing the protocol of (method of )study to be
conducted
B. Reviewing the Informed Consent Document.
C. Approving / Not approving Protocol
D. Raising objections when they see any activity in protoco
affecting ‘Ethics’.
E. Even Stopping the study
F. Asking for interim reports
G. Reading safety information updates.

81. HOW ETHICS COMMITTEE
PROTECTS ETHICS…
Getting report on the Adverse reactions.
Seeking reports on the events and what actions
were taken.
Advising on compensation in any trial related
injury.
Visiting Clinical Research Sites periodically to
oversee ongoing procedures.

82. Records
Keep records & make them available for at least three
years to regulatory authorities.
Copies of list of members & written SOP may be sought
by sponsors , investigators & regulatory authorities

83. 8
Phases of Clinical Trial
Pre-Clinical
Study
Clinical
Study
Animal Study
Phase I
Phase II
Phase IV
Phase III
To Assess Safe
Dose
To Assess Efficacy
To Assess Safety &
Efficacy
Post Marketing
surveillance

84. Phase I
Objectives
1. To assess a safe & tolerated dose
2. To see if pharmacokinetics differ much from animal to man
3. To see if kinetics show proper absorption, bioavailability
4. To detect effects unrelated to the expected action
5. To detect any predictable toxicity
Inclusion criteria
1. Healthy volunteers : Uniformity of subjects: age, sex,
nutritional status [Informed consent a must]
2. Exception: Patients only for toxic drugs Eg AntiHIV,
Anticancer
Exclusion criteria
1. Women of child bearing age, children,

85. Phase I contd
Methods:
1. First in Man : Small number of healthy volunteers
2. First in a small group of 20 to 25
3. Start with a dose of about 1/10 to 1/5 tolerated animal dose
4. Slowly increase the dose to find a safe tolerated dose
5. If safe in a larger group of up to about 50 –75
6. No blinding
7. Performed by clinical pharmacologists
8. Centre has emergency care & facility for kinetics study
9. Performed in a single centre
10. Takes 3 – 6 months [ 70% success rate]

86. Phase II
1. First in patient [ different from healthy volunteer]
2. Early phase [20 – 200 patients with relevant disease]
3. Therapeutic benefits & ADRs evaluated
4. Establish a dose range to be used in late phase
5. Single blind [Only patient knows] comparison with standard
drug
6. Late phase [ 50 – 500]
7. Double blind
8. Compared with a placebo or standard drug
Outcomes
1. Assesses efficacy against a defined therapeutic endpoint
2. Detailed P.kinetic & P.dynamic data
3. Establishes a dose & a dosage form for future trials
4. Takes 6 months to 2 years [ 35% success rate]

87. Phase III
1. Large scale, Randomised, Controlled trials
2. Target population: 250 – 1000 patients
3. Performed by Clinicians in the hospital
4. Minimises errors of phases I and II
Methods
1. Multicentric Ensures geographic & ethnic variations
2. Diff patient subgroups Eg pediatric, geriatric, renal
impaired
3. Randomised allocation of test drug /placebo / standard
drug
4. Double blinded:
5. Cross over design
6. Vigilant recording of all adverse drug reactions
7. Rigorous statistical evaluation of all clinical data
8. Takes a long time: up to 5 years [25% success]

88. GUIDELINES FOR RESEARCH ON HUMAN SUBJECTS
Good Clinical Practices For Clinical Research In India
http://cdsco.nic.in/html/GCP1.html
INDIAN COUNCIL OF MEDICAL RESEARCH, NEW DELHI – 2006
http://icmr.nic.in/ethical_guidelines.pdf
ICH, Guidance for Industry - E6 Good Clinical Practice
http://www.fda.gov/cder/guidance/959fnl.pdf
Council for International Organizations of Medical Sciences (CIOMS)
http://www.cioms.ch/frame_guidelines_nov_2002.htm

89. ETHICAL ISSUES AND
SCIENTIFIC INTEGRITY

90. Safeguards Against Fraud
• A safeguard against fraud is peer review,
which takes place when a researcher
submits a research article for publication.
• Replication is repetition of a research
study using the same basic procedures
used in the original to test the accuracy.

91. Plagiarism
You can literally copy an entire paper word
for word and present it as your own work or
you can copy and paste passages from
articles and sites found on the Internet.

92. What about
You may be inspired by someone’s ideas or
influenced by the phrases someone used to
express a concept.
After working on a project for an extended time, it can become difficult
to separate your own words and ideas from those that come to you
from outside sources. As a result, outside ideas and phrases can
appear in your paper without appropriate citation.

93. Evaluating a Study
• Does the study ask an important/valuable
question?
• Is the study design reasonable?
• Would I or my relatives be willing to be in this
study / trial?
97

94. 98

95. 99

96. 100

97. Buzz 1
 A study was conducted to evaluate the efficacy of an
analgesic. The investigator approached the head of a
remote village and explained all the details of the study.
The head of the village instructed that one person from
every house should participate in the study.(Everyone in this
village obeys the chief in all matters) The investigator recruited
these people and completed the study.
 The investigator’s friend feels that he was unethical. The
investigator argues that he has explained all the details
completely to the village head and hence was right.
Did the investigator violate any principle(s) of ethics?

98. Buzz 2
Research was undertaken to evaluate the quality of care in
family welfare program. Investigators wanted to interview all
healthcare workers in PHC. IEC recommended that all
information that could lead to identification of specific PHC
should be avoided. An investigator noticed a health worker is
reusing disposable needles. Without mentioning the name,
the investigator reported this to the supervisor. A week later
he observed that the health worker is still reusing the
needles and nothing has been done. He knows that
confidentiality to the clinic and its workers was assured.
Should the principle of confidentiality be strictly upheld in this
case?

100. Buzz 3
 The Head of the Department of Pharmacology
wanted to conduct a bioavailability study for a
new drug. He asked the undergraduate (3rd
and 4th semester) students and
pharmacology PGs to participate in the study
as healthy volunteers. Written informed
consent was obtained from all volunteers.
Are there any ethical issues involved in this
study?

102. Buzz 4
 A drug company wanted to test a new antiepileptic and
contacted a neurologist. It was proposed to administer
the new drug to one group of epilepsy patients and
placebo to another group of epilepsy patients. The
neurologist was hesitant to use placebo, but the
company assured him that the primary aim of this study
is to establish the safety of new drug and not evaluation
of efficacy. Hence comparing with a placebo is more
appropriate for such studies. The neurologist agreed to
this and undertook the study.
Are there any ethical issues involved in this study?

103. Give the new drug to rich patients and placebo to the
poor. No sense getting their hopes up. They wouldn’t
be able to afford even if it works.

104. How to maximize benefits? – cont…
2. Use of placebo
 Effectiveness of a new intervention must be
tested against the best proven intervention.
 Where no proven intervention exists, the use of
placebo or no intervention is acceptable.
(Declaration of Helsinki)
 Placebo or no intervention is justifiable, if it does
not lead to additional risk or irreversible harm.
(Declaration of Helsinki)

105. Buzz 5
 A drug company from Europe conducted a
clinical trial (with three years follow up) for a
new antiretroviral drug in Africa. After two
years, the interim analysis clearly showed that
the new drug is very effective. The drug
company stopped the trial, filed application for
approval of the new drug in Europe. Later the
drug was made available in Europe but not in
Africa.
Are there any ethical issues involved in this
study?

106. How to maximize benefits? – cont…
3. Benefits after trial (Post trial access)
 At the end of trial every participant should be
assured of access to the best proven
prophylactic, diagnostic and therapeutic
methods identified by the study. (Declaration of
Helsinki)
 Rationale – The patient has voluntarily taken
the risk and has aided in the development of
this drug. Hence he should be supplied the
drug free of cost. Moreover, harm might be
inflicted if we withdraw the drug.

107. Buzz 6
 Ayusoft, an Ayurveda company approached
a famous cardiologist to conduct a trial for
their new ayurvedic drug for angina.
Approval was obtained from the
Independent Ethics Committee and after
this the cardiologist obtained full written
informed consent from all the participants
and completed the study successfully.
Did the cardiologist violate any principle(s)
of ethics?

108. Incompetency can lead to maleficence
 It would neither be ethical nor morally
justifiable if an allopathic physician carries
out clinical evaluation of a plant product
without any concept or training in these
systems of medicine (ICMR Guidelines 2006, p.
55).
 It is essential that such clinical trials be
carried out only when a competent Ayurveda,
Siddha or Unani physician is a coinvestigator
(ICMR Guidelines 2006, p. 55).

109. Nonmaleficence – cont…
2. Compensation for participation
 Can be paid for the time spent, expenses
incurred for participation in research.
 When a participant withdraws for any reason,
he should be paid a proportionate amount.
 This compensation cannot be termed as
benefit.
 The amount should be approved by the
ethics committee.

110. Nonmaleficence – cont…
3. Compensation for injury
 Participants who suffer physical injury during
research are entitled for financial and medical
assistance.
 In a clinical trial conducted for regulatory
approval, this is an obligation of the sponsor.
 An Arbitration Committee or Appellate Authority
could be setup to decide the issue of
compensation on a case by case basis.
Participants should not be asked to waive their right to
compensation.

111. Buzz 7
A drug company conducted a multinational,
multicentric, clinical trial to evaluate the efficacy of a
new drug for a metabolic disease. For the sites in USA
& Europe, the new drug was compared with the drug
that is already available in these countries. Placebo
was used as a comparator for the sites in Africa. Some
investigators in Africa objected to this. The drug
company argued that there is no drug available for this
disease in Africa and hence the use of placebo in these
sites is justified. It also stated that if this trial is done in
Africa, this new drug will be introduced and their
patients will be benefitted
Did the drug company violate any principle(s) of
ethics?

112. Not publishing your research is
unethical
 Researchers have ethical obligations with
regard to the publication and dissemination
of the results of research.
 Researchers have a duty to make publicly
available the results of their research on
human subjects and are accountable for the
completeness and accuracy of their reports.
(Declaration of Helsinki, 2013).

113. ICMR Ethics resources
• http://icmr.nic.in/ethics_SOP.pdf
• http://icmr.nic.in/bioethics/bioethics%20cell/SOP_of
_IEC.pdf
• http://www.icmr.nic.in/ethical_guidelines.pdf
• http://icmr.nic.in/bioethics/cc_biothics/presentation
s/haryana/session2.pdf
117

114. Key Resources
• Emmanuel, Wendler & Grady (2000) What makes clinical
research ethical, JAMA, 283: 2701-2711.
• Tri Council Policy Statement: Ethical Conduct for Research
Involving Humans http://www.pre.ethics.gc.ca/eng/policy-
politique/initiatives/tcps2-eptc2/Default/
• Course in Human Research Participant Protection
https://phrp.nihtraining.com/users/login.php
• Network of Networks: Online Good Clinical Practice (GCP)
Training http://www.citiprogram.org
• The Lab: Avoiding Research Misconduct
http://ori.hhs.gov/TheLab/

116. »Thank Y