ETHICS IN MEDICAL RESEARCH

References

* Ezekiel J., Emmanuel, Christine C Grady The Oxforf Textbook

of Clinical Research Ethics, Oxford University Press, 2008
* E.J. Emanuel, D. Wendler, C. Grady What makes clinical
research ethical?, J Am Med Assoc, 283 (20) (2000),
H.K. Beecher Ethics and clinical research Bull World Health
Org, 79 (4) (2001)
Objectives
* Synthesize research ethical and historical landmarks, principles
and requirements

- |dentify different strategies to safeguard the rights and welfare

of the vulnerable population
 Importance of Research Ethics

* Human participants in research may be harmed

* Human participants may be wronged
* Research produce benefits
* Abuses in research have occurred
 Ethical Research
* Our duty to experiment does not mean we can do it any way
we want or under any type of conditions
» There are correct ways of doing Research established ethical
guidelines, regulatory systems
* The vigilant conscientious researcher has ultimate
responsibility and accountability for the ethical soundness
of the research and the protection of rights, safety and
welfare of study subjects
* Preserves Credibility/trust
* Results in efficient, useful, helpful, worthy outcomes
* Leads to better sponsor — investigator — participant —
public relationship
* Keeps researcher and ERC out of jail
RA 10532 PHRSA of 2013
 Elements of Ethical Research
1. Of scientific, ethical and social good

1. Scientific soundness:
Objectives, design, collection and interpretation of results,
recommendations

“Bad science is bad ethics!”

Elements of Ethical Research

3) Ethical soundness:
Value person as one with inherent dignity
Not to be harmed/wronged
Benefited
Respected as a person
Treated justly
 Elements of Ethical Research
4) Ethical Researcher
"Can he do it?
" Competence: Scientific, Clinical, Ethical
" Resources: Time, Support staff, Facilities,
Agreements/approval (ERC, Sponsor and National)
"|s he trustworthy?
" To protect the subject
= To be truthful (no COI)
5) Involvement of community
 Ethics in Research
PIs a of thinking:
D> Our responsibilities to others (motive, objective, method,
accountability)
PIs a way of doing:
What is right for others (equal opportunity, benefit,
consent)
PIs a way of being:
» Trustworthy (faithful to others, use of outcome)

In a research Environment
Nazi experiments WW ||

BFreezing hypothermia
BHigh altitude
BM Sterilization
HBinfectious diseases
BGenetics experiments
BmDrugs
BmSurgery
Twin Studies

* One twin given infectious disease

* At time of death of diseased twin, ‘control’ twin put
to death and both twins autopsied
High Altitude

* To investigate the limits of endurance od extremely

high altitudes, studies were carried out in low
pressure chambers that duplicated atmospheric
conditions
* Experiments resulted to death
Hypothermia

* To investigate the most effective means of treating

persons who had been severely chilled or frozen.
* Subjects were forced to remain in a tank of ice
water
* Experiments resulted in death
 Sterilization Experiment

The purpose of these experiments was to develop a

method of sterilization which would be suitable for
sterilizing millions of people with a minimum of time
and effort.
These experiments were conducted by means of X-
ray, surgery, and various drugs. Thousands of victims
were sterilized.
 Genetic Experiments
BThe twins were arranged by age and sex and kept in
barracks between experiments, which ranged from
injection of different chemicals into the eyes of
twins to see whether it would change their color to
literally sewing twins together to try creating
conjoined twins
 Sulfonamide Experiments
Wounds inflicted on the subjects were infected with
bacteria such as Streptococcus, gas gangrene, and tetanus.
Circulation of blood was interrupted by tying off blood
vessels at both ends of the wound to create a condition
similar to that of a battlefield wound.
Infection was aggravated by forcing wood shavings and
ground glass into the wounds.
The infection was treated with sulfonamide and other
drugs to determine their effectiveness.
 Nuremberg Code 1947

Voluntary consent of the human subject

The good of society
Animal experiment before human experiment
No unnecessary physical and mental suffering and
Injury
No research if death or disabling injury will occur
 Nuremberg Code 1947

6. Risk involved not too much

7. Proper protection for subjects
8. Scientifically qualified persons
9. Right of subject to withdraw
10. Experiment can be terminated by the scientist at
any stage
 Tuskegee Syphilis Study

M1932, 400 low income African American men infected

with syphilis and 200 controls study continued till
1972, men not given treatment, even if penicillin was
found to be effective in 1947
WM1997 US Pre. Clinton apologized to the study
participants and their families
 Willowbrook Hepatitis Study

WM1964, newly admitted mentally disabled children

were inoculated with infectious hepatitis
BObjective: to determine the period of infectivity for
the disease
BBenefit of study for participants: better hospital
facilities and care for the children
 Codes, Declaration, Guidelines
* Nuremberg Code (1947)
* Universal Declaration of Human rights (UN 1948)
* Declaration of Helsinki (WMA 1964, 1983, 1989, 1996, 2000)
* International Covenant on Civil and Political Rights (1966)
* International Ethical Guidelines fir Biomedical Research Involving
Human Subjects (CIOMS 1993, 2002)
* Council of Europe: Convention on Human Rights and Biomedicine
(1997)
 Codes, Declaration, Guidelines
WHO Guidelines for Good Clinical Practice (1995)
* ICH — GCP (1996)
UNAIDS Guidance Document Ethical Considerations in HIV
Preventive Vaccine Research (2000)
* Convention on the Rights of the Child
Convention on the Elimination of All Forms of Discrimination
Against Women and Children
* International Declaration on Human Genetic Data (UNESCO 2003)
 Declaration of Helsinki, WMA

* World Medical Association (London, 1946)

Resolution for guidelines for human experimentation
* 1964
* Well-being of subject takes precedence
* Respect for persons
* Protection of subjects health ad rights
* Special protection for vulnerable population
Helsinki Declaration 2013 changes

* Requires compensation and treatment for research-related

injuries
Addresses several issues related to dissemination of health
research information
* Informed consent needs to involve others in a close-knit societies
* Encourages to explain their studies in innovative ways
 CIOMS International Ethical Guidelines for
Biomedical Research Involving Human Subjects
(1982, 1993, 2002)
BM Council for International Organizations of Medical Science
(CIOMS) with WHO
BMPurpose: How the ethical principles set forth in Helsinki
Declaration can be applied
BM Dealt with special circumstances of developing countries
 CIOMS International Ethical Guidelines for
Biomedical Research

BStatement of general ethical principles: Respect for

persons, Beneficence (Non-maleficence), Justice
BPreamble: Definition of research, kinds of research
B15 guidelines (1993); 21 (2002)
Belmont Report (1979)
* Respect for persons
* Informed consent
* Protection of vulnerable population
* Beneficence
* Nonmaleficence
* Maximize benefits . Minimize risk

* Justice
* Fairness in subject selection
Vulnerable Population

* Unable to make independent decisions because of:

Mental status
e Social status
e Lack of education
 Declaration of Helsinki, WMA 2000

Informed consent: Protection of persons with impaired or

diminished autonomy
BMD should be cautious if the subject is in a dependent relationship
with the MD or may consent under duress
BML egally incompetent, physically or mentally incapable of giving
consent or legally incompetent minor — consent from the legally
authorized representative
BAssent form subject (minor child) if able, in addition to consent
representative
Independent Ethics Committee/ Institutional
Review Board
BFormally designated by an institution to review, approve and conduct
periodic review of biomedical research involving human participants
MPurpose:
BM Assure the protection of rights and welfare of the study participants
 SHARED VALUES
v" HONESTY — conveving information

truthfully and honoring

commitments,

v" ACCURACY — reporting findings precisely

and taking care to avoid
errors,

v" EFFICIENCY — using resources wisely and

avoiding waste, and

v" OBJECTIVITY — letting the facts speak for

themselves and avoiding
improper bias.
® “Fabrication, falsification, or plagiarism in proposing,
performing, or reviewing research, or in reporting research
results
® Fabrication is making up data or results and recording or
reporting them.
® Falsification is manipulating research materials, equipment,
or processes, or changing or omitting data or results such
that the research is not accurately represented in the
research record
 Plagiarism is the appropriation of another person’s ideas,
processes, results, or words without giving appropriate
credit.

Research misconduct does not include differences of

opinion.
Represent a “significant departure from accepted
practices”
Have been “committed intentionally, or knowingly, or
recklessly” and
Be “proven by a preponderance of evidence.”
 REASONS FOR FRAUD
* In all cases, the perpetrators,
* were under career pressure;
* knew, or thought they knew what the answer would
turn out to be if they went to all the trouble of doing
the work properly, and
* were working in a field where individual experiments
are not expected to be precisely reproducible.
PROTECTION OF HUMAN SUBJECTS
* Human subjects are “living individual(s) about whom
an investigator conducting research obtains:
(1) data through intervention or interaction with the
individual; or
(2) identifiable private information”
Risks to subjects are minimized
Risks to subjects are reasonable in relation to
anticipated benefits, if any, to subjects, and the
importance of the knowledge that may reasonably
be expected to result
Selection of subjects is equitable
Informed consent will be sought from each
prospective subject or the subject’s legally
authorized representative
Informed consent will be appropriately documented
*When appropriate:
* The research plan makes adequate provision for
monitoring the data collected to ensure the
safety of subjects; and
* There are adequate provisions to protect the
privacy of subjects and to maintain the
confidentiality
Informed Consent

Children,
* Adults with impaired decision making capacity,
* Critically ill patients,
WELFARE OF ANIMALS
* Replacement
* using non-animal models such as microorganisms or cell culture
techniques, computer simulations, or species lower on the
phylogenetic scale.
Reduction
* using methods aimed at reducing the numbers of animals such
as minimization of variability, appropriate selection of animal
model, minimization of animal loss, and careful experimental
design.
* Refinement
* the elimination or reduction of unnecessary pain and distress.
COLLABORATIVE RESEARCH
* Who is the Principal Investigator
* Financial Interest
* Ownership
* Conflict of Interest
AUTHORSHIP AND PUBLICATION
 Authorship
* This includes anyone who:
* was intimately involved in the conception and design of
the research,
e assumed responsibility for data collection and
interpretation,
* participated in drafting the publication, and
e approved the final version of the publication.
* There is disagreement, however, over whether authorship
should be limited to individuals who contribute to all phases
of a publication or whether individuals who made more
limited contributions deserve authorship credit.
Practices that should be avoided

* Honorary Authorship
* Salami Publication
* Duplicate Publication
* Premature Public Statements
 HONORARY AUTHORSHIP
Misconduct?

The chair of the department or program in which the

research was conducted,
Provided funding for the research,
_eading researcher in the area,
Provided reagents, or
Served as a mentor to the primary author.
PEER REVIEW

NIC h projects to fund (grant reviews),

NIC h research findings to publish (manuscript reviews),
NIC h scholars to hire and promote (personnel reviews), and
NIC h research is reliable (literature reviews and expert testimony).
" Researchers who are in a position to pass judgment on the
work of colleagues have significant power.
®" They can hasten or slow that work; credit or discredit it.
" They have the power to shape entire fields of research
and to influence public policy.

" |f you have that power, make sure you use it responsibly
and with some compassion, knowing that what you say
and do directly affects the careers of other researchers