Basic principles of biomedical research ethics with few case studies

1. RESEARCH
BIOETHICS:
AN INTRODUCTION
Sufyan Akram
MBBS PhD

2. • How scientists and health professionals ought to
behave in the biomedical sciences
• The attempt to understand and justify the link
between values (fundamental principles) and
actions
BIOETHICS

3. • Deontology
– One should adhere to his duties and responsibilities
• Utilitarianism (or Consequentialism)
– Based on consequences of an action
• Virtue theory
– Takes into account the person’s overall character
• Principlism
– “a mixture” based on 4 principles…
SOME ETHICAL
THEORIES

4. • ‘The four principles’ approach
– The most widely used approach in Western bioethics
• 1. Autonomy
• 2. Beneficence
• 3. Non-maleficence
• 4. Justice
PRINCIPLISM

5. – Autonomy
• Right of self-determination
– Related to ‘informed consent’
– In order to give consent:
autonomy/competency/capacity must be
possessed
– Beneficence – to do well, to promote well-being
– Non-maleficence – to do no harm, to avoid doing harm
– Justice – treat like alike
WHAT ARE THESE 4
PRINCIPLES

6. • Oath of Hippocrates (4th c BC)
• Nuremberg Code (1947): issue of human experimentation
• Declaration of Helsinki (1964) (WMA): issue of human
experimentation
– First serious attempt of medical community to regulate itself
• Declaration of Geneva (1948)
– Issued as a development on the Oath of Hippocrates
• CIOMS Guidelines (1993)
– ‘International Ethical Guidelines for Biomedical Research Involving
Human Subjects’
(CIOMS: the Council for International Organizations of Medical
Sciences)
• Universal Declaration on Bioethics and Human Rights (UNESCO)
(2005)
PROMINENT ETHICAL
CODES

7. BIOETHICS AND
RESEARCH

8. • Basic research (also called fundamental research) is a
systematic study directed toward greater knowledge
or understanding of the fundamental aspects of
phenomena without specific applications or products
in mind
– May involve cells and tissues from animal or human
origin
• Applied research is a form of systematic inquiry
involving the practical application of science
– May involve animal experimentation
BASIC AND APPLIED
RESEARCH

9. • Translational research (or clinical research) helps to
make findings from basic science useful for practical
applications that enhance human health and well-
being (including new diagnostics and therapeutics)
• It requires testing the newly discovered technique/
drug to be tested on human subjects before
approving it for widespread use
TRANSLATIONAL
RESEARCH

10. • Informed consent
• IRB review
• Informed consent and IRB review
• Compliance with Nuremberg, Helsinki, and Belmont
• All of the above?
WHAT MAKES CLINICAL
RESEARCH ETHICAL?

11. TRANSLATIONAL CYCLE
Assessment &
Priority
Setting
DevelopmentDiscovery
DeliveryOutcomes

12. • Clinical research develops generalizable knowledge
that improves health or increases understanding
• People who participate in clinical research are a
means to securing that generalizable knowledge
• As a means, these people can be exploited, that is be
used as a means for the benefits of others
• Ethical benchmarks for clinical research are meant to
minimize the possibility of exploitation
WHY DO WE NEED
ETHICAL GUIDELINES?

13. 1. Collaborative Partnership
2. Social Value
3. Scientific Validity
4. Fair Subject Selection
5. Favorable Risk-Benefit Ratio
6. Independent Review
7. Informed Consent
8. Respect for Human Subjects
8 ETHICAL
BENCHMARKS

14. • Clinical research should involve the community in
which it occurs
• This requires:
– Community participation in planning, conducting and
overseeing research, and integrating research results
into the health system
– Patient advocates on scientific advisory boards and IRBs
1. COLLABORATIVE
PARTNERSHIP

15. • Clinical research should lead to improvements in
health or advancement in generalizable knowledge
• Must consider how the research will affect:
– Participants in the research
– Community in which research is conducted
– World
2. SOCIAL VALUE

16. • Research should produce reliable and valid data that
can be interpreted
• Research must be conducted in a methodologically
rigorous manner that is practically feasible
• Invalid Research:
– Studies with biased endpoints, instruments or statistical
tests
– Studies that cannot enrol sufficient subjects
3. SCIENTIFIC VALIDITY

17. • Convenient groups should not be selected
• Groups should not be excluded without scientific
reasons
• Should not select rich, politically powerful or
otherwise well connected people for “promising
research” studies
4. FAIR SUBJECT
SELECTION

18. • Risks to participants should be balanced by the
benefit to individual participants
• The approach
– Risks identified, assessed and minimized
– Potential benefits to individuals enhanced
– If potential benefits to individual outweigh risks to the
individual, then proceed
– If risks outweigh the benefits to the individual then
evaluate risks against the benefits to the society
– Consider risks to the community
5. FAVOURABLE RISK-
BENEFIT RATIO

19. • Potential risks to consider include:
– Physical —death, disability, infection
– Psychological —depression and anxiety
– Social —discrimination
• Evaluate the:
– Likelihood of harm
– Magnitude of harm
• Identify mechanisms to minimize risks:
– Additional diagnostic tests
– Hospitalizations
5. FAVOURABLE RISK-
BENEFIT RATIO

20. • Because investigators have multiple legitimate
interests, they have potential conflicts of interest
• Independent review of the research minimizes these
conflicts
• Independent review also assures society it will not
benefit from abuse of subjects
6. INDEPENDENT
REVIEW

21. • Informed consent ensures individuals decide whether
they enrol in research and whether research fits with
their own values, interests, and goals.
• For those who cannot consent—such as children and
mentally impaired—must be sure research fits with
their interests
7. INFORMED CONSENT

22. • Competence/capacity of the subject
• Disclosure of information to the subject
• Understanding or comprehension by the subject
• Voluntariness of the decision
7. INFORMED CONSENT

23. • The ethical requirements of research do not end with
a signed consent document. Also include:
– Protecting confidentiality
– Permitting withdrawal
– Providing new information
– Monitoring welfare
– Informing participants what was learned from the
research
– Providing “fair benefits” for participation in research
8. RESPECT FOR HUMAN
SUBJECTS

24. • All 8 benchmarks are necessary and essential to make
clinical research ethical
• Independent review and informed consent are
procedural benchmarks to ensure certain values are
achieved
• Other procedures may achieve these values
– In some circumstances, independent review and
informed consent can be waived
8 ETHICAL
BENCHMARKS

25. • All 8 ethical benchmarks are universal. They apply to
clinical research everywhere
• The 8 ethical benchmarks must be adapted to the
local health, economic, cultural and technological
circumstances
– For instance, disease risk affects risk-benefit evaluation
8 ETHICAL
BENCHMARKS

26. • What is fair in subject selection may increase risks
• What enhances scientific validity may increase risks
• What is necessary to respect enrolled subjects or
obtain informed consent may compromise scientific
validity
BENCHMARKS MAY
CONFLICT!

27. • No simple formula for resolving conflicts
• Adjust design to meet the requirements
– This is sometimes termed “balancing”, “weighing” or
“specifying” the principles
• The important point is to be clear about what is being
done and give reasons why
• Different approaches may be equally ethical !!
RESOLVING CONFLICTS

28. • The expertise necessary to implement these
benchmarks includes:
– Educated and trained investigators
– IRBs with investigators, statisticians, ethicists, and
community representatives
EXPERTISE

29. SOME CASE STUDIES

30. • Although codes, policies, and principals are very
important and useful, like any set of rules, they do
not cover every situation, they often conflict, and
they require considerable interpretation
• For example, consider the following case:
ETHICAL DECISION-
MAKING IN RESEARCH

31. • The research protocol for a study of a drug on
hypertension requires the administration of the drug at
different doses to 50 laboratory mice, with chemical and
behavioural tests to determine toxic effects
• Tom has almost finished the experiment. He has only 5
mice left to test. However, he really wants to finish his
work in time to go on a break with his friends
• He has injected the drug in all 50 mice but has not
completed all of the tests. He therefore decides to
extrapolate from the 45 completed results to produce the
5 additional results
CASE 1

32. • Many different research ethics policies would hold
that Tom has acted unethically by fabricating data
• Actions that nearly all researchers classify as
unethical are viewed as misconduct
• It is important to remember, however, that
misconduct occurs only when researchers intend to
deceive: honest errors related to sloppiness, poor
record keeping, miscalculations, bias, self-deception,
and even negligence do not constitute misconduct
CASE 1

33. • Also, reasonable disagreements about research
methods, procedures, and interpretations do not
constitute research misconduct. Consider the
following case:
CASE 2

34. • Dr. T has just discovered a mathematical error in a
paper that has been accepted for publication in a
journal. The error does not affect the overall results
of his research, but it is potentially misleading. The
journal has just gone to press, so it is too late to catch
the error before it appears in print
• In order to avoid embarrassment, Dr. T decides to
ignore the error
CASE 2

35. • Dr. T's error is not misconduct nor is his decision to
take no action to correct the error. Most researchers,
as well as many different policies and codes would
say that Dr. T should tell the journal about the error
and consider publishing a correction or errata
• Failing to publish a correction would be unethical
because it would violate norms relating to honesty
and objectivity in research
CASE 2

36. • Situations frequently arise in research in which
different people disagree about the proper course of
action and there is no broad consensus about what
should be done
• In these situations, there may be good arguments on
both sides of the issue and different ethical principles
may conflict
• These situations create difficult decisions for research
known as ethical dilemmas
CASE 2

37. • BY is a 46 year old post-menopausal mentally
disabled woman with DCIS
• Caregivers from her “home” with power of attorney
for health care decisions, bring her to the clinic for
enrolment in STAR trial, randomized trial of
tamoxifen vs. raloxifene for the prevention of breast
cancer in high risk women
• She fulfils all entry criteria but cannot consent
CASE 3

38. • The physician who saw BY wants the IRB to
reconsider the subject selection criteria for the STAR
trial
• The IRB debates the question:
– Is it ethical to enrol a mentally incompetent patient in a
Phase III randomized chemo-prevention trial?
CASE 3

39. • Is it ethical to enrol a mentally incompetent patient in
a Phase III randomized chemo-prevention trial?
• Is it ethical to enrol BY in a randomized trial to
determine which of two hormonal therapies is better
at preventing cancer with the fewest side effects?
CASE 3

40. • BY cannot consent
• BY is not necessary to the trial
• Enrol patients who can consent
Emphasize
informed
consent
• Informed consent is not an absolute
requirement
• The risk-benefit ratio is positive
• As long as mentally disabled patients are not
being unfairly targeted, enrol BY
Emphasize
Risk-Benefit
& Social
Value
• She meets eligibility criteria and has a similar
risk-benefit ratio to other potential
participants
• The only reason for excluding her is unrelated
to science but related to mental condition
Emphasize
Fair Subject
Selection
CASE 3

41. • What is the problem or issue?
• What is the relevant information?
• What are the different options?
• How do ethical codes or policies as well as legal rules
apply to these different options?
• Are there any people who can offer ethical advice?
HOW TO DEAL WITH
ETHICAL DILEMMAS?

42. • Many of us may think why we are required to have
training in research ethics. We may believe that we
are highly ethical and know the difference between
right and wrong
• Luckily, misconduct is rare, but it can have a
tremendous impact on research
– Consider an analogy with crime: if murderers are not
prosecuted, it will erode the community's sense of trust
and increase the community's fear and paranoia
– The same is true with the most serious crimes in science,
i.e. fabrication, falsification, and plagiarism
PROMOTING ETHICAL
CONDUCT IN SCIENCE

43. • Misconduct probably results from environmental and
individual causes, i.e. when people who are morally
weak, ignorant, or insensitive are placed in stressful
or imperfect environments
• Many of the deviations that occur in research may
occur because researchers simple do not know or
have never thought seriously about some of the
ethical norms of research
PROMOTING ETHICAL
CONDUCT IN SCIENCE

44. • Training courses in research ethics may result in
significant reduction of these incidences
• Training in research ethics should be able to help
researchers grapple with ethical dilemmas by
introducing researchers to important concepts, tools,
principles, and methods that can be useful in
resolving these dilemmas
PROMOTING ETHICAL
CONDUCT IN SCIENCE

45. ULTIMATE GOAL
Protect participants
and communities
Promote scientific
knowledge
Trustworthy research
practices

46. • http://www.bioethics.nih.gov/home/index.shtml
• http://www.niehs.nih.gov/research/resources/bioethics/w
hatis/index.cfm
RESOURCES: