Transcript Case Study #5

Use of Humans in
Biomedical Experimentation
Ethics and Scientific Integrity
Programa Gulbenkian de Formação
Médica Avançada
Lisbon, 24th February 2009
Mário Miguel Rosa
Summary
• Introduction
• Historical Background
• Human Biomedical Research
• Present Practice
• Rules and Regulations
• Ethical issues
• Case studies
Mário Miguel Rosa
2
Introduction
Deontology
Values
Teleology
Principles
Virtue
Values
Rules
Mário Miguel Rosa
3
Virtue Ethics
• Virtues (Human)
• Compassion
• Discernment
• Trustworthiness
• Integrity
• Conscientiousness
• Good relationships
Mário Miguel Rosa
E. Anscombe, 1958;
A. MacIntyre, 1981;
R. Taylor, 1985
4
Ethics: Values
• Values (Human)
• Professionalism
• impartiality
• Discretion
• Transparency
• Integrity
•Paul Ricoeur, Lectures 1: Autour du
politique, Paris: Éditions du Seuil, 1991, p. 2
•OECD, Trust in Government: Ethics in OECD
Countries, OECD Publishers, Paris, 2000, p. 31.
•Fonds de la Recherche en Santé du Québec,
Code of ethics and professional conduct, 2003
Mário Miguel Rosa
5
Integrity
Involves:
Is involved in:
• Sincerity
• Not abusing position
• Research Fraud
• Relationship w/ subjects
• abuse
• Promise-keeping
• Consistency
• Signing documents
• Conflict of interests
•Fonds de la Recherche en Santé du Québec,
Code of ethics and professional conduct, 2003
Mário Miguel Rosa
6
Historical Background
• Human Ethics in Biomedical Research
evolved upon
• Ethical (and Philosophical) theories
• Disaster
• Technology driven
• Safety: Radiation, Drugs
• Physician driven
• WW II…
Mário Miguel Rosa
7
Milestones
• 1906:
• Cocainisme associated
with over the counter
sales of cocaine
(marketed for
toothaches)
• Pure Food and Drug Act
• FDA
Mário Miguel Rosa
8
Milestones
• 1937:
• More than 100 people (dozens of children)
died in the USA after consumption of
“Strep-Elixir” containing sulfanilamide
and
diethyleneglycol
• F, D and
Cosmetics Act,
1938
Mário Miguel Rosa
9
Milestones
• WW II
• Nazi Experiments
• Thousands of people (mostly Jewish) were
forced to participate in inhuman experiments
• Child victims of
provoked
burning and
wounds for
experimental
purposes
Mário Miguel Rosa
10
Milestones
• WW II
• Nazi Experiments
• Experimental starvation to test the symptoms
of hunger
• Hypobaric experiments to test decompression
• Induced hypothermia to test body resistance
Mário Miguel Rosa
11
Milestones
• 1947
• Nüremberg Trial
Mário Miguel Rosa
12
Milestones
• Post “Nuremberg Code” experiments:
• 1957 Willowbrook State School study:
• Hepatitis virus inoculation on hypophrenics
• 1963 Jewish chronic disease hospital, USA:
• Injection of live cancer cells in terminally ill
patients
• 1930-1970 Tuskeegee experiment:
• Untreated syphilis in African-American people
from Alabama, USA
Mário Miguel Rosa
13
Milestones
• Shortage of experimentation / off label
use of medication:
• Thalidomide
Mário Miguel Rosa
14
Flow of Biomedical Research
Epide
miologi
cal
Basic Re
search
Observa
tional
research
Hypothesis generation
Clinical Research
Mário Miguel Rosa
15
Animal – Human Dilemma
• Why do we need to test our hypothesis
on humans?
Mário Miguel Rosa
16
Animal – Human dilemma
• Pre clinical research is dependent on
• In vitro studies
• Animal models
• Improved in the last 50 years, but barely
satisfactory, in “human” systems
• Central Nervous System
• Immunology / Oncology, etc…
• Translational medicine
• Improving…
Mário Miguel Rosa
17
Animal – Human dilemma
N Engl J Med 2006;355:1018-28.
Mário Miguel Rosa
18
Importance of Medical
Research
• Medicine is not an exact science in the way
that mathematics and physics are.
• It does have many general principles that are
valid most of the time, but every patient is
different and what is an effective treatment
for 90% of the population may not work for
the other 10%.
Medicine is inherently experimental.
Medical Ethics Manual - World Medical Association, 2005
Mário Miguel Rosa
19
Types of Human Biomedical
Research
• Epidemiological /
Observational
Vs
• (Experimental)
Trials
• Beneficial
Vs
• Non beneficial
• Phase I trials
• Testing non
medication / non
diagnostic procedures
Mário Miguel Rosa
20
Types of Human Biomedical
Research
• Trials of new diagnostic approach to
human disease
• Trials in which human subjects undergo
novel therapeutic interventions
• Treatment
• Prevention
Mário Miguel Rosa
21
Clinical Investigation
• If the preclinical phase proves
promising, the four steps, or phases, of
clinical research, follow:
Mário Miguel Rosa
22
Clinical Investigation
• Phase one research (what the body does to
the drug), is usually conducted on a relatively
small number of healthy volunteers, who are
often paid for their participation. (no benefit)
• It is intended to determine what dosage of the
drug is required to produce a response in the
human body, how the body processes the
drug, and whether the drug produces toxic or
harmful effects.
Mário Miguel Rosa
23
Clinical Investigation
• Phase two research, is conducted on a
group of patients who have the disease that
the drug is intended to treat (but not other
diseases). Its goals are to determine whether
the drug has any beneficial effect on the
disease and has any harmful side effects.
Mário Miguel Rosa
24
Clinical Investigation
• Phase three research, involve clinical trials
in which the drug is administered to a large
number of patients and compared to another
drug, if there is one for the condition in
question, and/or to a placebo.
• Where possible, such trials are ‘doubleblinded’, i.e., neither research subjects nor
their physicians know who is receiving which
drug or placebo.
Mário Miguel Rosa
25
Clinical Investigation
• Phase four research, takes place after the
drug is licensed and marketed.
• For the first few years, a new drug is
monitored for side effects that did not show
up in the earlier phases. Additionally, the
pharmaceutical company is usually interested
in how well the drug is being received by
physicians who prescribe it and patients who
take it.
Mário Miguel Rosa
26
Clinical Investigation
• But things are not so clear cut as they
may seem:
• There is a temporal animal - human
overlap:
• Animal safety studies continue long after
phases I, II and III have started
• Safety package
Mário Miguel Rosa
27
Drug Development:
the «fast/safe» imbalance
Worldwide harmonization of requirements
for clinical trials and MA (ICH M3 guideline)
Appropriate and early
development planning
(FDA INDA and EMEA SciA)
Simultaneous non-clinical
& clinical development
Fast
Safe
Harmonization of format
For data presentation
(CTD)
Mário Miguel Rosa
28
Preclinical
•Pharmacodynamics
Related to indication
General Pharm
CNS
Safety
Respiratory
Pharm. Cardiovascular
... ...
Clinical
Phase I studies
Single dose; «clean dose»
Healthy volunteers
•Pharmacokinetics
Genotoxicity (in vitro)
•Toxicology
Single dose toxicity (rodents)
2w-repeat dose toxicity
(male reprod. organs)
(rodent/non-rodent)
Mário Miguel Rosa
•Pharmacology
•Pharmacokinetics
•Safety
29
Repeated Dose Toxicity Studies
Supportive duration for clinical trials & MA
ICH M3; CPMP/ICH/286/95
duration of
human therapeutics
Phase I & II
Phase III & MA
Up to 2 weeks
2 Weeks
2 weeks
1 month
1 month
Up to 1 Month
1 month
1 month
3 months
3 months
Up to 3 Months
3 months
3 months
6 months
3 months
> 3 Months
6 months
6 months
6 months
chronic*
> 6 Months
6 months
chronic
* EU 6 months; FDA 9-12 months; ICH 9 months
Mário Miguel Rosa
30
Published documentation
• 1947, Nuremberg Code
• 1964, World Medical Association: Declaration
of Helsinki
• 2002, CIOMS: International Ethical Guidelines
for Biomedical Research Involving Human
Subjects
• 2005, EU Council: Additional Protocol to the
Convention on Human Rights and
Biomedicine concerning Biomedical Research
Mário Miguel Rosa
32
Published documentation
• Portugal
• Decreto Lei 97/1995 de 10 de Maio
• Ethics ‘ Committee Law
• “Regulamenta as Comissões de Ética para a
Saúde em Portugal”
• Lei n.o 46/2004 de 19 de Agosto
• Clinical Trials Law
• “Aprova o regime jurídico aplicável à realização de
ensaios clínicos com medicamentos de uso humano”
Mário Miguel Rosa
33
Declaration of Helsinki
• Main Topics:
1.
2.
3.
4.
5.
6.
7.
8.
Ethics Review Committee Approval
Scientific Merit
Social Value
Risks and Benefits
Informed Consent
Confidentiality
Honest Reporting of Results
Whistle-blowing
…Unresolved Issues…
Mário Miguel Rosa
34
Declaration of Helsinki
9. …Unresolved Issues…
• “...only 10% of global research funding
is spent on health problems that affect
90% of the world’s population”
• Subject Insurance when participating
Mário Miguel Rosa
35
Independent Review Board
• Decision Criteria
• Review Boards must consider several
aspects of the research when deciding
whether or not to permit it, including:
1. Risk vs. Reward
• Does the proposal identify all the potential
risks?
• Does the protocol minimize the risks?
• Are the potential benefits worth the risks?
Mário Miguel Rosa
36
Independent Review Board
• Decision Criteria
2. Selection of Subjects
•
•
•
•
No discrimination by gender, race or
ethnicity.
Safeguards for vulnerable populations.
Benefits distributed fairly (i.e. not testing a
population that couldn’t benefit from the
results)
Privacy of subjects adequately protected.
Mário Miguel Rosa
37
Independent Review Board
• Decision Criteria
3. Informed Consent
•
•
•
Do subjects agree to participate?
How is assent documented?
If deception is required, is it warranted?
Mário Miguel Rosa
38
Independent Review Board
• Decision Criteria
4. Research Design
• Are the methods scientifically valid enough to
warrant the risks?
• Is the principal investigator (PI) and team
qualified for this kind of research?
• How will the data be collected and stored?
Mário Miguel Rosa
39
Informed Consent
• The investigator duty is to inform the
patient of the main benefits and
common or significant risks. The subject
agrees to the procedure on the
understanding that the nature and
effects of it have been explained
Mário Miguel Rosa
41
Informed Consent
• No-one can really be fully informed
about the benefits and risks of a
procedure – indeed the investigator
may not know all the risks of the
procedure for a particular subject
• Investigator brochure (confidential)
Mário Miguel Rosa
42
Researcher vs. Physician
• Physician’s role in the physician-patient
relationship is different from the
researcher’s role in the researcherresearch subject relationship, even if the
physician and the researcher are the
same person.
Mário Miguel Rosa
43
Researcher vs. Physician
• The physician’s primary responsibility
is the health and well-being of the
patient
• The researcher’s primary responsibility
is the generation of knowledge (which
may or may not contribute to the
research subject’s health and wellbeing)
Mário Miguel Rosa
44
Researcher vs. Physician
The physician
The researcher
• When there is a conflict
(health vs. knowledge),
the health of the pt
prevails…
• …But there are rewards for
participating in trials:
• Cash payments for enrolling
or following pts
• equipment such as computers
to transmit the research data
• invitations to conferences (to
discuss the research
findings…)
• co-authorship of publications
on the results of the research
Mário Miguel Rosa
45
Shady / Slippery Fields
• Non competent people
• Children
• Psychologically impaired patients
• Hypophrenic
• Psychiatric
• Demented
• Pregnant, Breastfeeding females
• Potentially Childbearing females
• Old aged
Mário Miguel Rosa
46
Shady / Slippery Fields
• Technology assessments
• Diagnostic tools
• Surgical procedures
• Economic studies
• Cost – benefit
• Cost –utility
• QALY
Mário Miguel Rosa
47
Ethical Priority order
1.
2.
3.
4.
5.
Truth and Integrity
Beneficence and Non-maleficence
Justice and fairness
Autonomy and consent
Confidentiality
Making Sense of Medical Ethics: Johnson AG &
Johnson PRV. 2007 Hodder Arnold Publ.
Mário Miguel Rosa
48
Legal Priority order
1.
2.
3.
4.
5.
Autonomy
Beneficence and Non-maleficence
Confidentiality
Truth and Integrity
Justice and fairness
Making Sense of Medical Ethics: Johnson AG &
Johnson PRV. 2007 Hodder Arnold Publ.
Mário Miguel Rosa
49
Integrity
“Integrity without knowledge is weak
and useless
Knowledge without integrity is
dangerous and dreadful”
[The Astronomer] In The History of Rasselas,
Prince of Abissinia by Samuel Johnson, 1759
Mário Miguel Rosa
50
Case Study #1
• Fabrication, falsification and plagiarism
• How prevalent?
Mário Miguel Rosa
52
Case Study #1
Mário Miguel Rosa
53
Case Study #1
Anderson M et al.
Acad Med. 2007;
82:853–860.
Mário Miguel Rosa
54
Case Study #2
• Pesticides on Humans
• A Chem. Manufacturer pretends to test
pesticides in humans, to assess its safety and
toxicological manifestations
Mário Miguel Rosa
55
Case Study #2
• Arguments for testing pesticides on humans:
• Developing pesticides is extremely costly, risky,
and time-consuming
• With fewer and more expensive pesticides for
growers to use, cost of food to consumers rises
• Product liability of companies marketing
pesticides is high
• Testing on humans is best predictor of pesticide
toxicity; result is safer chemicals for humans
• Testing on humans lowers food costs to the
nation's poorest and neediest consumers
Mário Miguel Rosa
56
Case Study #3
• An International Pharmaceutical Company has
applied for a marketing authorization of a new
antipneumococcal vaccine to be used in children.
• When you analyze the main studies, you find that the
largest study was a multinational, multicenter study.
Most of the recruited subjects were abandoned
children from Rio de Janeiro and other cities alike.
Although the study had informed consent for parents
/ tutors, you find that most kids were not
accompanied by adults (their parents or tutors) in
most of the visits besides the screening (where an
adult signature was needed).
Mário Miguel Rosa
57
Case Study #4
• Fetal nigra cells for Parkinson’s disease
• Sham surgery vs. fetal nigra cell implant in
the putamen
Mário Miguel Rosa
58
Case Study #4
• Fetal nigra cells for Parkinson’s disease
Mário Miguel Rosa
59
Case Study #4
• Fetal nigra cells for Parkinson’s disease
Mário Miguel Rosa
60
Case Study #5
• What Is Ethically Important in
Psychiatric Clinical Research?
Mário Miguel Rosa
62
Case Study #5
L.W. Roberts et al.
Schizophrenia
Bulletin, Vol. 29,
No. 3, 2003
Mário Miguel Rosa
63
Case Study #5
Mário Miguel Rosa
64
Case Study #5
Mário Miguel Rosa
65
Case Study #5
Mário Miguel Rosa
66