Transcript Conflicts of interest

Metodologia cercetării ştiinţifice
Etica in cercetarea ştiinţifică
Corin Badiu, 2007
Etica
Definitii academice si practice
• Ramura a disciplinelor filozofice, considerata stiinta de
normare intrucat se ocupa de normele conduitei
umane. [academic]
• Procesul prin care se aplica valorile morale la situatii
actuale de viata. [practic]
Aspecte istorice si religioase
• Etica: un corp de norme si standarde de conduita
umana care guverneaza comportamentul indivizilor si
grupurilor. [istoric]
• Etica: disciplina de viata rezultata din aplicarea
normelor si preceptelor religioase [Religie]
Individ si Grupuri
• Etica: domeniu de studiu care ajuta individul
pentru aplicarea propriilor valori si principii
pentru a le conduce comportamentul.
[individual]
• Etica: un set de reguli pe care le studiem si
aplicam pentru a duce la indeplinire misiunea
unei organizatii / institutii. [group]
Etica institutionala
• Institutie = grup:
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Actioneaza colectiv pentru indeplinirea
scopurilor institutionale
• Institutie = individ:
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Foloseste valori comune cu etica
individuala pentru a lua decizii
• Atat institutiile cat si indivizii:
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Norme de etica
Protocolul de evaluare etica in cercetare
1. Fond, Scopuri, Obiective
2. Metodologia cercetarii
3. Participanti
4. Recrutare
5. Riscuri si Beneficii
6. Confidentialitate
7. Compensare
Protocolul de evaluare etica in cercetare
8. Conflict de Interese
9. Elaborarea si aplicarea consimtamantului
Informat
10. Evaluarea prin comitete si institutii
11. Contract
12. Trialuri Clinice
13. Anexe
Fond, Scopuri, Obiective
 Care este subiectul cercetarii?
 Ce scopuri se vor indeplini prin cercetare?
 Care sunt principalele intrebari la care se doreste
raspuns?
 Descrie pe scurt fondul stiintific al studiului
 ½ pagina
Metodologia cercetarii
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Secventa logica de evenimente din cadrul studiului (protocol)
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Cum se vor obtine datele?
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Descriere detaliata pentru fiecare metoda. Pune urmatoarele
intrebari:
 Cat dureaza interviul/chestionarul/observatia experimentala?
 Cand (in ce perioada) va avea loc?
 Unde va avea loc?
 Participantii vor avea posibilitatea sa intervina in chestionar/studiu?
Daca da, ofera detalii.
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Care sunt implicatiile /aplicatiile cercetarii?
Participanti
 Cine sunt participantii? Organizatii? Indivizi?
 De ce au fost alesi pentru studiu? (criterii de
excludere / includere)
 Cati sunt?
 Argumenteaza dimensiunea esantionului
Recrutare
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Cum veti obtine o lista a potentialilor participanti?
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Sistem de contact
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telefonic
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Email
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scrisoare ?
Grupuri de studiu:
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control,
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Test
Riscuri si Beneficii
 Standarde de aplicare:
Nu exista risc minim anticipat.
Participantii vor fi informati despre natura studiului si
modalitatii de participare, inclusiv asupra faptului ca
se pot retrage oricand.
Participantii (si raspunsurile lor privind includerea in
studiu) vor fi luate ca atare
Anexe
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Text Telefonic/email
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Exemple de scrisori de consimtamant
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Ghiduri de observatie clinica
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Chestionare
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Interviu sau intrebari de grup
Principii ale eticii in cercetare
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Onestitate
Obiectivitate
Integritate (cine esti, ce faci, ce spui)
Utilizarea eficienta a resurselor (timp,
materiale, echipamente, personal)
• Colegialitate (utilizare in comun)
• Recunoasterea autoritatii (ca authorship si
mentor)
• Deschidere (dezvaluirea detaliilor)
Ethics of Clinical Research
• Ethical requirements in clinical research
aim to:
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minimize the possibility of exploitation;
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ensure that the rights and welfare of subjects
are respected while they contribute to the
generation of knowledge.
Codes and Guidelines
• Nuremberg Code
(1949)
• Declaration Of Helsinki
• The Belmont Report
(1964- 2000)
(1979)
• CIOMS/WHO International Guidelines (1993, 2002)
• ICH/GCP-International Conference on
Harmonization- Good Clinical Practice
(1996)
Emergence of Ethical Principles
Nuremberg Code of 1947
• Judgment at Nuremberg trial included a
set of standard known as the
“Nuremberg Code”
• “Ethical yardstick against which
defendents were judged”
Sentinel events
• Nazi war crimes
Nuremberg trial (1948)
• Human radiation
experiments, etc.
Declaration of Helsinki
(1963)
• Tuskegee Syphilis
study
National Commission
Belmont Report
(1977)
Nuremberg, Germany
December 9, 1946 to August 20, 1947
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Required voluntary
consent prior to
participation
Investigator responsibility
to obtain consent
Information gained by
using human subjects
would be unprocurable
any other way
Declaration of Helsinki
(World Medical Association)
• Articulated ethical principles for use by
physicians conducting human research
• Affirmed the autonomy of the individual
• Universally adopted to ensure the rights
and welfare of human subjects of
research
Declaration of Helsinki
• World Medical Association, 1964.
• Last amended 2000
• Ethical Principles for Medical Research
Involving Human Subjects
• Take home point: Research with human
subjects is justified only when the degreee of
risk to subjects does not exceed the
humanitarian importance of the knowledge to
be gained. The D of H is the basis for Good
Clinical Practice used today.
Declaration of Helsinki
Issues addressed:
 Research with humans should be based on
laboratory and animal experimentation
 Experimental protocol should be reviewed by
independent committee
 Informed consent
 Research conducted by
medically/scientifically qualified individuals
 Risks and benefits
 Privacy of the subject
 Publication of research results
Belmont Report
• 3 basic principles that should govern all
research involving human subjects
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Respect for persons
Beneficence (maximize benefits, minimize
risks, avoid harm)
Justice (benefits and burdens equally
distributed)
The Belmont Report
Ethical Principles and Guidelines for the
Protection of Human Subjects of Research
(April, 1979)
• Established three basic principles which are
the cornerstone of regulations involving
human subjects protection
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Autonomy/respect for persons
Beneficence
Justice
THE BELMONT REPORT
National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research
• Distinction between clinical research
and clinical practice
THE BELMONT REPORT
• Ethical principles underlying the
conduct of research:
Respect for persons
 Beneficence
 Justice
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Federal regulations (DHHS)
• 1991 Federal Policy for Protection of
Human Subjects (The Common Rule)
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Adopted by all agencies which conduct,
supervise, regulate, fund or sponsor
human research
Two major requirements:
• Informed Consent
• IRB approval
Romanian regulations
• National ethics committee
• National Drug Agency
• Nonclinical studies research guide
MHO 1224/2004 according to International
Conference for Harmonisation – ICH,
Committee for Proprietary Medicinal
Products - CPMP guide 286/95
• Good clinical practice regulations - MHO
615/2004
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Are we doing it right?
• Voluntariness:
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Freely coming to a decision
Free from coercion or undue influence
Assumes capacity
• Capacity
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Understand nature and ramifications
• Who is not able to do this?
Vulnerable populations
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Children ?
Prisoners?
Mentally retarded individuals
Dementia/Coma/Vegetative state
Mental illness
Pregnant women
Emergency patients? (pain, fear, etc.)
Vulnerable Populations: Children
• If child can understand (> age 6-8)
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We are obligated to obtain assent
• Can parents overrule?
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In studies with more than minimal risk and
not without prospect of direct benefit
Other vulnerable populations
• Research on individuals who lack
capacity also requires prospect of
benefit
• Not promulgated in federal regulations
• Family member can consent
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If consistent with state law
How do we get informed consent?
• Will vary according to study design and
nature of participation
• Verbal vs. Written
• Investigator vs. proxy
Informed Consent Process
• Cornerstone of human subjects
research
• Process and not just a form. Consent
form is only the documentation that the
consent process has taken place
Informed Consent Process
Basic elements of the Informed consent
process (ICP)
• Oral and written info at the 7th grade level
• Statement that study involves research,
description of procedures, duration,
identification of experimental procedures
• Foreseeable risks and discomforts
• Anticipated benefits to subject or others
• Voluntary nature of participation
• Ability to withdraw at any time
Informed Consent Process
Basic elements of ICP (cont’d)
• Disclosure of alternatives
• Statement regarding
confidentiality/anonymity
• Statement regarding
compensation/medical treatment
• Statement regarding appropriate
contact for inquiries related to subject
rights, research concerns, and for
research-related injury
Informed Consent Process
Costs
• The ICP must include a clear
explanation of the costs for which the
subject will be responsible
Managing Risks to Subjects
Adverse Event Reporting
• Unanticipated problems
• Serious adverse events
• New data
May lead to:
• Reassessment of risk
• Changes to consent form or reconsent
• More frequent oversight by the IRB
• Early termination of the protocol
Healthy volunteers
• Volunteers may not stand to benefit
directly, but could ultimately contribute
to development of a new therapy that
the participant might then use.
• Require particularly close monitoring,
because they can pose a risk to a
volunteer's health or life.
Why do people participate in
biomedical research?
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Altruism
Free medical care and medications
Trust
Self-interest
Attention
Do we want to constrain people if they
are doing things for the wrong reasons?
Role of the IRB
• Protect the institution
• Can introduce complexity
• Responsibility of PI to terminate if they
sense the patient is not really involved
in the process
• No one knows how risk is really
determined
Ethical framework: 7 principles
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Valuable scientific question
Valid scientific methodology
Fair subject selection
Favorable risk-benefit evaluation
Independent review
Informed consent
Respect for enrolled subjects
Emanuel E, Wendler D, Grady C. What makes clinical research ethical? Journal of the
American Medical Association 2000; 283(20):2701-11
Essential Elements of Ethical
Research
Valuable Scientific Question
Limited Resources and Avoidance of
Exploitation
A socially, clinically, or scientifically useful
research question that will generate useful
new knowledge about human health
Essential Elements of Ethical
Research
Valid Scientific Methodology
Limited Resources and Avoidance of
Exploitation
Study design, methodology, statistical power,
and feasible strategy that will yield valid,
reliable, generalizable, and interpretable data.
Essential Elements of Ethical
Research
Fair Subject Selection
Justice
Selection of subjects for reasons of
science, related to the purpose of the study,
not because they are readily available,
vulnerable, or otherwise easily exploited, or
are favored.
Selection of subjects
• Consistent with scientific goals:
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Select subjects to minimize risks and
maximize benefits
Do not exclude subjects without a good
reason of science, vulnerability, or
susceptibility to risk or burden.
Consider distribution of burdens and
benefits of research
Research as burden or benefit?
Research as
‘burden’
Research as
‘benefit’
Subjects need
protection
Subjects
need access
Vulnerability
• There is an order of preference in
selecting subjects, for instance, adults
before children (Belmont Report)
• Exclude vulnerable subjects unless their
participation is needed for scientific
reasons (CIOMS)
Essential Elements of Ethical
Research
Balance of Risks and Benefits
Non-maleficence and Beneficence
• Minimize risks to subjects
• Maximize benefits to individual subjects
and to society
• Benefits should be proportional to or
outweigh risks.
Risks in research
• Defining risks
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Probability and magnitude
Types of risk
Uncertainty
• Minimizing risks
• Limiting risk
Benefits in research
• Defining benefits
 Direct versus secondary benefits
• Maximizing benefits
• Balancing risks and benefits
Benefits and Risks in Research
[I]nterests other than those of the
subject may on some occasions be
sufficient by themselves to justify the
risks involved in the research, so long
as the subjects’ rights have been
protected.
The Belmont Report
Essential Elements of Ethical
Research
Independent Review
Minimize conflict of interest
Public Accountability
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.
Essential Elements of Ethical
Research
Informed Consent
Respect for Persons
Voluntary agreement to participate,
based on understanding the objectives,
risks, benefits, and alternatives of the
research.
Integrity
• Don’t be lazy – research is time-consuming
but don’t take shortcuts
• Don’t disregard data that you find
inconvenient
• Don’t claim more than the evidence
supports
• Don’t falsify evidence
• Don’t be afraid to face up to the fact that the
data collected has not produced any
significant readings
• Don’t forget to be self-aware – know your
own attachments / agenda
Confidentiality
• Unless you guarantee confidentiality you
probably won’t gain consent and you certainly
won’t obtain significant data.
• Once you agree confidentiality then this must
be honoured (BUT: our duty of trust / promise
is outweighed by our obligation to prevent
harm to others).
• Must ensure that confidentiality is not
breached directly (gossiping) or by accident
(leaving notes lying around).
Anonymity
• Confidentiality is best assured by
anonymising collection of data.
• Anonymity is increasingly difficult as
advances in technology are made
Respect for children
• Legal considerations: duty of care
• Gaining informed consent from children
• Empowerment: giving children a voice
Essential Elements of Ethical
Research
Respect for Enrolled Subjects
Beneficence and Respect for Persons
• Right to withdraw.
• Confidentiality of subject data.
• Informing subjects of new information and of
study results.
• Monitoring subject welfare.
Respect for enrolled subjects
• During the course of the experiment the
human subject should be at liberty to bring
the experiment to an end… Nuremberg Code
• …Every precaution should be taken to
respect the privacy of the subject ,the
confidentiality of the subject’s information,
and to minimize the impact of the study on …
physical and mental integrity and on the
personality of the subject. Helsinki 2000
Balancing principles
• Example: Randomized Controlled Trials
• Balancing the need for a rigorous design
with the obligation to maximize benefits
and minimize harms
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Equipoise
Randomization
Choice of control
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)
• Balance the need to answer the valuable
question in a scientifically rigorous way, while
minimizing risks and maximizing benefits to
participants.
Conflict of Interest
• Financial
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Equity interest, consultant, paid speaker
• Non-financial
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Recognition, desire to advance one’s
theory
• You might not be able to eliminate your
conflicts of interest, but there are other
options: reduce, avoid, disclose
Conflict of Interest in Human
Research Studies
Impossible to eliminate all conflicts of
interests
Types can be financial, personal,
individual, or institutional
Federal regulations and UK policy
focuses on financial
Nevertheless, ethics dictates for
investigators to be sensitive to all types
Conflicts of interest
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Usually resulting from a researcher’s dual role
e.g. a teacher/researcher wanting to collect data from
her/his own students, or another type of relationship where
the researcher has an evaluative role in relation to
participants
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Issue:
Potential participants may feel some pressure to participate
resulting from the power relationship between
teacher/student and not feel completely comfortable saying
‘no’ to participation
What is a Conflict of Interest?
• A situation in which financial or
other personal considerations
may bias, or be perceived by
others as biasing, professional
judgment or action.
Why Do We Care About
Conflicts?
• Impact on rights and welfare of
subjects
• Appearance of bias lead to loss of
public confidence
• Impact on integrity of data submitted
to regulators and journals
Ethics is about…
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Minimizing harm
Maximizing benefit
Being fair
Being respectful of others
Types of Data
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Body temperature
Body weight
Room temperature, humidity
Food/water use
Animal behavior (e.g., sleeping,
aggression)
• Assay data
Data Selection & Retention
• Be careful how you “pick and chose”
• Be consistent with regard to “high
background”, “artifact”, “low confidence
values”, and “noise” (versus signal)
• When reporting your data, disclose what you
did:
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Two obese rats were excluded because…
The first three data points were excluded
because…
Dilemmas with Gels & Digital Data
Gels, X-Rays, photos are considered DATA
Digital Data Ethics
• Simple adjustments to the ENTIRE image are
usually acceptable.
• Selectively manipulating one area of the
image is questionable.
• Cropping an image is usually acceptable.
• If used, software filters must be noted in the
figure caption.
• The more processing you ‘have’ to do, the
more ethically problematic the manipulations
become.
Who Owns “Your” Data & Materials?
• Employees & medical students that relate in
any way to his/her job/research
responsibilities must be assigned to the
Clinic.
• Exchanges of research material with outside
researchers must be framed in written
agreements, since further discoveries may be
made using the material. Clinic may be
compensated for such exchanges.
Practica responsabilitatii cercetarii
• Ce inseamna?
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Urmarirea si aplicarea unui protocol scris
Verificarea si documentarea datelor (inclusiv lotul
de reactivi, date de exp., etc.)
Pastrarea adecvata a rezultatelor si specimenelor
Pastrarea adecvata a reactivilor si chimicalelor
Mentinerea si calibrarea adecvata a
echipamentelor
Utilizarea Standardelor Procedurilor de Operare
(SOP)
Grija pentru animalele de experienta
Pastrarea datelor
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Caiet de laborator semnat si datat
Scris LIZIBIL
Fara pasta corectorare
Se taie cu o linie, se semneaza si se
dateaza.
• Fara Postit (sticky notes).
• Fara pagini albe.
Authorship*
Acquisition of funding, collection of data,
or general supervision of the research
group, alone, does not justify authorship.
*Intl Comm of Medical Journal Editors. Uniform Requirements for
Manuscripts Submitted to Biomedical Journals: Writing and Editing for
Biomedical Publication. November 2003.
An Underlying Principle of the
Authorship Requirements
• Those credited with
authorship should be able to
take public responsibility for
the research.
Author Requirements*
Authorship credit should be based on:
1) substantial contributions to conception and design,
or acquisition of data, or analysis and interpretation of
data; and
2) drafting the article or revising it critically for important
intellectual content; and
3) final approval of the version to be published.
Authors should meet conditions 1, 2, and 3.
*Intl Comm of Medical Journal Editors. Uniform Requirements for
Manuscripts Submitted to Biomedical Journals: Writing and Editing for
Biomedical Publication. November 2003.
Authorship
Decide up front who will work on the
manuscript and what the order of
authors will be.
(Not all people working on the project
will meet authorship requirements).
Research Misconduct
• Fabrication (creating data)
• Falsification (changing data)
• Plagiarism (using another’s words or
ideas without giving them credit).
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This includes cutting and pasting from the
Internet.
Why is Misconduct “Bad”?
• It affects the integrity of science as a
profession (which potentially adversely
affects research funding)
• It is not collegial
• It is an example of poor resource
stewardship
• Propels further generation of “bad” data
as the initial data foundation is “bad”
Misconduct Research
• Survey of 3247 researchers:
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28% admitted to poor record keeping
16% admitted to changing the design, methodology, or
results of a study in response to pressure from their funding
source
15% admitted to dropping observations/data points based
on a gut feeling
10% admit to giving authorship to people who didn't earn it
ref: Martinson et al. Nature 2005;435:737-738
What to do if you suspect
misconduct…
• Don’t assume you are “right”
• Don’t accuse
• Try to verify your suspicion (there may
be an acceptable reason for what is
going on)
• Ask yourself, “what is my motive for
getting involved?”
• Ask the advice of someone you trust
Issues in Animal Research
Your Guide:
• Guide for the Care and Use of Laboratory
Animals – info about vet care, housing, pain
control euthanasia, etc.
(http://www.nap.edu/readingroom/books/labrats/)
Issues in Animal Research
• Have you attempted to REPLACE animals with
another model?
• Have you REDUCED the number of animals to the
minimum needed for statistical purposes?
• Have you REFINED your lab techniques so that
animal pain and suffering are as low as possible?
• Is your protocol approved by the CCF Institutional
Animal Care and Use Committee?
Identification
• Make sure your animals are clearly
identifiable, whether singularly or in
groups.
• Options include cage labels, neck
labels, tattoo, microchip, etc.
Housing Your Animals
• Consider the animal species
• Housing should consider size of animal,
temperature, bedding needs, food, clean
water, light, noise, humidity, contact with other
animals, air exchange, vibration, etc.
• Keep the cages clean, and the animals free
from harm from other animals. (This includes
avoiding crowding within a cage).
Avoiding Animal Stress
If possible, before starting your project,
CONDITION your animals to their
environment, procedures, and research
personnel.
Pain/Suffering
• An animal with signs of pain or distress not
predicted in the protocol, must have the pain
or distress alleviated promptly.
• Alleviation of such pain or distress must take
precedence over completing a project.
• If this is not possible the animal must be
euthanized without delay.
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
CONCLUSIONS
• Ethics is research starts with grant
application
• Applies to all involved in research
process
• Ends with publication and further follow
- up (clinical & scientific)