Transcript SJGP Presentation - University of Tasmania

Ethics Training
Dr Nik Zeps
1
What is Ethics?
 Moral
philosophy
–Right and wrong
–Good and bad
–Justice and virtue
2
Codes of ethics

Applied ethics
– Not always dichotomous

Bioethics
– Coined in 1927 by Fritz Jahr
– Field emerged in last 90 years

Prompted by unethical behaviour
3
“getting” ethics
4
The Ethics Framework

Australian Context
– Guidelines
– Legislation
– Policies
5
• Research merit
and integrity
• Justice
• Beneficence
• Respect for
human beings
6
6
Code of Responsible Conduct

Is mandatory to
implement by Australian
Research Institutes
– But who does?
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Training?
Written policies on data
collection, retention,
distribution?
Key to public trust is
transparent and
accountable researcher
behaviour
7
HRECs or other?
Who is required to do the review?
 5.1 Institutional responsibilities

– 5.1.3 Institutions may establish their own
processes for ethical review of research, or
use those of another institution.
– 5.1.7 (low risk-5.1.18-5.1.21) and 5.1.8
(negligible risk 5.1.22-5.1.23)
8
NS: Ethical Considerations

Guided by the National Statement on ethical
conduct in human research 2007
– Not simply a matter of regulatory compliance

1.1 Research Merit and Integrity
– Is the study worth doing?
– Are those doing the work competent and
trustworthy?

2 Risk and benefit
– Consent
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3 Specific types of research
4 Specific populations
5 Governance and ethical review
9
Important Distinctions
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…between substantive ethics and regulatory
ethics
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…between ethics and governance
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…between ethics/governance and bureaucracy

J Kenner 2010
10
10
Substantive Ethics vs Regulatory Ethics

“Substantive (research) ethics” relates to the
evaluation of proposed research with a view toward
ensuring proper respect for and protection of
participants in that research as well as the promotion
and facilitation of good research design and practice.

“Regulatory ethics” involves the quasi-regulatory,
administrative systems used to review and approve
proposed research.

J Kenner 2010
11
Components of Research
Governance

Site-related assessments prior to project startup
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Fit with organisational priorities
Clarification of roles and responsibilities
Identification of potential/actual conflicts of interest
Supervisory relationships
Credentialing
Assessment of resources
Completion of grants processes
Budgetary matters
Contractual relationships/documentation (including IP and
publication)
Establishment of proper indemnity/insurance coverage
Compliance with relevant laws/regulations/codes/guidelines/policies
Ethics approval, including scientific/technical assessments
Other risk management considerations
J Kenner 2010
12
Components of Research Governance

Responsibilities during research and after project
completion
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Monitoring by HREC of conditions of approval
Safety of participants
Data management and storage/confidentiality of research data
Financial management
Training/supervision/mentoring within project team
Exposure and management of research misconduct
Compliance with progress reporting obligations
Auditing (self, internal and external)
Managing complaints/concerns of (a) research team and (b) participants
Ensuring proper project closure processes
Final reporting
Ensuring promised feedback to participants is provided
Monitoring security of data/tissue sample storage (including destruction,
if intended)
– Consideration of secondary use of data/tissue samples
J Kenner 2010
13
The Governance – Ethics Hierarchy

Old model = Research projects are reviewed by a local HREC.
(Many) governance matters devolved to site ethics
administration.

Current model = Ethical review and research governance sit
side by side as related and complementary processes. Promotes
introduction of streamlined review programs.

Future model = Recognition that ethical review is but one
component (amongst many) of research governance within an
organisation.
Note: The last model more readily liberates an organisation to
devolve ethical review to off-site HRECs if it wishes to – for
single-site research as well as multi-centre research.
J Kenner 2010
14
Beyond Ethics and Governance
Bureaucracy …

Refers to administrative aspects of review and
governance of research that do not appear to have a
rational purpose in promoting or protecting the interests
of participants, researchers or research sites

Usually emanates from misinterpretation or overzealous
application of regulatory requirements or requirements
developed by lawyers or wanna-be-lawyers that have
not previously been considered necessary
J Kenner 2010
15
Beyond Ethics and Governance (2)

UFO = Unnecessary Formalistic Obstruction

Consequence of blind adherence to (apparent)
regulatory requirements

The problem of “Ethics Creep”

Forces re-consideration of what we who are
responsible for review, approval and monitoring of
research are doing
J Kenner 2010
16
E vs G vs B – Which is Which?
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Proper insurance coverage
Proposed consent processes for eligible participants lacking decisionmaking capacity
Review of collaborative research agreements
Review of budget
Statistical rigour
Amendment to a protocol
Correspondence announcing an upcoming amendment to a protocol
Reporting of expected adverse events from Sweden
Sign off from the hospital IT department or outpatient clinic
Sign off from Associate Investigators
Typographical errors in the PICF form
Typographical errors on the application form
Repetition of participant information sheet information on the consent form
Sponsor requirement for inclusion of US law references in an Australian PICF
Disclosure of potential conflict of interest of the Principal Investigator
Disclosure of potential conflict of interest of a study coordinator
Sponsor requirement for responsive correspondence from the HREC regarding
submission of a file note
Review of request for patient input on layout of reception area
J Kenner 2010
17
HoMER and 5.3.1


Wherever more than one institution has a
responsibility to ensure that a human research
project is subject to ethical review (see paragraph
5.1.1, page 77), each institution has the further
responsibility to adopt a review process that
eliminates any unnecessary duplication of ethical
review.
HoMER provides a framework to deliver on 5.3.1
18
Benefits and risks: risks and review
NS identifies three risk levels and relates these to proportionate levels
of ethical review
More than low risk = risk is more than discomfort:
HREC review required
Low risk = risk is no more than discomfort:
Low risk review mechanism permitted
Negligible risk = risk is no more than inconvenience:
ONLY WHERE research uses EXISTING collections of non-identifiable
data about human beings, institutions MAY exempt research from
review
19
Low risk research 5.1.7
For research that carries only low risk
(see paragraph 2.1.6, page 18) and
does not fall under any of the chapters
listed in paragraph 5.1.6, institutions
may choose to establish other levels of
ethical review.
 These levels are described in
paragraphs 5.1.18 to 5.1.21.

20
Low risk research

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5.1.20 The levels of ethical review referred to in
paragraph 5.1.18 may include, but need not be
limited to:
(a) review or assessment at departmental level by
the head of
department;
(b) review or assessment by a departmental
committee of peers
(with or without external or independent members);
(c) delegated review with reporting to an HREC; or
(d) review by a subcommittee of an HREC.
21
Quality Improvement vs Research
Means to avoid review
 Not defined by whether intend to publish
 Ethics review should be determined by
consideration of ethical issues

– Some don’t believe researchers capable of
this


But doesn’t have to be an HREC
Currently a project for AHEC
22
Elements of a Good Ethics Application

Communication
– Application form
– Supporting documents
– Interview

National Ethics Application Form (NEAF) is a
means to communicate that researchers have
recognised and addressed the ethical issues
23
NEAF - aims
Designed to collect
– in one application all information about a human research
proposal that an HREC reviewing that proposal would need, so as
to be satisfied that
– the proposal met the relevant requirements of the National
Statement and was ethically acceptable .
Hence, use of helps:
 Information buttons – explain what terms meant
 Guidance buttons – help in answering questions
 National Statement links – to relevant paragraphs of NS
 Help phone line
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24
NEAF
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Demonstrate that ethical issues have been considered
NEAF sections
1 Title and Summary
2 Researchers and investigators
3 Resources
4 Prior Reviews
5 Project
6 Participants
7 Participants specific
8 Confidentiality/ Privacy
9 Project Specific
25
NEAF Demo
26
Why do we ask for consent?
Respect (NS 1.10)
 Expression of
Autonomy

– empowerment
Altruism
 Compliance with
guidelines/legal
requirements

27
Demonstrating Trust

Consent is the material demonstration
of a process that indicates a patient
‘trusts’ the person/system they give it
to.

Alternatives to consent are community
trust in a system that demonstrates
responsibility and accountability
28
Consent (Chapter 2.2)
 Respect
for a person = consent
– Voluntary
– Informed
 Considerations
– Communication

Mutual understanding
– No coercion or pressure
– Payment for participation
29
Competence
 Functional
based
approach not status
 Competence
to make particular
decision at particular time
30
Incompetence
Simple
Competence
Complex
31
Information
 Providing
information is not merely
satisfying a formal requirement
(2.2.4)
– Material information - participant
centred concept
– Information that a reasonable person
would think was significant for
making the decision to participate
32
Skills for obtaining consent

NS 3.1.13 Predicting what topics are
likely to lead to distress will not always
be easy. Researchers should have
sufficient training to help them in
making such predictions.
33
Flexibility

NS 3.1.16 The method of providing
consent in qualitative research depends
on various factors, including the type of
research, its level of sensitivity, its
cultural context, and the potential
vulnerability of the participants. In
some contexts, the protection of
vulnerable participants may favour a
formal, written process of consent; in
other contexts, an oral process.
34
Implied consent

NS 3.1.17 In some circumstances,
consent may be implied by
participation, for example the return of
a survey, or the answering of a verbal
question
35
Renegotiating consent

2.2.8 In some research, consent may need to
be renegotiated or confirmed from time to
time, especially where projects are complex
or long-running, or participants are
vulnerable. Research participants should be
told if there are changes to the terms to
which they originally agreed, and given the
opportunity to continue their participation or
withdraw (see paragraphs 5.2.16 and 5.2.17,
page 84).
36
Research participants – impaired consent
Coercion
Deception
NS 2.2.9
}
NS 2.3.1-2.3.4}
limited disclosure
NEAF 5.1.2
Dependent relationships = example of coercion
NEAF always asks about this – 6.4.1 – 6.4.5
NEAF 6.1.1 assumes knowledge of examples in NS 4.3
See also other NS references, e.g. NS 3.1.3-3, 3.3.13-18
Leads to NEAF 7.4
Inducement
NS 2.2.10/11*
*NHMRC Using the NS: payment
NEAF 6.6.1..
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Waiver of Consent

Section 2.3.6 of the NS
–
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–
–
–
A) low risk
B) benefits outweigh harms
C) Impracticable to get consent
D) No reason why a person would say no
E) Privacy protected
F) Adequate plan to protect confidentiality
G) A plan to feedback results (or not)
H) Commercial outcomes will not cause disadvantage
I) Waiver is not unlawful
38
39
Privacy and Confidentiality

Privacy Laws
– Commonwealth
– State
– Private sector

Confidentiality
– Requirement of employment contract
– Guarantee to patients (participants)
40
Potential Harms

Invasion of privacy
– A sense of violation

Concerns regarding
– inappropriate use
– who has access
– What use the information is put to
41
A Good PICF – The Basic Elements
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Invitation
Nature and purpose of research
Procedures/requirements of participation
Risks and potential benefits
Alternatives to participation
Voluntary participation/right to withdraw
Privacy and confidentiality
Sponsorship/financial support
Reimbursement (if any)
End of project
– Reasons for termination
– Consequences for participant

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Availability of results
Who to contact re concerns or complaints
Approval by HREC
Consent Form
42
Breakout into table discussion
Issues related to recruitment of specific
groups
 Consent processes
– how much to rely upon PICF or are there
other considerations more important?

Feedback/discussion
43
Alternative processes

Standard information and process for
recruitment in departments that do
research
– Only provide information about


non-standard therapies and procedures
Additional burdens and risks
– No PICF should be longer than 2 pages
– Current system ignores usual practice and
leads to the conclusion that the only item of
importance is the PICF
44
Break for Lunch
45
Research Involving Human biospecimens
 Translational
Research?‘
 Bench to bedside and back again’
 Requires a multidisciplinary team
approach
– Laboratory
– Clinical
– Health Services
– Primary care
46
Developing new treatments
Preclinical testing
Clinical trials
Advances in
Technology
Lab tests
Clinical
practice
Phase 1:
Right dose?
Phase 2:
Can it work?
Phase 3:
What is best?
47
Clinical Registries
Clinical Practice
Patients
Clinical Phenotyping
Treatment
Medical notes
• Diagnostic Tests
•Pathology
•Imaging
•Genetics
•Medical History
•Standard
•Trial
Follow Up
48
Research Databases
Clinical Research
Patients
Biospecimens
•Clinical Phenotype
Genomics-Proteomics
•Genotyping
Follow Up
•Prognosis
•Prediction
49
Types of ‘biobank’

Population based
– Dedicated collections eg Busselton

Pathology services
– Surgical resections
– Biopsies
– ‘Waste’ blood
– Mortuary

Outpatient (biopsy/blood)
– Direct to researcher
50
Public trust: The result of good ethical research
But….
51
Guidelines for Biobanks/databanks
Privacy Act
 NATA/NPAAC
 ISBER Best Practices Manual
 NHMRC-HGAC Biobanks Information Paper

–

http://www.nhmrc.gov.au/your_health/egenetics/practitioners/practitioners.htm
OECD Biobanks paper
– Guidelines for Human Biobanks, Genetic
Research Databases & Associated Data
52
Consent
How much should the participant
understand?
 What do we mean by ‘informed’
consent?

– Poly-omic research?
– Gene lists?
53
Consent form
FORM 730.8
SURNAME:
WA RESEARCH
TISSUE NETWORK
CONSENT FORM
URN:
FORENAME:
DOB:
SEX:
Consent for tissue/blood taking and tissue/blood banking for clinical research
I, ________________________of_______________________________________________
have read the Information Brochure entitled “WA RESEARCH TISSUE NETWORK”. (Doctor or
health professional) ……………………………….. has explained to me and I understand the
consequences involved in my voluntary donation of tissue and/or blood for the WA Research Tissue
Network. I have had an opportunity to ask questions and am satisfied with the answers given
1) the tissue/blood (which in this consent form, includes its constituents and any cell lines derived from
the tissue/blood) will be used in relation to (WRITE IN PROJECT NAME),
2) samples of any tissue/blood or derived cell line/s held in a bank will be discarded upon my written
request to the WA Research Tissue Network Project Manager,
3) the results of research studies are deemed experimental and not for diagnostic purposes and therefore
not intended to be passed back to me or my immediate family,
4) I wish/ do not wish to be informed of important general results and the progress of any study
through a newsletter which will contain information about these studies in a form that will not allow
individuals to be identified,
5) I can request to know more specific details of any studies that used my samples at any time by
contacting the WARTN,
6) Research results, and the fact that I have made this donation, will not be revealed to any 3 rd party not
directly part of medical research without my written consent, except under subpoena ,
7) The WA Research Tissue Network will not be liable for any loss of or damage to, the tissue/blood
used in accordance with this form,
8) I will not benefit financially if this research leads to development of a new treatment or medical test,
9) storage of and access to my tissue/blood will be managed by an Advisory Committee and only
released where the research proposal has been approved by a Human Research Ethics Committee,
10) I understand that international research collaboration using my tissue/blood will only take place
where researchers abide by equal or more stringent regulations of privacy and ethics as those in
Australia, as assessed by a Human Research Ethics Committee
11) I give permission to access health information about me related to the research area defined in point
1 above, such as is kept in a medical record or by the WA Department of Health, to assist medical
research only where the research proposal has been approved by a Human Research Ethics
Committee.
I
Do
Do Not
consent to the storage and use of my tissue and/or blood (delete as appropriate) for biochemical and
genetic based medical research.
………………………
……………..…………………
.…………
Name of Patient
Signature of Patient
……………………….
Name of Doctor
………………………….…..
Signature of Doctor
Date
……….…
Date
54
WA RESEARCH TISSUE NETWORK CONSENT FORM
Sir Charles Gairdner Hospital – Hospital Avenue, NEDLANDS WA 6009 Tel +618 9346 3333 Fax +618 9346 2534
In making my donation, I understand and agree that:
Medical Research
I have read the Information Brochure
entitled “WA Colorectal Research Group”,
and Give my voluntary consent to the use
of my biological specimens and health
information for medical research as
described therein.
Agree/Disagree (delete as
appropriate)
Signed
________________
Name (printed)________________
Date
________________
55
Genetic Information

Is it Exceptional?
– Different to any other information?
– Predictive
– Deterministic
– Nature versus nurture
– Genes versus environment
– Redundancy
56
57
Molecular Events During
Tumourigenesis
Epigenome:
Changes in DNA methylation
Histone modifications
Chromosomal instability
nucleosome
Genome
Chromosomal Organization
Copy Number Variation
Gene Fusion Event
Single Nucleotide Polymorphism
Small Insertions/deletions
DNA
euchromatin
RNA
pol II
chromosome
heterochromatin
Transcriptome
Gene expression
Aberrant expression
Altered miR –mRNA networks
Gene fusions
Expressed SNPs and mutations
mRNA, miRNA,
ncRNA
58
Genome Sequencing
1) Profile matched DNAs on CNV/SNP array (Illumina 1M)
and call ploidy and stromal gDNA contamination
2) Sequence fragment and long-mate pair libraries to a depth
of 25 fold (75Gb)
3) Define Copy Number Variations
SNP/CNV Chip
analysis, gDNA
sequencing
4) Define Structural Variations
5) Mine Single Nucleotide Variations
6) Mine insertion and deletions
Tumour & normal
gDNA
7) Determine which events are somatic Vs germline
8) Benchmark calls against array data & validate leads
9) Collate all variants into the DCC
59
ICGC Ethics and Policy Committee

Mandate
– The Ethics and Policy Committee (EPC) is
responsible for




examining and raising issues of consent,
privacy protection,
data access,
ethical and legal topics relevant to the International
Cancer Genome Consortium (ICGC).
– The EPC will draft recommendations and policy
statements or guidelines.
60
Returning Results


Consideration must be made
regarding return of results (NS
section 3.5.1)
Should not be an option for
participants to decide yes or
no at time of donation
– How could they possibly know
whether they do or do not
want results?

Researchers must not give
results of any testing to
individuals
– Must be done by specialist
genetic services

There is no ‘right’ to results
under Australian law
61
First case in Australia

35 year old male
– Pancreatic cancer (has subsequently dies)
– BRCA1/2 and PALB2 mutations
– Has sisters

What do we do?
– S95/s95a/s95aa
62
Proposed ICGC data embargo


A key challenge with such prepublication release of data is to
balance the interests of the ICGC
members to carry out and publish
the initial global analysis on the
data they have generated while
accelerating the use of the data
by the wider scientific community.
1 year moratorium?
– On publication not access
– In all cases data shall be free of
any restriction two years after its
initial release
 Is
this ethical?
63
DTC genetics
64
Insurance Implications

Duty to disclose
– Should a participant tell their insurance
company they are a part of a study?
– No Australian moratorium

Uk has don’t ask don’t tell policy
65
Confidentiality: Data Publishing Risk?
“Our findings show that such an
approach does not completely conceal
identity, since it is straightforward to
assess the probability that a person or
relative participated in a GWA study”
“greater emphasis is needed for
providing mechanisms to confidentially
share and combine individual genotype
data across Studies”
Motive
Opportunity
Means
66
Job candidates getting tripped up by Facebook
many students learn the hard way that online
image can limit opportunity
By Wei Du msnbc.com updated 1:30 p.m. ET Aug. 14,
2007
 Van Allen runs a company that recruits job
candidates for hospitals and clinics across the
country. With physicians in short supply, he was
happy to come across the resume of a well-qualified
young female psychiatrist. As part of his due
diligence check, Allen looked her up in Facebook, a
popular social networking Web site, and found things
that made him think twice. “Pictures of her taking off
her shirt at parties,” he said. “Not just on one
occasion, but on another occasion, then another
occasion.”
67
Commercialisation



Should anyone be
allowed to make $$ out
of selling the human
body?
Do patients have an
interest in trade or
discovery?
NHMRC paper on
Commercialisation of
Human Tissue Products
– Release July 2010
– Possible guidelines to
come
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70
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DTC genetics
72
Revision to 3.4/3.6
Combine the two chapters
 New title “Biospecimens”
 Focus is on consent, identifiability and
risk to donor.
 Targeted consultation finished

73
Safety Reporting
A. The
SAE labyrinth
B. The
NHMRC Alerts – Rationale and
Interpretation
C. (Data)
Safety Monitoring
Committees
74
Safety Reporting (2)
SAEs/SUSARs
Why we have them
 What we are expected to do with them
 Why the Australian system doesn’t work
 What the NHMRC Alerts advise/require
 Why the problem isn’t solved
 Options for coping in the short and long
term

75
Safety Reporting (3)
Safety Monitoring Committees (SMCs)


Purpose is to ensure the safety of participants
Reviews the efficacy and safety data from a clinical trial
– analyses the risks and benefits to the subject population
– advises on serious safety considerations or lack of efficacy arising out of
the trial
– safeguards the integrity of the trial data

Key factors:
– expertise
– independence


from project
from sponsor
76
Safety Reporting (4)
Models for SMCs

Commercially sponsored Phase I trials
– PIs + company reps + independent experts

Commercially-sponsored Phase II/Phase III non-reg trials
– Pharmacovigilance committee (appointed, often internal)

Commercially-sponsored Phase III registration trials
– Independent experts only

Cooperative group-sponsored trials
– Investigators +/- project-independent experts

Investigator-initiated (in-house) trials
– Investigators +/- in-house project-independent researchers
_________________________________________________________
** HRECs should review and approve a properly constituted SMC.
** A properly constituted/properly functioning SMC can help resolve
the SAE/SUSAR conundrum.
77