Sought consent for blood sampling, made no reference to study

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Sought consent for blood sampling, made no
reference to study
Acquired patients' medical records / data without
their consent used them for recruitment
Told Parkinsons patients to delay, omit or vary
L-Dopa dosage without getting approval from their
doctors or checking patients suitability
Make no reference to study
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(No Transcript)
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Outline of Discussion

• Ethical concerns of clinical research
• Ethical foundations of clinical research
• Enforcing research ethics in HA
• Managing research-related liabilities

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Clinical Research has Ethical Concerns

• Place some people at risk for the good of others
• Involved parties have conflicting interests
  values
• Clinical judgment about a patients well-being
  (primary interest) is subject to influence by
  research agenda, sponsorship, personal ambition
  conveniences
• Academia competes for research output resources
• Multibillion dollar business with huge potential
  profits
• Involved parties have unequal powers

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Research Ethics

• Clinical research is ultimately premised on
  TRUST, embodied in the willing cooperation of
  people serving as subjects, thus creates a
  legitimate expectation for a system of protection
  that is TRUSTWORTHY
• Research ethics, however, was not addressed
  systematically until the late 1940s, following
  revelations of human experimentation in WWII

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Research Ethics Development

• Research ethics often evolves in response to
  disgraceful events. The price of inadequate
  ethical scrutiny could be serious
• Human suffering, injury, death
• Bad science, e.g. fabrication plagiarism of
  data
• Loss of credibility, regulatory enforcement,
  legal liabilities (Tort, Malpractice Law)

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Is Protection Adequate?

• Until recently, systems of research subject
  protection rely heavily on EC / IRB

• Shortfalls
• Systems are largely self-regulating work in
  favor of research communities
• Scientific community industry dominate
• Professional paternalism undermines ethical
  concern
• Lack reliable enforcement mechanism

2001
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Ethical Foundations of Clinical Research (
Policy Implications)

• Ethical principles
• Respect for persons
• Nonmaleficence (Do No Harm)
• Beneficence (Do Good)
• Justice
• Putting ethics into practice

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Respect for Persons
Human Dignity
????,????
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Respect for Persons
Self-determination
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Consent for Clinical Research
REC will scrutinize the consent form for evidence
of

• Must use an approved consent form unless waived
  by REC
• Use language wordings suitable for subjects
  understanding
• Purpose of study, which aspects are experimental
• Study details (nature of intervention,
  ?invasiveness, ?use of placebo, method of
  assignment probability to different arms,
  duration of involvement, sample size, likelihood
  of premature termination, etc.)
• Foreseeable risks discomforts to subject (
  embryo, fetus, nursing infant)
• Expected benefits (must specify if none is
  expected)

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• Update of new information relevant to willingness
  to continue study (consent is a continuous
  process)
• Protection of privacy (subject to potential audit
  needs)
• Right to refuse, withdraw at any time without
  reprisal
• Alternatives if refuse study
• Possible reasons to terminate subjects
  participation
• Anticipated expenses by or payment to subject
• Commitments of sponsor(s), study institute(s)
  investigators
• Compensation Rx available for study-related
  injury
• Research institution investigators
• Contacts for queries adverse event reporting

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Beneficence
Utilitarianism
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Beneficence
Scientific Validity
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Beneficence
Availability of Study Article after Study
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Nonmaleficence
Favorable Risk-benefit Ratio
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Risk Benefit Considerations

• What are the risks linked to research as distinct
  from those associated with standard care?
• Not limited to the study articles, e.g.
  additional invasive Ix
• Are foreseeable risks minimized to the extent
  possible?
• Are there adequate provisions for early detection
  of risks?
• Is there necessary expertise to carry out the
  research?
• Do anticipated benefits (excluding extraneous
  ones, e.g. more attention) outweigh risks (all
  risks burdens)?
• Will subjects be adequately informed updated of
  risks, burdens anticipated benefits?
• Are there sufficient additional safeguards for
  vulnerable subjects?

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Nonmaleficence
Competence
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Justice
Avoid Conflict of Interest
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Justice
Distributive justice
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Putting Ethics into Practice
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Enforcing Research Ethics in HA(Outline of
Discussion)

• Sharing ethical responsibilities
• Enforcing research ethics
• Jurisdiction power of Cluster REC
• Activities requiring review
• The review process
• Necessary approvals for clinical research
• Compliance oversight
• Obligations of investigator study site

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Sharing Ethical Responsibilities
Sponsors
Dept of Health
Medical Council
Global references

• IDMC
• Site audit

Research Organizations
CUHK, HKU
Hospital Authority
HAs jurisdiction

• Policy Standards
• Compliance oversight
• Training
• Appeal (REC decision)

Medical Faculty
HA REC
Policy requirements on research Study Site
Administration
Study Site Administration

• Investigator privilege
• Study site facilities
• Clinical trial agreement
• Indemnity agreement
• Risk Mx, insurance
• Handle complaints malpractice

Teaching hospitals
Non-teaching hospitals
University facilities
CU / HKU REC
Cluster REC

• Gate keeping
• Ethical review
• Study oversight
• AE oversight
• Progress reports

Investigators
Investigators
Research subjects
Research subjects
HA patients
Non-HA patients
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HAs Role in Research Ethics

• HK has no Statute specifically on clinical
  research
• Ethical oversight in HK relies on
• Professional self-discipline
• Administrative control (HC providers, academia)
• HA is obliged to develop research ethics
• Practically the sole provider of study sites
• Research subjects are invariably HA patients
• Bear direct vicarious liabilities

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Research Ethics Development in HA
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HA delivers research ethics through
by adopting a Quality System approach
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3 guiding documents
forms
lay out explicit standards
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Establishing REC Operating Requirements
Local standards practices

• Established by Cluster REC
• Guides operation
• Enables audit

Cluster REC Standard Operating Procedure Forms

• Established by HA REC
• HA-wide Standards
• Guiding document for Cluster REC
• Enables audit
• Basis for harmonizing with CU HKU

ICH GCP (E6) Other references, e.g. FDA IRB Guide
HA Guide for Cluster REC
International requirements practices
Applicable regulations Professional Code
Conduct HA policy
Declaration of Helsinki
Local requirements
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Jurisdiction Power of Cluster-REC

• Cluster REC is institutional (HA) based charged
  with a mandate to protect research subjects
• Jurisdiction applies to the respective cluster
• Sole ethical review right (decision from another
  REC has reference value only)
• Validity of approval links to study oversight
  (reports of AE study progress)
• Authority to examine all aspects of study
  intervene, even terminating a study

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Activities Requiring Ethical Review

• Clinical research on human including body tissue,
  fluid, records data. This also applies to
• prior collected data in a format linking to
  individual identifiers
• waste or extra tissue / fluid
• collection storage of extra material for
  future study
• QA activity involving additional risk, burdens,
  intrusion of privacy possibly overlap with
  research

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Ethical Review

• Consistent, impartial transparent procedure is
  the best guarantee for fair outcomes to gain
  trust
• Justice must be seen to be done
• Standard of documentation must allow evaluation
  of the conduct of review the quality of the
  decision reached
• In audit, not documented not done
• In dispute, intention is judged (inferred)
  objectively

Procedural Justice ??????
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Application Dossier
Indicate version / revision number date
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• A structured approach to obtain information
  necessary for ethical review
• Investigators responsibility to submit
  information (impractical for REC secretaries to
  extract information from research protocols)
• Download file of updated Application Form
  complete all sections (nil entry is required)
• As per protocol is not accepted
• Information is genuine, accurate layman
  friendly
• The declaration section must be signed by all
  investigators endorsed by COS / Head of
  Department
• Endorsement from other involved departments
• Indemnity agreement clinical trial agreement,
  where applicable, must be signed by appropriate
  authorities

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Full Panel or Expedited Review?
CREC Chairman
Cluster REC Office
No additional invasive intervention No vulnerable
subject No sensitive privacy concern (Section 5.3
HA Guide)
Not fulfilled
Full Panel Review
All fulfilled
CREC Chairman assign reviewers
Expedited Review
Uncertain or unfavorable opinion
Approve
Report to Committee
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REC Considerations
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General Considerations

• Value of study
• Scientific validity of study design methodology
• Risks benefits
• Equity subject selection, treatment allocation,
  special considerations for vulnerable subjects
• Informed consent freedom of choice, absence of
  undue influence, right to withdraw (consent form)
• Risk of inducement arising from payment
• Research plan has adequate provision for
  monitoring the data collected to ensure safety of
  subjects
• Foreseeable problem after study (removal of an
  effective Rx)
• Indemnity agreement / insurance cover
• Subjects privacy data confidentiality
• Disclosure of funding source potential
  conflicts of interest

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Nature of Ethical Approval

• Ethical approval is conditioned on
• Compliance with ethical principles, institution
  policy applicable regulations
• Adherence to approved protocol documents, which
  can only be changed upon approval from the REC
  (unless required urgently to eliminate immediate
  hazard)
• Prompt reporting of SAE
• Submit progress report at least annually as
  requested by REC
• Abide by other REC decisions

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Necessary Approvals for Clinical Trial

• Initial continual ethical approval
• Ignoring REC requirement may invalidate approval
• Administrative endorsement from
• Heads of all departments involving in trial
• Hospital administration to sign contract
  (Clinical Trial Agreement) with external sponsor
• Authorities of non-affiliated study sites
• Education institute if study is part of a
  students course work
• Regulatory requirement, e.g. clinical trial
  certificate

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Compliance Oversight

• REC is institutional based its performance is
  subject to monitoring by the institution
• Annual inspection by HA REC
• Review CREC operating procedures against HA
  standards
• Random checking of records for compliance to HA
  standards CREC operating procedures
• Interview staff on practices
• Report to respective CREC, CCE HA REC
• Continuous improvement corrective actions,
  revising standards, refresher training

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Study Sites Obligations Clinical Research
Study Site Guide

• Institutes engaging in clinical research are
  obliged to
• Support REC
• Control research privilege investigator
  qualification, policy in granting access right to
  non-employees
• Verify adequate facility resource support for
  study no undue influence on service
• Undertake formal dealings with sponsor indemnity
  agreement, clinical trial agreement
• Manage risk insurance, policy on collaboration
  with non-affiliated study sites
• Handle complaint misconduct

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Investigators ObligationsInvestigators Code
of Practice in Undertaking Clinical Research

• Has prime responsibility in protecting research
  subjects be answerable to the institution.
  Investigator should
• qualify scientifically, i.e. proficient in the
  area of study
• understand willing to comply with regulatory,
  professional institutional requirements on
  research
• declare conflict of interest
• abide by REC decisions
• PI has overall responsibility in technical,
  administrative fiscal management of study. Need
  to address financial liabilities avoid unfair
  contract terms with sponsor

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Research-related Liabilities

• Research-related liability
• Vicarious liability
• Investigator is not an Employee
• Performing Study in an Non-affiliated Site

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Control Risk Liability

• Liability can not be waived but risk can be
  controlled
• Indemnity insurance are last resort for
  transferring / financing risk - one should aim at
  prevention
• Investigators, study site administration REC
  have shared responsibilities in controlling risk
• Basic consideration
• What is the risk?
• Is it worthy to take the risk?
• Can myself, the organization bear the risk?

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Research-related Liability
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Vicarious Liability

• An employer is vicariously liable for negligent
  acts or omissions by her employee in the course
  of employment. Vicarious liability does not apply
  if
• employee was not negligent
• employee is acting in his/her own right rather
  than on the employer's business
• investigator is not an employee

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Special Considerations

• Investigator is not an employee
• Vicarious liability does not apply, insurance
  does not cover
• RO may be charged direct liability for granting
  patient access / research rights to an unsuitable
  person
• RO bears OSH liability to investigator
• Study site is not affiliated to RO
• REC has no jurisdiction over non-affiliated sites
• RO has no control over non-affiliated sites
• Investigator has duty of care to research
  subjects RO by endorsing the research may be
  vicariously liable for negligent acts or
  omissions by her employee

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Pietro Perrugino1497
Prudence
Justice

Research ethics has evolved into a complex system
of social conventions, professional codes,
institutional procedures law
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HA web-page on Research Ethics a comprehensive
source of information