Sought consent for blood sampling, made no reference to study

1. Sought consent for blood sampling, made no reference to study Acquired patients' medical records / data without their consent & used them for recruitment Told Parkinson’s patients to delay, omit or vary L-Dopa dosage without getting approval from their doctors or checking patients’ suitability Make no reference to study

2. HA Policy & Strategyon Research Ethics- Investigator’s Perspective Clinical Effectiveness Unit PS & MD Division 2005

3. Outline of Discussion • Ethical concerns of clinical research • Ethical foundations of clinical research • Enforcing research ethics in HA • Managing research-related liabilities

4. Improper decision is a real risk 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 patient’s 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

5. Social Conventions → Professional Codes → Law (Shared norms, values & practices rooted in ‘respect for persons’, ‘nonmaleficence’, ‘beneficence’ & ‘justice’) Research Ethics • Clinical research is ultimately premised on TRUST, embodied in the willing cooperation of people serving as subjects, thus creates alegitimate 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

6. Mistreatment of human in research is not exclusive to wartime or less developed countries. In the Tuskegee study, doctors of US PHS denied syphilis Rx to 399 African-Americans from 1932-72 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)

7. Ethics is often disturbing as we do not like being told what to do 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

8. Ethical Foundations of Clinical Research (& Policy Implications) • Ethical principles • Respect for persons • Nonmaleficence (Do No Harm) • Beneficence (Do Good) • Justice • Putting ethics into practice

9. Respect for Persons: Human Dignity 己所不欲,勿施於人

10. Self-determination Respect for Persons:

11. Participants being given inadequate or misleading information is the most frequent cause of concern to REC, & a common cause of GCP inspection failure in US & UK 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 areexperimental • 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)

12. Besides observing these requirements, they must be adequately explained to subject ! • 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 timewithout reprisal • Alternatives if refuse study • Possible reasons to terminate subject’s 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

13. Utilitarianism Beneficence:

14. Scientific Validity Beneficence:

15. Beneficence: Availability of Study Article after Study

16. Favorable Risk-benefit Ratio Nonmaleficence:

17. 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?

18. Competence Nonmaleficence:

19. Avoid Conflict of Interest Justice:

20. Distributive justice Justice:

21. Healthcare professionals & bio-medical scientists are not lay members Putting Ethics into Practice

22. 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

23. Sharing Ethical Responsibilities Sponsors Global references Dept of Health Medical Council • IDMC • Site audit Research Organizations HA’s jurisdiction Hospital Authority CUHK, HKU • 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 Non-teaching hospitals 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

24. HA’s 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

25. Goal: Develop a sound ethical framework for clinical research Research Ethics Developmentin HA

26. HA REC Cluster RECs Research Subject Protection Investigators Hospital (Study Sites) Administration HA delivers research ethics through by adopting a Quality System approach

27. 3 guiding documents & forms lay out explicit standards

28. 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

29. 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

30. 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

31. 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 必須有目共睹

32. Application Dossier * Indicate version / revision number & date

33. 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

34. Application, study oversight report WHO to decide? What is suitable? HOW? 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

35. REC Considerations

36. 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 • Subject’s privacy & data confidentiality • Disclosure of funding source & potential conflicts of interest

37. Failure to comply invalidates an ethical approval 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

38. 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 student’s course work • Regulatory requirement, e.g. clinical trial certificate

39. 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

40. Study Site’s 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 • Handlecomplaint & misconduct

41. Investigator’s Obligations“Investigator’s 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 responsibilityin technical, administrative & fiscal management of study. Need to address financial liabilities & avoid unfair contract terms with sponsor

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

43. 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?

44. Research-related Liability

45. Is a trial without ethical approval part of RO’s business? • Is research part of the terms of appointment of an honorary staff? • Case: a Govt driver used a Govt vehicle for his own purpose & the Court ruled that Govt (employer) was not liable 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

46. More stringent standards for approval 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 OS&H 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

47. Prudence & Justice Pietro Perrugino1497 Research ethics has evolved into a complex system of social conventions, professional codes, institutional procedures & law

48. HA web-page on Research Ethics: a comprehensive source of information