The Human Biomedical Research Act: Compliance and Risks. A/Prof Goh Yeow Tee Singapore Research Ethics Conference

Transcription

1 The Human Biomedical Research Act: Compliance and Risks A/Prof Goh Yeow Tee Singapore Research Ethics Conference

2 Agenda Biomedical Research Regulations What is HBRA expectation? Local Research Landscape Challenges Faced by Organization, IRB and Researchers 2

3 Why Research? Academic: To expand medical and scientific knowledge Technological: To enhance efficiency of interventional methods and/or techniques used Quality of Life: Screen new drugs or to create new methods for treatment or diagnosis Economic: To access and evaluate the efficiency and cost incurred in innovations 3

4 What is HBRA Expectation? The nature of research is a very broad and complex process Requires a multifaceted and interconnected systems of protections Research is a double-edged sword Research can bring medical sciences advancement At the same time, research is subjected to abuse or mishandling Therefore, it is of paramount importance to regulate human biomedical research 4

5 Biomedical Research Agencies U.S. Health and Human Services Ministry of Health Office of Human Research Protections Federal Policy for the Protection of Human Subjects (Common Rule) Ministry of Health Human Biomedical Research Act Food and Drug Administration Health Sciences Authority Health Products (Clinical Trials), Medicines (Clinical Trials) Regulations The Office of Research Integrity Oversee research misconduct inquiries and investigations No Equivalent in Singapore 5

6 Biomedical Research Regulations Food & Drug Administration Regulations FDA regulations are published as part of chapter 21 of the CFR, and FDA s human subject protection regulations are in parts 50, 56, 312 and 812 FDA regulations speak to all entities that might be involved with the conduct of clinical studies - clinical investigators, IRBs, sponsors, CROs 21 CFR Part 312 for pharmaceutical studies Part 812 for device studies Federal Policy for the Protection of Human Subjects (Common Rule) Protection of Human Subjects Applicable to all research contacted with federal funding Does not directly regulate the clinical investigators Implementation of the Final Revisions to the Federal Policy is delayed until July 19, 2018 Human Biomedical Research Act (HBRA) Health Products (Clinical Trial), Medicines (Clinical Trial) Regulations HBRA: Human Biomedical Research (HBR) Framework Human Tissue Framework Health Products (Clinical Trials), Medicines (Clinical Trials) Regulations: Medicinal Products Therapeutic Products 6

7 Timeline of U.S. Common Rule 1991 Common Rule implemented 2011 Advance Notice of Proposed Rulemaking 2015 Notice of Proposed Rulemaking (NPRM) Published on SEP 08, Final Rule Published date: JAN 19, 2017 Effective date: JAN 19, Interim Final Rule Final revisions delayed Till JUL 19, 2018 Timeline of Local Regulations 1977 Medicines Act 2007 Health Products Act 2014 to 2015 MOH Public Consultation for HBRA (6 Nov 2014 to 15 Jan 2015) 2015 Enacted as Human Biomedical Research Act (Aug 2015) 2016 Stakeholder Communication Sessions for HBRA 2017 Prohibition against commercial trading of human tissue (1 JAN 2017) 2017 MOH Online Consultation for HBRA (1 Mar to 15 Apr 2017) 2017 Human Biomedical Research Regulations In Force (1 Nov 2017) 7

8 Major Changes to the Interim Final Rule: 1 Eliminating continuing review requirement for minimal risk research 2 Establish new exemption categories of research 3 Revised Informed Consent Form 4 Broad Consent may be obtained on stored identifiable information or identifiable biospecimens 5 Single IRB-of-Record (sirb) Continuing review is not required for certain minimal risk research. Establishing new exempt classification of research in accordance to the level of risk posed to subjects. Categories include research that require limited IRB review or low risk research that is self-determinating. The Informed Consent Form is revised and the information is designed to aid the subject s understanding of the research in order to make an informed decision. Broad Consent may be obtained in lieu of informed consent for stored and secondary uses of identifiable data and biospecimens. For most federally-funded collaborative research projects located in the U.S., a single IRB have to be appointed for U.S. institutions engaged in multi-site. For studies that complies with National Institutes of Health (NIH) policy on sirb review, the effective date is 25 Jan JUL, JUL, JUL, JUL, JAN,2020 (Except for NIH sirb: JAN 25, 2018) 8

9 RIE2020 Strategic Goals RIE2020 Strategic Goals (Health and Biomedical Sciences): Develop framework that enhances research to improving public health Emphasis to help the public contain economic means of healthcare costs To enhance delivering efficient healthcare services REGULATIONS RESEARCH How is HBRA aligned with RIE2020 Objectives? HBRA provides a guideline and standard on ethical and regulatory issues in biomedical science industry To strive for research development and advancement, at the same time safeguarding human welfare and ethics 9

10 Challenges Faced by Organization Establish Policy and Procedures to meet specific standards System for tracking research (conduct and performance) Modular approach to address risk Higher risk studies Tighter governance Lower risk studies Lighter control Key areas of compliance: Regulatory reporting (Eg. SAE, contraventions) Organizational Tissue Banking framework Declaration Relevant Quality Management System (QMS) Financing 10

11 How Organization is Addressing? A more responsive and flexible organizational structure Alignment of policies across institutions - Ensure highest standard of service to stakeholders and patients Establish a relevant Quality System complying with legal and regulatory requirements - ICH GCP, GxP guidelines, HBRA Periodic reviews of a relevant Quality System to ensure continuous improvement - Measuring performance and acting on basis of KPIs (metrics) Ensuring employee awareness and understanding of QMS through training and education programmes 11

12 Monitoring strategies Requested Review: once-off review based on request from IRB. A follow up visit will be made to review outcomes of findings noted. IRB will recommend further actions after RCM provides the report from the follow-up visit. Self-Monitoring: Self-directed monitoring by PI or person designated by PI. Remote Monitoring: Off-site review using available electronic records and data (i-share, ROAM, e-hints). On-site visits only in exceptional situations (e.g. when site is unable to provide necessary information for an adequate review). Excludes SDV/SDR. Snapshot Monitoring: Once-off on-site visit followed by off-site review until study completion. SDV/SDR on sample of subjects. Sequential Monitoring: Short-term on-site visits followed by off-site review until study completion. SDV/SDR on sample of subjects Risk-Based Monitoring: Continuous monitoring using risk-based approach. Monitoring activities and frequency of on-site visits or centralised monitoring are dependent on occurrence of Key Risks Indicators (KRIs) and associated thresholds. SDV/SDR on sample of subjects. 12 Workstream #2_EXCO_27Feb2018

13 Combating Challenges Accountability To assure research integrity and ethical conduct Adequate resources To assure that sufficiently robust governance activities are in place Ethics education programs To provide research personnel and oversight committees with the knowledge necessary to carry out their obligation to conduct or oversee ethically sound research Transparency To ensure open communication and interaction with the research community: research participants, investigators, and other stakeholders 13

14 Challenges Faced by Researcher Ethical conduct Obtaining consent for research Handling consent for collection of biological materials for future research Ongoing oversight and monitoring Ongoing monitoring activities such as protocol review processes should be correlated to the level of risk posed to participants Need to monitor adverse events, unanticipated problems, and changes to a protocol and their subsequent incorporation into the informed consent process Compliance in study conduct Sound research design Implementing fair and equitable recruitment practices Regulatory Reporting Broad Consent and Incidental Findings 14

15 Obtaining Consent ICH-GCP HBRA Subject unable to read (Illiterate or unable to read due to visual impairment) Impartial witness should be present Does not require witness to be impartial. SingHealth will adopt the use of impartial witness for illiterate subjects Specific HBRA elements for Human Biological Materials -- Specific language required for subject to be informed on Challenges: Difference in witness requirement SingHealth will adopt the use of impartial witness for illiterate subjects. For literate subjects in HBRA studies, the witness can be the study team member. Consent for future research (Broad Consent ) 15

16 Regulatory Reporting ICH-GCP HBRA Reporting of Unexpected SAE: Death/Life Threatening Reporting of Unexpected SAE: Non-Death/Non Life Threatening Expected SAE: Definitely / Probably / Possibly Related Non-compliance Similar timeline. Initial report is submitted within 7 days. Additional report is reported within 8 additional days Similar timeline. Report is submitted within 15 days No reporting to HSA is required Serious Breaches to be reported No reporting to MOH is required. Internal reporting is required from PI to RI immediately Contraventions to be reported Challenges: Regulatory Reporting may cause confusion due to cross clusters recognitions Broad definition for contraventions SingHealth will adopt the definitions of HSA Serious Breach for MOH reporting of contraventions 16

17 Broad Consent Is it Ethical? Why is Broad Consent not Ethical? Broad Consent is an act of paternalism Does not attain the principle of autonomy Disrespectful of the donor, subject should have an informed choice whether to donate their human biological sample Why is there a need for Broad Consent? Researchers argue the importance of remaining/ left-over tissues and cells for research purposes Dynamic Consent while superficially appealing suffers from more ethical flaws 17

18 Broad Consent Paramount importance to obtain prior consent from subjects before using human biological materials for future research Respectful of subject s decision whether to donate human biological material for future research Allows donors to make decisions on whether to contribute to research which may have no direct benefit to them Gaining public trust and awareness by being transparent and open to the public about research aims and procedure Technical issues (To be discussed at Tissue Framework session) 18

19 Incidental Findings Incidental Finding (IF): a finding about a research subject that has potential health or reproductive importance to the research subject and is discovered in the course of conducting research but is unrelated to the purposes, objectives or variables of the study Technology has outpaced the capacity of researchers and has produced massive amounts of information Images, scans and data (Neuro-imaging scans, Computed Tomography (CT) Colonography research, Genomic Microarray research) Significant potential for IF to reveal unexpected information about the genetics of subject participants Investigators face ethical dilemma when IF is surfaced: Must the investigator disclose IF to the research subject? Hard to draw the line between physician duties to patients and researcher duties to human research participants in bioethics and health law Absence of systematic ethical analysis of the reporting of incidental findings 19

20 Incidental Findings Scope and Limitations 1) Physician s Professional Duties - Accountable and responsible to evaluate IFs that arises - Review possibility of IFs with subjects during informed consent - Responsible to alert subjects of potential health problem 2) General Beneficence - T.M. Scanlon proposes 2 dimensions: - Rescue Principle general duty of rescue - Helpfulness Principle 3) Risk of False-Positive Error and False-Negative Error. Disclosing incidental findings carries risks of distress to the subject False-Positive Error: Reporting a finding that turns out to be of no clinical significance False-Negative Error: Failing to report a finding linked to a serious health problem 20

21 How Combating the Challenges: Ethical Conduct Ensure proper consent obtained Ongoing Oversight and Monitoring Ensure all protocols received IRB review and approval Promptly report any unanticipated problems involving risks to subject or others to the IRB Promptly report any serious or continuing non-compliance with regulations Compliance in Study Conduct Comply with all sponsor requirements, when applicable Comply with IRB s determinations and stipulations Prevent a lapse in IRB approval, Eg researchers submit all continuing review applications at least 1 month prior to the expiration date of the study Training and Education To provide research personnel and oversight committees with the knowledge necessary to carry out their obligation to conduct or oversee ethically sound research 21

22 Challenges Faced by IRB RI to appoint an Institutional Review Board (IRB) which will perform the key functions for protocol review. Building a culture of trust and respect in the protection and welfare of human rights - Shared responsibility between RI, IRB and Researchers - IRB has huge responsibilities to uphold regulatory record keeping process - IRB ensure Institutions and Researchers abide to the regulations enforced Waiver of Consent - IRB will play a key part when waivers are granted for informed consent - Greater public good 22

23 Waiver of Consent HBRA (for RESEARCH INVOLVING INFORMATION OR HUMAN BIOLOGICAL MATERIAL EFFECTIVE 1 NOV 2017) a) the research cannot reasonably be carried out without the use of the human biological material or health information in an individually-identifiable form; aa) the process of obtaining consent from the person, to which the individually-identifiable human biological material or health information relates, will involve a disproportionate amount of effort and resources relative to the research requirements; b) the use of the individually-identifiable human biological material or health information, as the case may be, involves no more than minimal risk to the research subject or donor; PDPA 1.The research purpose cannot reasonably be accomplished unless the personal data is provided in an individually identifiable form; 2. It is impracticable for the organisation to seek the consent of the individual for the use; 3. The personal data will not be used to contact persons to ask them to participate in the research; AND 4. Linkage of the personal data to other information is not harmful to the individuals identified by the personal data and the benefits to be derived from the linkage are clearly in the public interest. c) the waiver concerned will not otherwise adversely affect the rights and welfare of the research subject or donor; and d) the human biomedical research or health information research would reasonably be considered to contribute to the greater public good. 23

24 Greater Public Good SG: Bioethics Advisory Committee (BAC) Respect for individuals can be subordinate to the public interest, but only in certain minimal risk research, typically: (i) (ii) Public health and Epidemiological research based on the principle of solidarity U.S. Department of Health & Human Services Examples of Public benefit under Exemption 45 CFR (b)(5) (for Public Benefit or Service Programs) Public Benefit (eg. Financial or medical benefits as provided under the Social Security Act) or service (eg. social, supportive, or nutrition services as provided under the Older Americans Act) England There are five main principles which show whether an organization provides benefit to the public. These are: The Benefit: i. There must be an identifiable benefit, but this can take many different forms. ii. Benefit is assessed in the light of modern conditions The Public: iii. The benefit must be to the public at large, or to a sufficient section of the public. iv. Any private benefit must be incidental. v. Those who are less well off must not be entirely excluded from benefit Latvia, Europe Public Benefit Law Public Benefit Law, Latvia Section 2 A public benefit activity is an activity, which provides a significant benefit to society or a part thereof, especially if it is directed towards charitable activities, protection of civil rights and human rights, development of civil society, education, science, culture and promotion of health and disease prophylaxis, support for sports, environmental protection, provision of assistance in cases of catastrophes and extraordinary situations, and raising the social welfare of society, especially for lowincome and socially disadvantaged person groups. 24

25 Collective Responsibility: RI, IRB and Researchers Local system of regulations of human biomedical research is most effective when RI, IRB and Researchers acknowledge a collective responsibility to maintain the standards of quality research Highest ethical standards are set Building a culture of trust and respect by promoting accountability and transparency in the regulations systems Collective Responsibility: RI, IRB and Researchers MOH Steven Peckman, Instituitonal Review Board Management and Function 25