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  • 1. INVESTIGATORMANUALAll That An Investigator Needs To Know
  • 2. 1st Edition: August 2009© National Healthcare Group, Research & Development Office, Singaporewww.b2bresearch.nhg.com.sgAll rights reserved. No part of this publication may be reproduced, stored in a retrieval systemor transmitted in any form or by any means, electronic, mechanical, photocopying, recording orotherwise without the permission of NHG Research & Development Office.Participating InstitutionsTan Tock Seng Hospital • National University Health System • Institute of Mental Health •National Skin Centre • Alexandra Hospital • National Healthcare Group Polyclinics •
  • 3. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 4. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 5. Chapter 01: Research Governance 1.1 NHG Human Subjects Protection Program (HSPP) 1 1.2 The Role And Structure Of Domain Specific Review Board (DSRB) 2 1.3 The Role Of Institutions (Investigators, Department Representatives, Institutional Representatives) 3 1.4 The Definition Of Research 6Chapter 02: Principles Of Research Ethics 2.1 Ethical Research 15 2.2 The Belmont Report 16 2.3 Code Of Ethical Practice In Human Biomedical Research 17Chapter 03: Overview Of Application And Review Process 3.1 Application Process 19 3.2 Review Process 21 3.3 Outcome Of Review 23 3.4 Post Approval Reporting Requirements 24Chapter 04: Submissions To DSRB 4.1 New Applications 26 4.2 Study Amendments 29 4.3 Continuing Review / Renewal 32 4.4 Unanticipated Problems Involving Risks To Subjects 35 Or Others (UPIRTSO) 4.5 Non-Compliance 40 4.6 Study Closure 44Chapter 05: Review Process 5.1 Exempt Review 46 5.2 Non-Exempt Review 49 5.3 Criteria For Approval 55Chapter 06: Outcome Of Review 57Chapter 07: Appeals To DSRB Decision 58
  • 6. Chapter 08: Guidance On Key Ethical Issues 8.1 Informed Consent 59 8.2 Recruitment Strategy 72 8.3 Risk / Benefit Assessment 76 8.4 Data And Safety Monitoring 79 8.5 Privacy And Confidentiality 84 8.6 Conflict Of Interest 85 8.7 Research In Vulnerable Population 87 8.8 Compensation For Research Related Injuries 103 8.9 Standing Database & Tissue Banking 107Chapter 09: Minimum Qualifications And Training To BeAn Investigator 9.1 Who Can Be A Principal Investigator? 113 9.2 Minimum Training Requirements 115Chapter 10: Responsibilities Of Investigator 117Chapter 11: Preparing For Audit 124Chapter 12: Suggested Readings 127Chapter 13: Appendices a. Participant Information Sheet Checklist 128 b. Short Form Consent - An Example 132 c. Waiver Of Documentation Of Consent - Examples 134 d. Waiver Of Consent – Examples 136 e. Investigator File Content 138 f. Pre Audit Checklist 142 g. Possible Questions During An Audit 146 h. Study Review Checklist 148 i. Applicable Fees 153
  • 7. 1.01.0RESEARCH GOVERNANCE1.1 NHG Human Subjects Protection Program (HSPP)1.2 The Role And Structure Of Domain Specific Review Boards (DSRB)1.3 The Role Of Institutions (Investigators, Department Representatives, Institutional Representatives)1.4 The Definition Of Research
  • 8. 1.1 NHG HUMAN SUBJECTS PROTECTION PROGRAM (HSPP)NHG Human Subjects Protection Program (HSPP) aims to promote highquality and ethical research, and to ensure protection of human subjectsparticipating in research in NHG, and all institutions under the oversight ofNHG DSRB (herein after referred to as “Institutions”). All parties engagingin research involving human subjects have a part to play to ensure thatthe rights, safety, and well being of research subjects are safeguarded.The NHG HSPP is under the oversight of the Research Ethics Committee(REC), which is appointed by the NHG Chairmen of Medical Boards (CMB)Committee. The REC develops and implements policies and proceduresrelated to human subjects protection, including both the Domain SpecificReview Board (DSRB) and the Research Quality Assurance Program. 1 1.1 NHG HUMAN SUBJECTS PROTECTION PROGRAM (HSPP)
  • 9. 1.2 THE ROLE AND STRUCTURE OF DOMAIN SPECIFIC REVIEW BOARD (DSRB) The DSRB is an independent committee constituted of medical, scientific and nonscientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a research study by, among other things, reviewing, approving, and providing continuing review of research studies, of protocols and amendments, and of the methods and materials to be used in obtaining and documenting informed consent of the research subjects. The DSRB is made up of five or more domains, and the domains are based on broad but related disease groupings. The NHG CMB Committee appoints members to the DSRB. Each domain will consist of at least five (5) members, who collectively have the qualifications and experience to carry out the DSRB’s stated objectives and terms of reference to review and evaluate the ethical and scientific aspects of the2 proposed research studies. Other officials of institutions which conduct research under the oversight of NHG DSRB, may not override the decision of DSRB (or REC, where applicable).1.2 THE ROLE AND STRUCTURE OF DOMAIN SPECIFIC REVIEW BOARD (DSRB)
  • 10. 1.3 THE ROLE OF INSTITUTIONS (INVESTIGATORS, DEPARTMENT REPRESENTATIVES, INSTITUTIONAL REPRESENTATIVES) The DSRB, as well as the Institutions, must approve a research proposal before it can be conducted in the Institutions. The protection of human subjects in research is a collaborative effort by DSRB and all Institutions. While the DSRB is an independent review committee responsible for ensuring that the research proposal protects the well-being, safety and rights of the research subjects, each Institution ensures that the proposal is in keeping with its overall research direction, objectives, standards and image. Principal Investigator, Co-Investigators and Other Study Team Members The “Principal Investigator” is the overall responsible person for the 3 proper conduct of research. In general, each study can have only one Principal Investigator who is responsible for the conduct of the clinical study. The other members of the research team should be listed as Co- Investigators / Collaborators. The Principal Investigator, Co-Investigators, and all study team members have the responsibility to comply with DSRB policies and applicable regulatory requirements. For multi-centre studies within NHG, and all institutions under the oversight of NHG DSRB, each institution should have a Site Principal Investigator who is responsible for the conduct of the study in his / her institution. One of the Site PIs should be designated as Principal Investigator for the study, who is responsible for the coordination of investigators at different institutions participating in the multi-centre study, including but not limited to communication with the DSRB. For more information Refer to Chapter 10 Responsibilities of Investigator.1.3 THE ROLE OF INSTITUTIONS (INVESTIGATORS, DEPARTMENT REPRESENTATIVES, INSTITUTIONAL REPRESENTATIVES)
  • 11. Department Representative The “Department Representative” (DR) plays a key role in assuring that a research study is keeping with the research objectives, image and standards of the relevant departments and institutions. The role of a DR is to provide an overview assessment of the significance, concept, and innovation of a research study; and whether the Principal Investigator is adequately trained, qualified, possesses sufficient time and resources to carry out the research study. The DR will endorse all applications made to the DSRB. The DR would generally be the Head / Chief or Department Research Head of the Principal Investigator’s department. In some departments, alternative persons may be appointed as DRs, provided he / she is able to adequately perform the responsibilities of a DR. Where there is a potential conflict of interest for the DR, the alternative DR or the Reporting Officer of the DR (e.g. Division Head or CMB) should fulfill this role. Where appropriate and available, the Head / Chief of a Division (e.g.4 Division of Medicine) who oversees several departments may comment in lieu of one of his / her Head / Chief of department. For an application that involves more than one department (whether in the same institution or otherwise), only the DR of the Principal Investigator is required to endorse the application. It is the Principal Investigator’s responsibility to ensure that the DRs of the other departments are in agreement to endorse the research study to be carried out in that department. Wherever appropriate and necessary, the DSRB may require endorsements from the DRs of all participating departments.1.3 THE ROLE OF INSTITUTIONS (INVESTIGATORS, DEPARTMENT REPRESENTATIVES, INSTITUTIONAL REPRESENTATIVES)
  • 12. Institutional Representative The “Institutional Representative” (IR) is the authority to approve any research study to be conducted in the institution. This authority lies with the CMB and CEO of that institution. The IR considers if the research is in keeping with the institution’s research objectives, image and standards. In general, the IR’s role is not to review the scientific or ethical merits of the research study, which will be considered by the DSRB or a grant approving body (if one is applying for a grant). The IR will endorse all applications made to the DSRB. This authority is generally delegated to either one of the following:- a. the Director of Research (or equivalent), OR b. the Chairperson of a specially appointed committee for this purpose. Where there is a potential conflict of interest for the IR, the CEO/CMB should fulfil this role. 5 For multi-centre studies within NHG, the IRs will endorse the application for his/her institution. In the B2BResearch Online system, the DRs and IRs of each department and institution have been pre-determined by individval departments and institutions to enable automatic routing of applications for endorsement. For more information Details on electronic endorsement process are available online at http://www.b2bresearch.nhg.com.sg (Downloads) and in the Online Manual (for DRs and IRs).1.3 THE ROLE OF INSTITUTIONS (INVESTIGATORS, DEPARTMENT REPRESENTATIVES, INSTITUTIONAL REPRESENTATIVES)
  • 13. 1.4 THE DEFINITION OF RESEARCH All research involving patients, staff, premises, or facilities of NHG institutions and all Institutions under the oversight of NHG DSRB must be reviewed and approved by NHG DSRB prior to initiation. All research reviewed and approved by the DSRB must comply with NHG DSRB requirements as outlined in the NHG DSRB Investigator Manual. The DSRB requirements are based on Declaration of Helsinki and the ethical principles in the Belmont Report. The DSRB requirements are also compliant with the Bioethics Advisory Committee’s recommendations outlined in the Guidelines for Institution Review Boards, November 2004. Research conducted in NHG may also be subject to other guidelines and applicable regulations such as: a. US Department of Health and Human Services (DHHS) Regulations 45 CFR 46 – when the research is funded by US Federal Funds6 e.g. funded by NIH, NCI, NIAIDS etc. b. US Food and Drug Administration (FDA) Regulations 21 CFR 56, 21 CFR 50 – when the research is being conducted under an Investigational New Drug (IND) Application or Investigational Device Exemptions (IDE) or when the results of research are intended to be submitted to FDA. c. Singapore Guideline for Good Clinical Practice (SGGCP) – All clinical trials involving medicinal products are subject to SGGCP. d. Medicines Act and Medicines (Clinical Trials) Regulations 2000 – All clinical trials involving medicinal products are subject to the Medicines Act and Medicines (Clinical Trials) Regulations 2000. Medicines Act and Medicines (Clinical Trials) Regulations The definition of clinical trial under Medicines Act (Chapter 176): CLINICAL TRIAL means an investigation or series of investigations consisting of the administration of one or more medicinal products of a particular description by, or under the direction of:1.4 THE DEFINITION OF RESEARCH
  • 14. a. a doctor or dentist to one or more of his patients; or b. two or more doctors or dentists, each product being administered by or under the direction of one or other of those doctors or dentists to one or more of his patients, where (in any such case) there is evidence that medicinal products of that description have effects which may be beneficial to the patient or patients in question and the administration of the product or products is for the purpose of ascertaining whether, or to what extent the product has, or the products have, those or any other effects, whether beneficial or harmful.MEDICINAL PRODUCT means any substance or article (not beingan instrument, apparatus or appliance) which is manufactured, sold,supplied, imported or exported for use wholly or mainly in either or bothof the following ways: a. use by being administered to one or more human beings or animals for a medicinal purpose; 7 b. use as an ingredient in the preparation of a substance or article which is to be administered to one or more human beings or animals for a medicinal purpose.MEDICINAL PURPOSE means any one or more of the followingpurposes: a. treating or preventing disease; b. diagnosing disease or ascertaining the existence, degree or extent of a physiological condition; c. contraception; d. inducing anaesthesia; e. otherwise preventing or interfering with the normal operation of a physiological function, whether permanently or temporarily, and whether by way of terminating, reducing or postponing, or increasing or accelerating, the operation of that function or in any other way. 1.4 THE DEFINITION OF RESEARCH
  • 15. SUBJECT means a person to whom the test material is to be administered in a clinical trial. CLINICAL TRIAL CERTIFICATE (CTC) a. In accordance with the Medicines (Clinical Trials) Regulations, no person shall conduct a clinical trial, without a valid Clinical Trial Certificate (CTC) issued by the Health Sciences Authority. b. The Principal Investigator (holder of the certificate) is responsible for applying to the Health Sciences Authority for the certificate. c. Every Sponsor, Principal Investigator or holder of certificate shall comply with any guidelines or instructions relating to conduct of clinical trials issued by the Health Sciences Authority, including Singapore Guideline for Good Clinical Practice (SGGCP). Depar tment of Health and Human Ser vices8 (DHHS), USA The definition of research and other related terms under DHHS: RESEARCH is a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalisable knowledge. RESEARCH SUBJECT OR PARTICIPANT is a living individual about whom an investigator conducting research obtains data through intervention or interaction with individual, or identifiable private information. INTERVENTION includes both physical procedures by which data are gathered and manipulations of the participant or participant’s environment that are performed for research purposes. INTERACTION includes communication or interpersonal contact between investigator and participant. PRIVATE INFORMATION includes information about behaviour that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has1.4 THE DEFINITION OF RESEARCH
  • 16. been provided for specific purposes by an individual and which theindividual can reasonably expect will not be made public (for example,a medical record). Private information must be individually identifiable(i.e., the identity of the subject is or may readily be ascertained by theinvestigator or associated with the information) in order for obtainingthe information to constitute research involving human subjects.ENGAGED – An institution becomes “engaged” in a particular non-exempt human subjects research when its employees or agents for thepurposes of the research project obtain: (1) data about the subjects of theresearch through intervention or interaction with them; (2) identifiableprivate information about the subjects of the research; or (3) the informedconsent of human subjects for the research.EMPLOYEE OR AGENT – An institution’s employees or agents referto individuals who: (1) act on behalf of the institution; (2) exerciseinstitutional authority or responsibility; or (3) perform institutionallydesignated activities. “Employees and agents” can include staff, students, 9contractors, and volunteers, among others, regardless of whether theindividual is receiving compensation.Food and Drug Administration (FDA), USAThe definition of clinical investigation and other related terms under FDA:CLINICAL INVESTIGATION is any experiment that involves a test articleand one or more human participants and that is one of the following: a. Subject to requirements for prior submission to Food and Drug Administration; or b. Not subject to requirements for prior submission to Food and Drug Administration, but the results of which are intended to be submitted later to, or held for inspection by Food and Drug Administration as part of an application for a research or marketing permit. 1.4 THE DEFINITION OF RESEARCH
  • 17. HUMAN SUBJECT means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. TEST ARTICLE means any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to FDA regulation. UNDER FDA IDE the definition of human subject is a human who participates in an investigation either as individual or on whom or on whose specimen an investigational device is used or as a control. Singapore Guideline for Good Clinical Practice (SGGCP) The definition of clinical trial / study under the SGGCP:10 CLINICAL TRIAL / STUDY – Any investigation in human subjects intended to discover or verify the clinical, pharmacological and / or other pharmacodynamic effects of an investigational product(s), and / or to identify any adverse reactions to an investigational product(s), and / or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and / or efficacy. The terms clinical trial and clinical study are synonymous. SUBJECT / TRIAL SUBJECT – An individual who participates in a clinical trial; either as a recipient of the investigational product(s) or as a control. Bioethics Advisory Committee (BAC) Guidelines for IRBs The definition of research and other related terms under the BAC: DIRECT HUMAN BIOMEDICAL RESEARCH comprises any kind of human research that involves:1.4 THE DEFINITION OF RESEARCH
  • 18. a. any direct interference or interaction with the physical body of a human subject, and b. that involves a concomitant risk of physical injury or harm, however remote or minor c. Examples – A research programme would qualify as Direct Human Biomedical Research if it involves i. the administration of any drug (whether it is for the purpose of testing the effects or efficacy of the drug, or ii. whether it is a means for establishing any other objective of the research programme), or iii. the trial or use of a medical device on a human subject, or iv. any test of a human subject’s physiological, emotional or mental responses (not being tests conducted for diagnostic purposes with a view to the therapeutic management of a patient). 11INDIRECT HUMAN BIOMEDICAL RESEARCH comprises any researchthat does not qualify as Direct Human Biomedical Research, and a. that involves i. human subjects, or ii. human tissue, or iii. medical, personal or genetic information relating to both identifiable and anonymous individuals, and b. that involves that is undertaken with a view to generating data about i. medical, genetic or biological processes, diseases or conditions in human subjects, or ii. of human physiology, or iii. the safety, efficacy, effect or function of any device, drug, diagnostic, surgical or therapeutic procedure (whether invasive, observational or otherwise); 1.4 THE DEFINITION OF RESEARCH
  • 19. Indirect Human Biomedical Research also comprises of research that is conducted in human subjects whether as one of the objectives or the sole objective, of the research study, trial or activity, and that has the potential to affect the safety, health, welfare, dignity or privacy of i. the human subjects involved in the study, or ii. of donors of human tissue or information used in the research, or iii. of the family members of any of the human subjects or donors thereof, or iv. to which such medical, personal or genetic information relates. Some Examples Activities that involve systematic investigation and are designed to develop or contribute to generalisable knowledge are considered research and12 will require review and approval by NHG DSRB. This includes clinical trials, epidemiological research, retrospective medical records review research, and genetic research. CASE REPORTS – Case reports do not involve systematic investigation; however the intent is to contribute to generalisable knowledge. Case reports are not considered to be human subjects research. CASE SERIES – A series of 3 or more subjects qualifies as a research project and hence should be submitted for review and approval by the DSRB prior to initiation. DATABASE STUDIES – Research proposals for setting up a database require DSRB review and approval. Databases that are not created for the sole purposes of research do not require review by the DSRB, such databases are termed as Standing Databases and need to be registered with NHG Research and Development Office. However when data from these databases is used for research related projects, each of these projects would require DSRB review prior to initiation.1.4 THE DEFINITION OF RESEARCH
  • 20. TISSUE REPOSITORIES – Operation of Human Tissue Repositories andits data management centre are subjected to oversight by the DSRB. TheDSRB will review and approve protocols specifying the conditions underwhich data and specimens may be accepted and shared, and ensuringadequate provisions to protect the privacy of subjects and maintain theconfidentiality of data. The DSRB will also review and approve a samplecollection protocol and consent document.QUALITY ASSESSMENT AND IMPROVEMENT (QA/QI) – Activitiesdesigned to determine if aspects of medical practice are in line withestablished standards are called quality assessment. When an activity isdesigned to improve the performance of medical practice in relation toan established standard, it is called quality improvement. These projectsinvolve systematic investigation and usually contribute to generalisableknowledge. Any QA or QI activity where participants are subjectedto additional risks or burdens beyond usual clinical practice will bereviewed as research. 13OUTBREAK INVESTIGATIONS – Outbreak investigations are importantactivities that benefit public health. Subjecting these to research standardsmight compromise these activities. So such activities are not consideredto be research and hence do not require DSRB review. However anyinterventional studies conducted during an outbreak would requirereview and approval by the DSRB and / or other clinical Committees.The DSRB will make an effort to expedite the review and approvalprocess for such protocols.DISEASE MANAGEMENT – Disease Management projects that do notrequire the participants to undergo additional burdens or risks do notrequire review and approval by the DSRB.INFECTION CONTROL – Investigations carried out as part of aninfection control program are not considered as research and these donot require review by the DSRB. 1.4 THE DEFINITION OF RESEARCH
  • 21. Determination of Research Status There are many research-like activities that are conducted as part of quality improvement, infection control, disease management etc., that may not meet the definition of research and hence do not need DSRB review and approval. Further, new innovative therapies used by many doctors during their clinical management of patients, may not necessary meet the definition of research as well. Given the vague boundary between research and non-research, the Principal Investigator must ascertain which regulations are applicable and then apply the definitions for research as described above. When in doubt whether an activity requires DSRB review and approval, the Principal Investigator must write to the DSRB with a summary of the proposal. The DSRB will review the information and make a determination whether or not the described activity meets the definition of research. The DSRB will then send a written notification to the Principal Investigator with the final determination.141.4 THE DEFINITION OF RESEARCH
  • 22. 2.02.0PRINCIPLES OFRESEARCH ETHICS2.1 Ethical Research2.2 The Belmont Report2.3 Code Of Ethical Practice In Human Biomedical Research
  • 23. 2.1 ETHICAL RESEARCHEthical Research is research that: a. Upholds the core ethical principles of respect for persons, beneficence and justice. b. Protects rights, safety and well-being of human subjects. c. Compliant with all applicable regulations and guidelines. 15 2.1 ETHICAL RESEARCH
  • 24. 2.2 THE BELMONT REPORT The Belmont Report describes THREE core ethical principles for human subject research: a. Respect for persons – recognition of the personal dignity and autonomy of individuals and special protection of these persons with diminished autonomy, e.g. the need to obtain informed consent. b. Beneficence – entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm, e.g. the need to engage in a risk / benefit analysis and to minimize risks. c. Justice – requires that the benefits and burdens of research be distributed fairly, e.g. the need to have a reasonable inclusion and exclusion criteria.16 The NHG Human Subjects Protection Program follows the ethical principles of The Belmont Report.2.2 THE BELMONT REPORT
  • 25. 2.3 CODE OF ETHICAL PRACTICE IN HUMAN BIOMEDICAL RESEARCH (MOH)The credibility of human biomedical research with society is dependentupon the maintenance of the highest ethical standards in its conduct.Research is ethically justifiable only if it is scientifically sound and does notexpose research subjects to unwarranted discomfort or risks without likelybenefit to the advancement of biomedical science. Research should alsoabide by accepted moral standards within the community and be carriedout responsibly, in ways that respect and protect the research subjects, andmaintain scientific integrity to promote trust and accountability.Researchers have a personal and non-delegable responsibility to ensurethe ethical conduct of their research. This Code lays down principles andstandards for ethical practice in human biomedical research in Singapore.Researchers should use this Code as a yardstick for their conduct andbehavior. In addition, researchers should have an understanding ofresearch ethics, develop the knowledge, skills and attitude needed to 17manage ethical conflicts, and to consult with colleagues, ethics committeesand other experts when ethical issues arise.Researchers are to uphold the principles fundamental to the protection ofhuman subjects. In general, researchers are expected to: a. Respect persons as individuals: i. obtain fully informed consent from subjects who are autonomous; ii. accord due protection to persons with diminished autonomy and who are vulnerable; iii. protect subject privacy and maintain data confidentiality at all times; b. Strive to promote the well-being and safety of human research subjects, protecting them from unnecessary risks, and never let the goals of research undermine this priority; 2.3 CODE OF ETHICAL PRACTICE IN HUMAN BIOMEDICAL RESEARCH
  • 26. c. Abide by local laws, regulations, guidelines and commonly agreed standards of good practice on the conduct of human biomedical research; d. Embody professionalism by upholding integrity, openness, and a commitment to intellectual honesty in the conduct of research, and avoid any actual, potential or apparent conflict of interest; e. Exercise responsible custodianship of resources under their charge and be a responsible steward in the use and management of those resources; f. Treat all fellow researchers with dignity and respect, and managing researchers under their supervision with care; g. Observe the Code in all respects of their professional lives. For more information18 The Belmont Report is available online at http://www.hhs.gov/ohrp The Code of Ethical Practice in Human Biomedical Research is available online at http://www.moh.gov.sg2.3 CODE OF ETHICAL PRACTICE IN HUMAN BIOMEDICAL RESEARCH
  • 27. 3.0 3.0OVERVIEW OF APPLICATIONAND REVIEW PROCESS3.1 Application Process3.2 Review Process3.3 Outcome Of Review3.4 Post Approval Reporting Requirements
  • 28. 3.1 APPLICATION PROCESS Endorsement Process by Institution Prior to making a submission to the DSRB, Investigators are required to obtain endorsements from their Department Representative and Institution Representative.For more informationRefer to Chapter 1.3 The Roles of Institutions. Submitting a Research Study to DSRB The submission deadline for new research studies is the first working day of each month (except December), or the next working day, if the first falls on a weekend or public holiday. 19 Research studies that qualify for expedited review, applications with request for exemption, or minor amendments to DSRB approved research studies may be submitted at any time of the month. All new applications are to be submitted online via http://www.b2bresearch.nhg.com.sg Triaging All research studies submitted to the DSRB for review will undergo appropriate in-depth review by triaging the research study to the DSRB that includes expert(s) in the disease group(s) that is (are) being studied in the study. The Principal Investigator should indicate the most appropriate DSRB in the B2BResearch Online Application Form. The DSRB will evaluate the Principal Investigator’s choice of DSRB based on the following considerations: 3.1 APPLICATION PROCESS
  • 29. a. PRINCIPAL INVESTIGATOR’S DISCIPLINE – A research study will be triaged to the DSRB that includes his / her discipline. b. DISEASE STUDIED IN THE RESEARCH STUDY – Depending on the primary disease group that is being studied in the research study, the study will be triaged to the DSRB that includes experts in this disease group. Where there is uncertainty about which domain a study should be triaged to, the decision will be escalated to the Triage Board. The Triage Board is a virtual board consisting of the DSRB chairpersons or their deputies. For more information Refer to Chapter 4.1 New Applications. Details on how to complete the B2BResearch Online DSRB Application20 Form are available online at http://www.b2bresearch.nhg.com.sg ( D o w n l o ads ) an d i n t h e On l i n e Ma n u a l . Details on the latest information on the disease groupings in DSRB are available online at http://www.b2bresearch.nhg.com.sg.3.1 APPLICATION PROCESS
  • 30. 3.2 REVIEW PROCESSAll research studies submitted will be classified under one of the followingreview categories: a. Exempt Review b. Expedited Review c. Full Board ReviewThe determination of the review category is made by the DSRB. In general,the determination is based on the level of risk in which research participantsis exposed to. Research studies that involve minimal or less than minimalrisk are reviewed under the Exempt or Expedited review categories, andstudies that involve more than minimal risk are reviewed under Full BoardReview category. a. EXEMPT REVIEW – Research studies that involve anonymous 21 surveys & questionnaires, collection or study of anonymous existing data or tissue specimens, where data / tissue are either publicly available or subjects cannot be identified, or Public Benefit Programs may qualify for review by Exempt Review category. b. EXPEDITED REVIEW – Research studies that involve collection of data or biological samples via non-invasive procedures, medical case-notes review, surveys or interviews, may qualify for review by Expedited Review category. c. FULL BOARD REVIEW – Research studies that do not qualify for Exempt or Expedited Review category will be reviewed under Full Board Review category. Such studies may include research studies that involve the study of the safety and efficacy of a medicinal product, medical device, or research study that involve invasive procedures.For more information Refer to Chapter 5.1 Exempt Review and Chapter 5.2 Non-Exempt Review. 3.2 REVIEW PROCESS
  • 31. Review Criteria All research studies that intend to enroll human subjects must meet certain criteria before study procedures can be initiated. The criteria are based on the principles of autonomy, beneficence and justice as discussed in the Belmont Report. In general, a research study must fulfill the following criteria: a. Risks are minimized, and are reasonable in relation to anticipated benefits. b. Selection of subjects are equitable. c. Informed Consent will be sought, and appropriately documented. d. Adequate provision for monitoring of data to ensure safety, protection of privacy of research participants and confidentiality of data collected.22 e. Additional protection for vulnerable populations. For more information Refer to Chapter 5.3 Criteria for Approval.3.2 REVIEW PROCESS
  • 32. 3.3 OUTCOME OF REVIEWFollowing the review of a research study, the DSRB will reach one of thefollowing decisions: a. approve, b. conditionally approve, c. table for next convened meeting, or d. not approveA research study that is reviewed under Exempt or Expedited Reviewcategory cannot be disapproved. Instead, it will be escalated to the nextlevel of review or approved with modifications.For more informationRefer to Chapter 6.0 Outcome of Review. 23 3.3 OUTCOME OF REVIEW
  • 33. 3.4 POST APPROVAL REPORTING REQUIREMENTS Study Amendments No deviation from, or changes to the approved study should be implemented without documented approval from the DSRB, except where necessary to eliminate apparent immediate hazard(s) to the study subjects, or when the change(s) involves only logistical or administrative aspects of the study (e.g. change of monitor or telephone number). Any deviation from, or a change of, the protocol to eliminate an immediate hazard should be documented and promptly reported to the DSRB within 7 calendar days. For more information Refer to Chapter 4.2 Study Amendments.24 Continuing Review / Renewal The DSRB will conduct continuing review of ongoing research (except studies reviewed by Exempt Review category) at intervals appropriate to the degree of risk, but not less than once per year. The Principal Investigator should submit a completed DSRB Online Study Status Report Form at least 4-6 weeks before the study approval period ends (as indicated in the approval letter of the study), and in time for DSRB to conduct its review and renew the approval of the study. If an approval expires, no research activities, including screening, enrollment, interventions, interactions, and collection of identifiable data can occur after the expiry date, unless specific permission is granted by the DSRB. For more information Refer to Chapter 4.3 Continuing Review / Renewal.3.4 POST APPROVAL REPORTING REQUIREMENTS
  • 34. Unanticipated Problems Involving Risks To Subjects OrOthers (UPIRTSO)The Principal Investigator is responsible for the accurate documentation,investigation, follow-up and timely reporting of all UPIRTSOs. The criteriafor reporting are that the problems have to be (1) unexpected and (2)related or possibly related to study. Special requirements are applicablefor reporting of events involving deaths of local research participants.For more informationRefer to Chapter 4.4 Unanticipated Problems Invdving Risks To Subjects OrOthers (UPIRTSO).Non–ComplianceAll research should be conducted in compliance with the research studyapproved by the DSRB, SGGCP, NHG DSRB requirements, institution 25requirements, and applicable regulations. The Principal Investigator isencouraged to report conduct of any non-compliance by him / herself,members of the research team and others.For more informationRefer to Chapter 4.5 Non-Compliance.Study ClosureWhen a study is completed, the Principal Investigator should submit studycompletion reports at least 4-6 weeks days after completion of the study.Completion reports should be submitted using the Study Status ReportForm.For more informationRefer to Chapter 4.6 Study Closure. 3.4 POST APPROVAL REPORTING REQUIREMENTS
  • 35. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 36. 4.0SUBMISSIONS TO DSRB 4.04.1 New Applications4.2 Study Amendments4.3 Continuing Review / Renewal4.4 Unanticipated Problems Involving Risks To Subjects Or Others (UPIRTSO)4.5 Non-Compliance4.6 Study Closure
  • 37. 4.1 NEW APPLICATIONSEach DSRB meets once a month, except December . The meetings are heldin the third / fourth week of the month. The submission deadline for newapplications is the first working day of each month, or the next workingday, if the first falls on a weekend or public holiday. For example, for anapplication to be reviewed in the month of April, the application mustreach the DSRB office on 1st April.Only completed applications will be considered for DSRB review.The Principal Investigator is strongly encouraged to submit his / herapplication well before the deadline for submission to allow some time forthe DSRB to check for any missing documents / information. Incompleteapplications that are submitted on the first working day of the month willbe scheduled for review in the following month.Research studies that qualify for expedited review or applications requestingfor exemption may be submitted at any time of the month. 26 What to Submit? The DSRB relies solely on the documentation submitted by Principal Investigator for review. Therefore these material must provide the DSRB with sufficient information about a research study to assess if it adequately meets the DSRB’s criteria for approval. A submitted research proposal will be scheduled for DSRB review only when the DSRB has determined that the information and materials submitted are adequate descriptions of the proposed research. All new applications are to be submitted online via http://www.b2bresearch.nhg.com.sg 4.1 NEW APPLICATIONS
  • 38. A new application must include the following, but not limited to: a. A duly completed B2BResearch Online DSRB Application Form. b. Consent Document / Application for Waiver of Consent. c. Study Protocol (for clinical trials involving drugs, medical devices and surgical procedure). d. Questionnaires, Surveys, Videotapes and other such research tools (if used). e. Copy of the Approved Grant Application (including DHHS approved Study Protocol and Sample Consent Form, if one exists). f. Investigator Brochure and other available safety information (for industry sponsored clinical trials). g. Recruitment materials intended to be seen or heard by potential subjects, including email solicitations and physician letters (if27 used). h. Written information intended to be provided to subjects (if used). i. Principal Investigator’s CV (the latest in the past one year). For more information Refer to Chapter 13 Appendices for ‘Applicable Fees’.4.1 NEW APPLICATIONS
  • 39. In addition, applicants may be requested to submit: a. Data Collection Form. b. Financial disclosure statement. c. Clinical Trial Agreement (industry sponsored research). d. Documentation that the study has been disapproved by other IRBs. e. Translated Consent Document and Translation Certificates (for industry sponsored clinical trials). f. Any other relevant documentation that the DSRB may specifically request. g. Any other relevant documentation to be given to subjects when, in the judgment of the DSRB, the additional information would add meaningfully to the protection of the rights, safety, and / or well- 28 being of the subjects.For more informationDetails on how to complete the B2BResearch Online DSRB ApplicationForm are available online at http://www.b2bresearch.nhg.com.sg(Downloads) and in the Online Manual. 4.1 NEW APPLICATIONS
  • 40. 4.2 STUDY AMENDMENTS No deviation from, or changes to the approved study should be implemented without documented approval from the DSRB, except where necessary to eliminate apparent immediate hazard(s) to the study subjects, or when the change(s) involves only logistical or administrative aspects of the study (e.g. change of monitor or telephone number). Any deviation from, or a change of, the approved study to eliminate an immediate hazard should be documented and promptly reported to the DSRB within 7 calendar days. The submitted amendments will be categorized according to the following definitions: a. CATEGORY A (Major Amendments) – Amendments that negativdy affect the risk benefit ratio will be reviewed by Full Board Review.29 b. CATEGORY B (Minor Amendments) – The DSRB will determine if the changes to the protocol affect the risk benefit assessment. Changes to the protocol that pose any increase in risk which is not more than minimal risk or new procedures added that fit within the categories eligible for expedited review, fall into this category. c. CATEGORY C (Administrative Amendments) – Administrative changes such as change in addresses, contacts, etc, and correction of typographical and grammatical errors. Some examples of changes that should be reviewed at a Full Board Meeting include, but are not limited to: a. Amendments that negatively alter the risk benefit ratio. b. Changes to the inclusion / exclusion criteria that add a potentially vulnerable population. c. Major changes to the consent document or process that increases the overall risk to the subjects involved in the study.4.2 STUDY AMENDMENTS
  • 41. d. Addition of any study procedures believed to be greater than minimal risk. e. Increase in study subjects for a study previously reviewed by Full Board Review. f. Alterations to the drug dose or delivery. g. Any other type of amendment to the study that in the opinion of the DSRB should be reviewed at a Full Board Meeting. A Study Amendment submission must include the following, but not limited to: a. A duly completed B2BResearch Online DSRB Study Amendment Form. b. Rationale of proposed amendments. c. Amended documents (both tracked and clean versions). 30 d. Any other documentation that the DSRB may specifically request. e. Any other relevant documentation to be given to subjects when, in the judgement of the DSRB, the additional information would add meaningfully to the protection of the rights, safety and / or well being of the subjects.For more informationRefer to Chapter 13 Appendices for ‘Applicable Fees’. 4.2 STUDY AMENDMENTS
  • 42. The above conditions are applicable to, but not limited to, amendments made to the protocols, consent documents, study sites and research personnel. For more information Details on how to complete the B2BResearch Online DSRB Study Amendment Form are available online at http://www.b2bresearch.nhg.com.sg (Downloads) and in the Online Manual.314.2 STUDY AMENDMENTS
  • 43. 4.3 CONTINUING REVIEW / RENEWALThe DSRB will conduct continuing review of ongoing research at intervalsappropriate to the degree of risk, but not less than once per year. ContinuingDSRB review is required as long as individually identifiable follow-up dataare collected on subjects enrolled.The Principal Investigator should submit a completed B2BResearch OnlineDSRB Study Status Report Form at least 4-6 weeks before the study approvalperiod ends (as indicated in the approval letter of the study).The Principal Investigator applying for renewal of approval of a studymust submit: a. A duly completed B2BResearch Online DSRB Study Status Report Form. b. Any other documents as indicated in B2BResearch Online DSRB Study Status Report Form. 32 c. Any other documentation that the DSRB may specifically request. d. Any other relevant documentation to be given to subjects when, in the judgment of the DSRB, the additional information would add meaningfully to the protection of the rights, safety, and / or well- being of the subjects. A duly completed B2BResearch Online DSRB Study Status Report Form must indicate the status of the study, details of each as follows: a. NOT YET INITIATED – No research-related activities have been performed since first approval. The Principal Investigator is to provide reasons for this status. b. ONGOING – Research-related activities are still being performed. 4.3 CONTINUING REVIEW / RENEWAL
  • 44. c. ENROLMENT CLOSED, SUBJECT FOLLOW UP ONLY – The study is permanently closed to new participants, and all participants have completed research-related interventions, and the research remains active only for long term follow-up. d. LAST PATIENT LAST VISIT OVER, DATA ANALYSIS ONGOING – There will be no more contact with subjects and the remaining research activities are limited to data analysis. e. COMPLETED – There will be no more research activities, including contact with subject or any data analysis. The Principal Investigator must indicate the completion date. f. WITHDRAWN – The study is stopped before DSRB approval is issued. The Principal Investigator is to provide reasons for this status. g. TERMINATED – The study is stopped after DSRB approval is issued. The Principal Investigator is to provide reasons for this status.33 The DSRB takes into consideration the following information about the progress of the study: a. Subject recruitment. b. Number and reasons for withdrawal of subjects. c. Unanticipated problems involving risks to subjects or others (UPIRTSO) including serious adverse events since last review. d. Study Amendments since last review. e. Assessment of the current risk, potential benefits, and the overall risk / benefit ratio of the study. f. Research findings, if any. g. Complaints about the research, if any. h. Non-compliance reports, if any.4.3 CONTINUING REVIEW / RENEWAL
  • 45. i. Any other relevant information, especially information about the risks associated with the research. Data Safety Monitoring Board Reports When a clinical trial is subject to oversight by a Data Safety Monitoring Board (DSMB) whose responsibilities include review of adverse events, interim findings and relevant literature, the DSRB conducting the renewal process may request for and rely on a current statement from the DSMB indicating that it has reviewed study-wide adverse events, interim findings and any recent literature that may be relevant to the research, in lieu of requiring that this information be submitted directly to the DSRB. However, the DSRB must still receive and review reports of local, on-site unanticipated problems involving risks to subjects or others (UPIRTSO) and any other information needed to ensure that its continuing review is substantive and meaningful. Evaluation reports other than that of a DSMB may also be accepted provided the evaluation meets the criteria 34 listed above.For more informationRefer to Chapter 8.4 Data And Safety Monitoring.Details on how to complete the B2BResearch OnlineDSRB Study Status Report Form are available online athttp://www.b2bresearch.nhg.com.sg (Downloads) and in theOnline Manual. 4.3 CONTINUING REVIEW / RENEWAL
  • 46. 4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO) ADVERSE EVENT – Any untoward or unfavorable medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS - A problem that is (1) unexpected, (2) related or possibly related and (3) suggests that the research places subject or others at greater risk of harm. Reportable Events The Principal Investigator is responsible for the accurate documentation, investigation, follow-up and timely reporting of the following problems.35 These problems have to be (1) unexpected and (2) related or possibly related to the study: These are not necessarily unanticipated problem involving risks to participants or others. These are the problems that the DSRB wants promptly reported to ensure that among the reported problems will be the problems that are unanticipated problems involving risks to participants or others. Examples: a. Adverse event (any harm experienced by a participant regardless of whether the event was internal (on-site) or external (off-site) and regardless of whether the event meets the FDA definition of “serious adverse event”), which in the opinion of the Principal Investigator are both unexpected and related. i. An unexpected adverse event is one, where the nature and severity of which is not consistent with information in the relevant source documents.4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO)
  • 47. ii. An adverse event is “related to the research procedures” when there are facts (evidence) or arguments to suggest a causal relationship.b. Information that indicates a change to the risks or potential benefits of the research. For example: i. An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different than initially presented to the DSRB. ii. A paper is published from another study that shows that the risks or potential benefits of your research may be different than initially presented to the DSRB.c. A breach of confidentiality.d. Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol. 36e. Change to the protocol taken without prior DSRB review to eliminate an apparent immediate hazard to a research participant.f. Incarceration of a participant in a protocol not approved to enroll prisoners.g. Event that requires prompt reporting to the sponsor.h. Sponsor imposed suspension for risk.i. Complaint of a participant when the complaint indicates unexpected risks or cannot be resolved by the research team.j. Protocol violation (meaning an accidental or unintentional change to the DSRB approved protocol) that harmed participants or others or that indicates participants or others may be at increased risk of harm.k. Unanticipated adverse device effect (any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of 4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO)
  • 48. incidence in the investigational plan or application [including a supplementary plan or application], or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects). Assessment of Reported Problems The Principal Investigator must make a judgment about the expectedness, of a reported problem. If the problem is an adverse event, the Principal Investigator must make a judgment about the causality of the adverse event. The Principal Investigator must also analyze the event and state whether protocol / consent form revisions are required. ASSESSMENT OF EXPECTEDNESS – The Principal Investigator must state whether the problem is expected or unexpected. An unexpected problem is one, where the nature and severity of which is not consistent with information in the relevant source document (s). For a medicinal37 product not yet approved for marketing in Singapore, the Investigator Brochure will serve as the source document. Reports that add significant information on specificity or severity of a known, already documented serious adverse event constitute unexpected events. For example, a problem more specific or more severe than described in the Investigator’s Brochure would be considered unexpected. An unexpected problem is also one that is not consistent with the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event. ASSESSMENT OF CAUSALITY – For adverse events, the Principal Investigator should evaluate the event and assess causality. The expression ‘reasonable causal relationship’ is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship. For purposes of reporting, adverse event reports associated with marketed drugs usually imply causality. The following conditions might help to assess causality:4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO)
  • 49. a. The event has a reasonable temporal relationship to the intervention. b. The event could not have been produced by the underlying disease states. c. The event could not have been due to other non-study interventions. d. The event follows a known pattern of response to the intervention. e. The event disappears with cessation of intervention. Reporting Requirements The Principal Investigator must report the reportable events described above (i.e. (1) unexpected and (2) related or possibly related) within 7 days, unless the report involves the death of a local participant, in which case the report needs to be provided to the DSRB in 24 hours. 38 a. All problems involving local deaths should be reported immediately – within 24 hours after first knowledge by the investigator, regardless of the causality and expectedness of the death. b. All other problems must be reported as soon as possible but not later than 7 calendar days after first knowledge by the investigator.Special ConsiderationsIn certain circumstances, for example, in studies whereby the study designrequires long term treatment-free follow up till death, the requirement toreport all local deaths, regardless of causality and expectedness of thedeath event, within 24 hours of first knowledge by PI, does not provideadditional information that would add meaningfully to the protection ofthe rights, safety and / or wellbeing of the subjects. The DSRB may alter 4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO)
  • 50. the reporting requirements of local deaths, provided that the rights, safety and / or wellbeing of the research participants continues to be protected, and provided that the REC and CMB (where applicable) has approved the specific procedure. Serious Adverse Events (SAE) As an additional requirement for sponsored clinical trials, investigators are required to report the following in accordance with Singapore Good Clinical Practice guidelines. Investigators report all serious adverse events (SAEs) to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting. The investigator follows regulatory requirements related to the reporting of unexpected serious adverse drug reactions to the appropriate regulatory authority and the DSRB.39 Investigators report adverse events or laboratory abnormalities identified in the protocol as critical to safety evaluations to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reports of deaths, the investigator supplies the sponsor and the DSRB with any additional requested information (e.g. autopsy reports and terminal medical reports). For more information Details on how to complete the B2BResearch Online DSRB UPIRTSO Form are available online at http://www.b2bresearch.nhg.com.sg (Downloads) and in the Online Manual.4.4 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO)
  • 51. 4.5 NON-COMPLIANCEAll research conducted in NHG institutions should be in compliance withthe research proposal approved by the DSRB, with SGGCP, with NHGDSRB requirements, institution requirements, and applicable regulations.COMPLIANCE is adherence to all the trial-related requirements,good clinical practice requirements, and the applicable regulatoryrequirements.NON-COMPLIANCE is a failure by an Investigator to abide by the policiesand procedures of DSRB or applicable regulations governing the protectionof human subject research. Some examples of non-compliance include, but are not limited to: a. Failure to obtain approval for research. b. Failure to obtain renewal of approval for research. 40 c. Failure to obtain informed consent when required. d. Failure to file an adverse event report. e. Performance of an unapproved research procedure. f. Performance of research at an unapproved site. g. Failure to submit study amendments for review and approval. h. Failure to adhere to the approved protocol. i. Any other failure to adhere to regulations, policies, and procedures related to research. SERIOUS NON-COMPLIANCE is an act or omission to act that has the potential to increase a physical, psychological, safety, or privacy risk to research participants. 4.5 NON-COMPLIANCE
  • 52. CONTINUING NON-COMPLIANCE is a repeated pattern, act, or omission to act that suggests a future likelihood of reoccurrence of the non-compliance. Reporting to the DSRB The Principal Investigator is encouraged to report conduct of any non- compliance by him / herself, members of the research team or others by submitting a duly completed B2BResearch Online DSRB Non-Compliance / Protocol Deviation Form. Reporter’s name will not be disclosed to the individuals involved in the non-compliance event, unless disclosure is required to reconcile the situation. The DSRB may receive an allegation / a report of non-compliance by many means that include, but are not limited to:41 a. Voluntary notification by the Principal Investigator. b. The Principal Investigator’s non-response to DSRB’s queries / reminders for renewal. c. Information given by other staff of the institution. d. Information given by other members of the research team. e. Monitoring reports. f. Audit reports. g. Complaints from research subjects. If the non-compliance is valid and is neither serious nor continuing, the DSRB will require the Principal Investigator to provide an explanation and outline a corrective action to avoid repeating the non-compliance. If4.5 NON-COMPLIANCE
  • 53. the Principal Investigator’s reply is not satisfactory or is not forthcoming,this is handled as a serious / continuing non-compliance.If the allegation of non-compliance is determined to be serious orcontinuing, the DSRB will conduct an inquiry and will provide anopportunity to the Principal Investigator to respond in person at aconvened meeting, informal conference or in writing.Outcome of DSRB InquiryIf the DSRB accepts the Principal Investigator’s explanation, the DSRB willinform the Principal Investigator within 30 days from the date the DSRBreceives the explanation.If the DSRB rejects the Principal Investigator’s explanation, or if thePrincipal Investigator fails to respond within the stipulated timeframe,the DSRB will determine if the Principal Investigator should remain 42eligible to continue to conduct research studies at institutions underDSRB governance and make a recommendation for further actions thatinclude, but are not limited to: a. Referring the study for an independent audit. b. Modification of the Study Protocol. c. Modification of the information disclosed during the consent process. d. Additional information provided to past participants. e. Notification of current participants (required when such information may relate to participants’ willingness to continue to take part in the research). f. Requirement that current participants re-consent to participation. g. Modification of the continuing review schedule. 4.5 NON-COMPLIANCE
  • 54. h. Monitoring of the research. i. Monitoring of the consent. j. Suspension of the research. k. Termination of the research. l. Obtaining more information pending a final decision. m. Referral to other organizational entities (e.g. legal counsel, risk management, institutional official). n. Mandating the Investigator to attend training programmes. o. Requiring the Investigator to work with a senior researcher (mentor) for a period of time. p. Disqualifying the Investigator from conducting any research for a period of time.43 q. Other actions appropriate for the local context. Special Circumstances UNAPPROVED RESEARCH – When unapproved research is discovered, the DSRB and the institution will act promptly to halt the research, ensure remedial action regarding any breach of regulatory or institutional human subject protection requirements. For more information Details on how to complete the B2BResearch Online DSRB Non Compliance / Protocol Deviation Form are available online at http://www.b2bresearch.nhg.com.sg (Downloads) and in the Online Manual.4.5 NON-COMPLIANCE
  • 55. 4.6 STUDY CLOSUREA research study is said to be completed when all of the followingcriteria are fulfilled: a. The research is permanently closed to the enrollment of new participants. b. All participants have completed all research-related interventions. c. Collection and analysis of individually identifiable data has been completed.When a study is completed, the Principal Investigator should submit studycompletion reports 4-6 weeks after completion of the study. Completionreports should be submitted using the B2BResearch Online DSRB StudyStatus Report Form.The DSRB will review the B2BResearch Online DSRB Study Status ReportForm and obtain any outstanding information or documentation from 44the Principal Investigator. If there are inconsistencies or if clarification isneeded, the DSRB will request additional information. Study Suspension / Termination by Institution, Principal Investigator or Sponsor When a study is suspended or terminated by the Institution, Principal Investigator or the sponsor, the Principal Investigator should submit a report within 7 days. Expired Study If a Principal Investigator has failed to provide continuing review information to the DSRB or the DSRB has not approved a research study by the specified approval expiry date, the DSRB approval expires. No research activities, including recruitment, advertising screening, enrollment, interventions, interactions, and collection of identifiable data can occur on the expiration date or after, unless specific permission is granted by the DSRB. Study Suspension / Termination by DSRB The DSRB may decide, at a convened meeting to suspend or terminate 4.6 STUDY CLOSURE
  • 56. a study that is not being conducted in accordance with the DSRB’s requirements or that has been associated with unexpected serious harm to the research subjects. However, the DSRB may suspend / terminate a research on an urgent basis, to eliminate immediate harm to subjects. This would be reported to the DSRB at the next convened meeting. Some examples of situations when a DSRB may suspend / terminate a research study include, but not limited to: a. Inappropriate involvement of human subjects in research. b. Inhibition of the rights or welfare of participants. c. Serious or continuing non-compliance with regulations or DSRB policies. d. New information regarding increased risk to human participants. e. Expiry of approval.45 Reactivation following Suspension The Sponsor / PI may request to reactivate studies that were put on hold either by the Sponsor / PI themselves or by the DSRB. The request for reactivation will be reviewed either as a continuing review or as a new study submission based on the following considerations: a. Duration since suspension. b. Circumstances surrounding suspension. c. Enrollment status of the study. d. Level of risk involved in the study. e. Any other issue deemed significant by the IRB membership. For more information Details on how to complete the B2BResearch Online DSRB Study Status Report Form are available online at http://www.b2bresearch.nhg.com.sg (Downloads) and in the Online Manual.4.6 STUDY CLOSURE
  • 57. 5.0REVIEW PROCESS 5.05.1 Exempt Review5.2 Non-Exempt Review5.3 Criteria For Approval
  • 58. 5.1 EXEMPT REVIEWThe DSRB may determine that a research activity that falls under any of thefollowing categories qualifies for exemption:Categories of Research EXEMPTION CATEGORY 1 – NORMAL EDUCATIONAL PRACTICES AND SETTINGS - Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as: a. Research on regular and special education instructional strategies and; b. Research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods. 46 EXEMPTION CATEGORY 2 – ANONYMOUS EDUCATIONAL TESTS, SURVEYS, INTERVIEWS, OR OBSERVATIONS - Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observations of public behaviour, unless: a. Information obtained is recorded in such a manner that human subjects can be identified, directly or indirectly through identifiers linked to the subjects. b. Any disclosure of the human subjects’ responses outside of the research could reasonably place subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation. 5.1 EXEMPT REVIEW
  • 59. EXEMPTION CATEGORY 3 – IDENTIFIABLE SUBJECTS IN SPECIAL CIRCUMSTANCES - Research involving the use of educational tests, (cognitive, diognostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempted under Excemption Category 2, if: a. The human subjects are elected or appointed public officials or candidates for public office. b. Statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. EXEMPTION CATEGORY 4 – COLLECTION OF EXISTING DATA - Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly47 or through identifiers linked to the subjects. The reviewed material should be in existence at the time the research is proposed and should not be prospectively collected. EXEMPTION CATEGORY 5 – PUBLIC BENEFIT OR SERVICE PROGRAMS Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: a. Public benefit or service programs. b. Procedures for obtaining benefits or services under those programs. c. Possible changes in or alternatives to those programs or procedures. d. Possible changes in methods or levels of payment for benefits or services under those programs.5.1 EXEMPT REVIEW
  • 60. EXEMPTION CATEGORY 6 – TASTE AND FOOD EVALUATION AND ACCEPTANCE STUDIES - Taste and food quality evaluation and consumer acceptance studies, a. if wholesome foods without additives are consumed, or b. if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe. Special Circumstances The criteria for exemption do not apply for: a. Research involving prisoners. b. Research involving children when the research involves survey or interview procedures or observations of public behaviour, except when the investigator(s) do not participate in the activities being 48 observed. c. FDA-regulated research. The determination of whether a research study meets the criteria for Exempt Review is made by the DSRB.For more informationDetails on h ow to complete the B2 BR e s e a rc h O n l in eD SRB E x e mp t Ap p l i c a t i o n F o r m a r e a v a i l a b l e o n l i n e a thttp://www.b2bresearch.nhg.com.sg (Downloads) and in theOnline Manual. 5.1 EXEMPT REVIEW
  • 61. 5.2 NON-EXEMPT REVIEW Expedited Review Expedited Review process may be used for: a. Initial Review of new research proposals. b. Continuing Review. c. Review of Study Amendments. d. Review of Modifications requested by DSRB to secure approval. The DSRB will determine if a proposed research study qualifies for a review by expedited process. To qualify for such, a research proposal must meet the following criteria: a. The research proposal presents no more than minimal risk to49 research subjects. Minimal risk is defined as “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests”. b. Identification of subjects and / or their responses does not reasonably place them at risk of criminal or civil liability or be damaging to their financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. c. The research is not classified. d. The research activity is listed in the Categories of Research stated below.5.2 NON-EXEMPT REVIEW
  • 62. Categories of ResearchCATEGORY 1 – Clinical studies of drugs and medical devices only whenone of the following is met: a. Research on drugs for which an investigational new drug application is not required. b. Research on a medical device for which an investigational device exemption application is not required or the medical device is cleared / approved for marketing and the medical device is being used in accordance with its cleared / approved labeling.CATEGORY 2 – Collection of blood samples by finger stick, heel stick,ear stick, or venipuncture as follows: a. From healthy, non-pregnant adults who weigh at least 50 kgs. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 50 times per week. b. From other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week. 5.2 NON-EXEMPT REVIEW
  • 63. CATEGORY 3 – Prospective collection of biological specimens for research purposes by noninvasive means. Examples: a. Hair and nail clippings in a non-disfiguring manner. b. Deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction. c. Permanent teeth if routine patient care indicates a need for extraction. d. Excreta and external secretions (including sweat). e. Uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gum base or wax or by applying a dilute citric solution to the tongue.51 f. Placenta removed at delivery. g. Amniotic fluid obtained at the time of rupture of the membrane prior to or during labor. h. Supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques. i. Mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings. j. Sputum collected after saline mist nebulization.5.2 NON-EXEMPT REVIEW
  • 64. CATEGORY 4 – Collection of data through noninvasive procedures (notinvolving general anesthesia or sedation) routinely employed in clinicalpractice, excluding procedures involving x-rays or microwaves. Wheremedical devices are employed, they must be cleared / approved formarketing. (Studies intended to evaluate the safety and effectivenessof the medical device are not generally eligible for expedited review,including studies of cleared medical devices for new indications).Examples: a. Physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject’s privacy. b. Weighing or testing sensory acuity. c. Magnetic resonance imaging. d. Electrocardiography, electroencephalography, thermography, 52 detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography. e. Moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.CATEGORY 5 – Research involving materials (data, documents,records, or specimens) that have been collected, or will be collected solelyfor non-research purposes (such as medical treatment or diagnosis).CATEGORY 6 – Collection of data from voice, video, digital, or imagerecordings made for research purposes.CATEGORY 7 – Research on individual or group characteristicsor behavior (including, but not limited to, research on perception,cognition, motivation, identity, language, communication, cultural 5.2 NON-EXEMPT REVIEW
  • 65. beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. Expedited Review – Continuing Review To qualify for review by expedited process at continuing review, the research must meet the following criteria: The research is not classified and the research activities involve procedures listed in one or more of the Category 1 to 7 as defined above or Category 8 or 9 defined below. CATEGORY 8A a. The research is permanently closed to new participants.53 b. All subjects have completed all research-related interventions. c. The research remains active only for long-term follow-up of subjects. (For a multi center study, expedited review procedure may be used by DSRB when all of the above are satisfied for NHG sites.) CATEGORY 8B a. No subjects have been enrolled – i.e. no subjects have ever been enrolled into the study at NHG sites. b. No additional risks have been identified. CATEGORY 8C a. Wh e r e t h e r e m a i n i n g research a c t iv i t ie s a r e l im i t e d t o data analysis.5.2 NON-EXEMPT REVIEW
  • 66. CATEGORY 9 a. The research is not conducted under an investigational new drug application or investigational device exemption. b. The DSRB has determined and documented at a Full Board meeting that: i. The research involves no greater than minimal risk. ii. No additional risks have been identified. Expedited Review – Study Amendments To qualify for review by expedited process for applications submitted for Study Amendment, the amendents must be one of the following: a. Category B (Minor Amendments) b. Category C (Administrative Amendments) 54For more informationRefer to Chapter 4.2 Study Amendments. Full Board Review Research proposals that do not qualify for Exempt or Expedited Review category will be reviewed by the Full Board Review category. 5.2 NON-EXEMPT REVIEW
  • 67. 5.3 CRITERIA FOR APPROVAL All research proposals that intend to enroll human subjects must meet certain criteria before study procedures can be initiated. The criteria are based on the principles of respect, beneficence and justice as discussed in the Belmont Report. The DSRB will consider the following elements of review, which are also the minimum criteria for DSRB Approval for New Applications, Study Amendments and Continuing Review / Renewal: a. Risks to subjects are minimized by using procedures which are: i. consistent with sound research design, ii. do not unnecessarily expose subjects to risk, and iii. when appropriate, already being performed for diagnostic or treatment purposes.55 b. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. i. The DSRB will consider only those risks and benefits that may result from the research (as distinguished from the risks and benefits of therapies participants would receive even if not participating in the research). ii. The DSRB will not consider possible long-range effects of applying knowledge gained in the research as among those research risks (such as possible effects of the research on public policy) that fall within the purview of its responsibility. c. Selection of subjects is equitable – in making this assessment, the DSRB will take into account the following: i. The purposes of the research. ii. The setting in which the research will be conducted.5.3 CRITERIA FOR APPROVAL
  • 68. iii. Special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. d. Informed consent will be sought from each prospective subject or the subject’s legally acceptable representative, in accordance with, and to the extent described in the section on Consent. e. Informed consent will be appropriately documented, in accordance with, and to the extent described in the section on Consent. f. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. g. When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. When some or all of the subjects are likely to be vulnerable to coercion or 56 undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects as outlined in the section on Vulnerable Subjects.For more informationRefer to Chapter 8.0 Guidance On Key Ethical Issues. 5.3 CRITERIA FOR APPROVAL
  • 69. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 70. 6.0OUTCOME OF REVIEW 6.0
  • 71. 6.0 OUTCOME OF REVIEWFollowing the review of a research proposal, the DSRB must reach one ofthe following decisions: a. to approve, b. conditionally approve, c. table for next convened meeting, or d. not approve the research proposal.The DSRB may make one of the following determinations as a result of itsreview of research submitted for initial review, continuing review and studyamendments: APPROVED – The research proposal is approved as submitted. The Principal Investigator is not required to change any aspect of the proposal or the consent document. 57 CONDITIONALLY APPROVED – There are no major problems with the study. If the Principal Investigator addresses the issues listed by the DSRB, the study can be formally approved. Subjects must not be recruited into the study until final approval has been issued. TABLED FOR NEXT CONVENED MEETING – A proposal may be tabled if there are Principal Imestigator significant questions raised that need further information from the PI. The DSRB decides on the subsequent action required. The PI may be asked to submit additional information, may be invited to a subsequent meeting or the proposal might be sent to an Independent Consultant for further review. When additional information has been obtained, the proposal is discussed at the next DSRB meeting. NOT APPROVED – The proposal fails to meet one or more criteria used by the DSRB for approval of research. Disapproval cannot be given through the expedited review mechanism and may only be given by majority vote at a convened meeting of the DSRB. 6.0 OUTCOME OF REVIEW
  • 72. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 73. 7.0APPEALS TO DSRB DECISION 7.0
  • 74. 7.0 APPEALS TO DSRB DECISIONThe Principal Investigator shall have an opportunity to respond in writingto the DSRB if a submitted research activity is not approved. The DSRB willgive the PI’s appeal a careful and fair evaluation. a. If the DSRB determines that a study is not approved, it provides the reasons for the disapproval, in writing, to the PI. b. The PI may appeal against the DSRB’s decision by responding in writing to the DSRB. This written response should contain the rationale for the appeal. c. Once the study has been included on the agenda, the PI will be notified and will be given the opportunity to attend the meeting and present information in person. d. The DSRB will carefully and fairly evaluate the PI’s response in reaching their final decision. If the study is disapproved, this letter 58 will include the reason(s) for the disapproval. e. If the PI is dissatisfied with the decision, the PI may write to the Research Ethics Committee. The Research Ethics Committee will then discuss the protocol and the DSRB’s decision at the next scheduled meeting. f. All PIs are encouraged to contact the DSRB to provide other types of feedback. However, other types of investigator feedback are accepted without this process. 7.0 APPEALS TO DSRB DECISION
  • 75. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 76. 8.0GUIDANCE ONKEY ETHICAL ISSUES8.1 Informed Consent 8.7 Research In Vulnerable8.2 Recruitment Strategy Population8.3 Risk / Benefit Assessment 8.8 Compensation For Research Related Injuries8.4 Data And Safety Monitoring 8.9 Standing Database & 8.0 Tissue Banking8.5 Privacy And Confidentiality8.6 Conflict Of Interest
  • 77. 8.1 INFORMED CONSENTThe DSRB requires that informed consent should be obtained from all humansubjects prior to their participation in any research unless the process, orany part thereof, has been waived by the DSRB.Informed consent is the process by which a subject voluntarily confirms hisor her willingness to participate in a particular research study, after havingbeen informed of all aspects of the research study that are relevant to thesubject’s decision to participate. Informed consent is to be documented bymeans of a written, signed, and dated informed consent form. Consent Process – Important Considerations Informed consent is a process that is necessary to assure that subjects are fully informed before deciding to volunteer as research subjects in research studies of any type. The following considerations should be kept 59 in mind while conducting an informed consent discussion, exceptions to these requirements must be specifically addressed and received prior to DSRB approval. a. Subjects must be given adequate time to consider before making a decision whether or not to participate. b. Subjects should be encouraged to discuss participation with their family. c. Subjects should be approached in a conducive environment, for example, it would not be appropriate to approach a subject immediately before a procedure or surgery, while in labor, while under sedation and any other situation where a subject might feel compromised. d. Informed Consent discussion should be conducted by the Principal Investigator, collaborator or a member of the study staff who is listed in the B2BResearch Online DSRB Application Form as the 8.1 INFORMED CONSENT
  • 78. designated person for conducting the Informed Consent discussion. Any change to study staff, should be submitted to DSRB for review and approval. e. Informed Consent discussion should take place in person. Consent documents should not be mailed to subjects with instructions to call back with questions, or to sign and mail back. f. Informed Consent should be obtained before initiation of the study i.e. before any procedures that are being performed solely for the research. g. Informed Consent must be presented in a language that is understandable to the subject. h. Informed Consent is not a one time single event prior to enrolling research subjects, but must be a continuous ongoing process. Investigators must inform subjects of any important new information that may affect their willingness to continue participation. The DSRB60 must approve the method of notification prior to implementation. The method could include, but is not limited to any of the following, i. Information Letter ii. Addendum to previously signed consent form to be signed by subject iii. Revised consent form to be signed by subject In general, consent to participation must be taken from the subject. In cases where the legally acceptable representative may be required to consent on behalf of the subject, the DSRB will assess the requirement based on the subject population being studied or other special circumstances.8.1 INFORMED CONSENT
  • 79. Required Elements of Informed ConsentThe following elements must be present in the consent document: a. A statement that the study involves research, an explanation of the purposes of the research, the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental. b. A description of any reasonably foreseeable risks or discomforts to the subject. c. A description of any benefits to the subject or to others that may reasonably be expected from the research. d. A disclosure of appropriate alternative procedures or courses of treatment, if any, which might be advantageous to the subject. e. A statement describing the extent to which, if any, confidentiality of records identifying the subject will be maintained and that notes 61 the possibility that the regulatory authorities, IRB, and sponsor’s monitors may inspect the records. f. For research involving more than minimal risk, an explanation as to whether any compensation is provided and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. g. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject, and whom to contact in the event of complaints about research. h. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. 8.1 INFORMED CONSENT
  • 80. Additional Elements of Informed Consent When appropriate, one or more of the following elements of information shall also be provided to each subject: a. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus if the subject is or may become pregnant), which are currently unforeseeable. b. Anticipated circumstances under which the subject’s participation may be terminated by the Investigator without regard to the subject’s consent. c. Any additional costs to the subject that may result from participation in the research. d. The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject.62 e. A statement that significant new findings developed during the course of the research, which may relate to the subject’s willingness to continue participation, will be provided to the subject. f. The approximate number of subjects involved in the study. g. Possibility of randomization to placebo, study or comparator arms. h. Anticipated pro-rated payment, if any, for reimbursement of travel, meal or other expenses incurred due to participation in the research. i. When the research involves tests such as HIV testing, that require mandatory reporting to the Ministry of Health if positive, this should be disclosed in the Patient Information Sheet. j. Any other information that is, in the DSRB’s judgment would add meaningfully to the protection of the rights and welfare of subjects.8.1 INFORMED CONSENT
  • 81. For more informationRefer to Chapter 13 Appendices for ‘Participant Information SheetChecklist’.Template for preparing consent document, “Participant InformationSheet & Consent Form Template“ is available online athttp://www.b2bresearch.nhg.com.sg (Downloads). Consent Document - General Considerations a. SECOND PERSON: The language of the consent document should be in the second person style so the consent document conveys a dialogue with information being provided and that there is a choice to be made by the subject rather than presumption of the subject’s consent with the use of the first person style. b. SIMPLICITY: The information provided in the consent document must be in language understandable to the subject. The consent 63 document should not include complex language that would not be understandable to all subjects. Technical and scientific terms should be adequately explained using common or lay terminology. c. EXCULPATORY LANGUAGE: The consent document may not contain any exculpatory language through which the subject is made to waive or appears to waive legal rights, or release or appears to release the Investigator, the Sponsor, or the institution from liability for negligence. d. FDA REGULATED TEST ARTICLES: For all research involving test articles regulated by FDA, the consent document must include a statement that the purpose of the study includes evaluation of both the safety and effectiveness of the test article. The consent document must also include a statement that the FDA has access to the subject’s medical records. 8.1 INFORMED CONSENT
  • 82. Documentation of Informed Consent Each subject or his / her legally accepted representative must sign and date a copy of the DSRB-approved consent document prior to enrollment or any participation in any aspect of the study, unless the requirement is waived by the DSRB. The subject must be given a copy of the signed document. The DSRB may approve procedures for documentation of informed consent that involve any of the three options listed below. The DSRB will determine which procedure is most appropriate for the research study being reviewed: a. A written consent form signed by the subject or legally acceptable representative. b. A short form written consent form with oral presentation.64 c. In limited circumstances, waiver of signed written consent form. In most circumstances, the DSRB will require that informed consent is documented by the use of a written consent form approved by the DSRB and signed by the subject or the subject’s legally accepted representative. A non-therapeutic clinical trial (i.e a trial in which there is no anticipated direct clinical benefit to the participant) should be conducted in participants who personally give consent and who sign and date the written consent document. Legally Acceptable Representative LEGAL REPRESENTATIVE: Under the Medicines (Clinical Trials) Regulations, the term legal representative is defined as “in relation to a person who is to be used as a subject in a clinical trial, means an8.1 INFORMED CONSENT
  • 83. individual or judicial or other body authorized under the law to consenton behalf of that person to his participation in the clinical trial.”LEGALLY ACCEPTABLE REPRESENTATIVE: Under the Singapore GoodClinical Practice Guidelines, the term Legally Acceptable Representativeis defined as “an individual or juridical or other body authorized underapplicable law to consent, on behalf of a prospective subject, to thesubject’s participation in the clinical trial.”LEGALLY AUTHORIZED REPRESENTATIVE: Under DHHS regulations, theterm Legally Authorized Representative means an individual or judicialor other body authorized under applicable law to consent on behalf ofa prospective subject to the subject’s participation in the procedure(s)involved in the research.For the purposes of research in NHG, the terms Legal Representative,Legally Acceptable Representative and Legally Authorized Representative,as defined above, are synonymous and may be used interchangeably. 65A legally acceptable representative may give consent on behalf of theindividual for participation in a research only when the individual is notcapable of giving legally effective informed consent, such as any of thefollowing: a. A child. b. An individual who is cognitively impaired. c. An individual who is unconscious.The applicable law for Singapore is the Medicines (Clinical Trial)Regulations and according to these regulations the following personsmay consent on behalf of an individual to participate in a research: a. Spouse. b. Parent. c. Guardian (if there is no parent). 8.1 INFORMED CONSENT
  • 84. d. Any other person having charge of that person. e. Judicial or other body authorised under applicable law to consent on behalf. There is no order of priority for the persons listed above, but when any of these persons express dissent as to the participation of the individual in the research, consent shall not be considered as having been given. Subjects who are Unable to Read When a subject or a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. a. The written informed consent form and any other written information to be provided to the subjects, should be read and explained to the66 subject or the subject’s legally acceptable representative. b. The subject or the subject’s legally acceptable representative must orally consent to the subject’s participation in the study. c. If capable of doing so, has signed and personally dated the informed consent form. d. The witness should sign and personally date the consent form. By signing the consent form, the witness attests that: i. the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and ii. the informed consent was freely given by the subject or the subject’s legally acceptable representative.8.1 INFORMED CONSENT
  • 85. Non-English Speaking SubjectsNon-English speaking subjects should be presented with a consentdocument written in a language understandable to them. It is notacceptable to exclude potential subjects based on their inability to speakand understand English.Informed consent may be documented using a short form procedure fornon-English speaking subjects. The short form consent document shouldembody, in language understandable to the subject, all the elementsnecessary for legally effective informed consent. When this procedure isused with subjects who do not speak English, a. the oral presentation and the short form consent document should be in a language understandable to the subject; b. the DSRB-approved English language consent document may serve as the summary; 67 c. the witness should be fluent in both English and the language of the subject; and d. the subject must be provided with both the short form consent document in a language understandable to the subject and a written summary of the information that is presented orally.The Principal Investigator must submit all language versions of theshort form consent document to be used at study sites as a condition ofapproval.Research involving pregnant women, fetuses, neonates, children,cognitively impaired persons and prisoners has additional considerationsfor consent requirements. 8.1 INFORMED CONSENT
  • 86. Oral Presentation and Short Form Consent Document As an alternative to standard written informed consent documents, oral presentation of informed consent information may be used. In such cases, the subject must be provided with both: a. A short form consent document stating that the elements of informed consent have been presented orally to the subject or the subject’s legally accepted representative; and b. A written summary of the information that is presented orally. A witness to the oral presentation is required. The witness must sign both the short form consent document and a copy of the written summary. The subject or the legally accepted representative must sign the short form consent document. The person obtaining consent (e.g., the Investigator) must sign a copy of the written summary of the information that is presented orally. The person obtaining consent may not be the witness68 to the consent. The subject or his / her legally accepted representative must be given a copy of the signed short form consent document and the signed written summary. For more information Refer to Chapter 13 Appendices for ‘Short Form Consent – An Example’. Waiver of Documentation of Consent The DSRB may waive the requirement for the Investigator to obtain a signed consent form for some or all subjects if the DSRB finds either: a. All the following are true: i. The only record linking the subject and the research would be the consent document.8.1 INFORMED CONSENT
  • 87. ii. The principal risk would be potential harm resulting from a breach of confidentiality. iii. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern. iv. The research is not subject to FDA regulations. b. All the following are true: i. The research presents no more than minimal risk of harm to subjects. ii. The research involves no procedures for which written consent is normally required outside of the research context.For US FDA–regulated studies, the waiver of documentation of consent formay be granted only if criteria b are met. 69In cases in which the documentation requirement is waived, the DSRB mayrequire the Investigator to submit a written description of the information thatmay be provided to the subjects for review. Investigators may also providesubjects with a written statement regarding the research. The Investigatormust submit the written statement to DSRB for review and approval.For more informationRefer to Chapter 13 Appendices for ‘Waiver of Documentation – Examples’. Waiver of Informed Consent The DSRB may approve a consent procedure that does not include, or which alters, some or all of the elements of informed consent, or waive the requirement to obtain informed consent provided the DSRB finds and documents that: a. The research involves no more than minimal risk to the subjects. b. The waiver or alteration will not adversely affect the rights and welfare of the subjects. 8.1 INFORMED CONSENT
  • 88. c. Whenever appropriate, the subjects will be provided with additional pertinent information after participation. d. The research could not practicably be carried out without the waiver or alteration. e. The research is not subject to FDA regulations. For more information Refer to Chapter 13 Appendices for ‘Waiver of Consent – Examples’. Consent in Emergency Situations In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present should be requested.70 When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol to protect the rights, safety and well being of the subject and to ensure compliance with applicable regulatory requirements. The latter includes written certification from the Principal Investigator and 2 specialists who are not involved in the trial that: a. The potential subject is facing a life-threatening situation which necessitated intervention. b. That person is unable to give his consent as a result of his medical condition. c. It is not feasible to request consent from that person or to contact his legally acceptable representative within the crucial period in which treatment must be administered.8.1 INFORMED CONSENT
  • 89. d. Neither that person or his legally acceptable representative nor any member of that person’s family has informed the principal investigator of his objection to that person being used as a subject in the clinical trial.The subject or the subject’s legally acceptable representative should beinformed about the research as soon as possible and consent to continueshould be requested. 71 8.1 INFORMED CONSENT
  • 90. 8.2 RECRUITMENT STRATEGY Any materials for direct advertising for research subjects should be used only after approval by the DSRB. Recruitment strategies include direct advertising, dear doctor letters, finder’s fee, recruitment bonuses etc. This information should be provided in the B2BResearch Online DSRB Application Form. The DSRB does not approve payment of finder’s fees or recruitment bonuses. Finders’ fees are defined as payments from the investigator or sponsor to a person who refers a potential participant. Recruitment bonuses are defined as payments from the sponsor to an investigator or organization based on the rate or timing of recruitment. The DSRB has no objection to the use of direct advertising to find potential research subjects. Direct advertising includes, but is not limited to –72 a. Newspaper advertisements. b. Posters, bulletins, flyers, brochures. c. Email messages. d. Invitation letters to potential subjects. DSRB’s review and approval is not required in the following cases: a. Letters to doctor for referring potential subjects. b. Stories in newspapers or magazines that mention the research project. c. Listing of clinical trials on research website internet when the format is limited to basic trial information such as protocol title, purpose of study, protocol summary, basic eligibility criteria, study site location and how to contact site for further information.8.2 RECRUITMENT STRATEGY
  • 91. Preparing AdvertisementsSubmissions for review of advertisements by the DSRB should includeinformation on: a. Where the material will be used e.g. newspaper, radio including number of times the advertisement will be run. b. Locations of posters / flyers. c. Final copy of the advertisement for printed material and video or audio tape that will be used for broadcast.Advertisements to recruit subjects should be limited to the information theprospective subjects need to determine their eligibility and interest. Thefollowing information must be included: a. That volunteers are being recruited for research. b. The name and address of the institution conducting the research. 73 c. The condition under study and / or the purpose of the research. d. In summary form, the criteria that will be used to determine eligibility for the study. e. A brief list of participation benefits, if any (e.g. A no-cost health examination). f. The time or other commitment required of the subjects. g. The location of the research and the person or office to contact for further information.The advertisement should not, either explicitly or implicitly, a. State or imply a certainty of favorable outcome or other benefits beyond what is outlined in the consent document and protocol. b. Make claims that the drug, device or biologic is safe or effective for the purposes under investigation. 8.2 RECRUITMENT STRATEGY
  • 92. c. Make claims that the test article is known to be equivalent or superior to any other drug, biologic or device. d. Use terms such as “new treatment,” “new medication” or “new drug” without explaining that the test article is investigational. e. Promise “free medical treatment,” when the intent is only to say subjects will not be charged for taking part in the investigation. Advertisements may state that subjects will be paid, but should not emphasize the payment by such means as larger or bold type. Advertisements should not state the amount that will paid. f. Include any exculpatory language. g. Make claims, either explicitly or implicitly, about the drug, biologic or device under investigation that are inconsistent with currently approved labelling.74 Payment to Research Subjects The Consent Document should include information on payment arrangements for subjects who participate in the research. The DSRB will consider the following issues while reviewing the payment arrangements: a. Payment to the subjects for participation is not considered a benefit, but a reimbursement for the subjects time and expenses incurred. b. The amount and proposed method and timing of payment should not present any undue influence. c. Payment to subjects should be pro-rated, and not be contingent upon the subject completing the study. d. Payment of a small proportion as an incentive for completion is acceptable, providing the incentive is not coercive.8.2 RECRUITMENT STRATEGY
  • 93. e. Compensation for participation should not include coupons for discount on the price of the study material after the product is approved for marketing.Review by DSRBRecruitment material may be submitted for review at the time of initialreview, at which time, they will be reviewed along with the otherdocuments submitted for initial review. When advertisements aresubmitted for review after the initial study approval has been granted,these submissions will be regarded as protocol amendments. 75 8.2 RECRUITMENT STRATEGY
  • 94. 8.3 RISK / BENEFIT ASSESSMENT The anticipated benefit, either to new knowledge or improved health of subjects should justify their taking the risk to participate in the research study. Potential Benefits to Subjects Risk to Subjects Importance of Knowledge Gained *Graphics reproduced with permission from AAHRPP Inc. The different risks to which subjects may be exposed to can be classified as follows: a. PHYSICAL – Bruising after blood draw, study drug related adverse events.76 b. PSYCHOLOGICAL – Psychological effects following survey asking sensitive questions. c. SOCIAL – Breaches in confidentiality revealing that a subject suffers from a psychiatric illness. d. ECONOMICAL – Additional expenses to be borne by subject due to participation in research. e. LEGAL – Mandatory reporting of drug abuse discovered during the research may cause legal problems for the subject. HARM P S Y E P C C S O H O H L DISCOMFORT Y N C O E S L O G I M I A O A C G I L L C A I INCONVENIENCE L C A A L L *Graphics reproduced with permission from AAHRPP Inc.8.3 RISK / BENEFIT ASSESSMENT
  • 95. Only research related risks should be considered while risks associatedwith treatment that the subject would undergo even if not participatingin the research and disease progression need not be considered whileassessing research related risks.MINIMAL RISK is defined as “the probability and magnitude of harmor discomfort anticipated in the research are not greater in and ofthemselves than those ordinarily encountered in daily life or duringthe performance of routine physical or psychological examinations ortests”.The Principal Investigator should constantly strive to minimize both themagnitude of harm as well as the likelihood of the risk. 77 *Graphics reproduced with permission from AAHRPP Inc.MAGNITUDE: Risks may range from a mere inconvenience (such as anextra visit to the clinic) to a serious harm or even death.LIKELIHOOD: The probability of occurrence of the risk.Some examples of the ways the investigator can minimize risks are: a. PHYSICAL – Procedures already being performed on the subjects for diagnostic or treatment purposes should be used, instead of performing additional tests for research. For example – drawing extra blood during a routine blood draw for treatment rather than drawing blood specifically for research. 8.3 RISK / BENEFIT ASSESSMENT
  • 96. b. PSYCHOLOGICAL – Debriefing after the completion of the research. c. SOCIAL – Ensure confidentiality is maintained especially while dealing with sensitive information. d. ECONOMICAL – Ensure that the subject does not have to pay out of pocket for research related expenses and that institution covers treatment for research related injuries. e. LEGAL - Inform the subject during consent process if mandatory reporting is required or employ a study design that assures anonymity. In the event that there are unanticipated problems involving risks to subjects or others (UPIRTSO), the Principal Investigator is responsible for the following: a. Management of Event – The Principal Investigator should ensure78 that adequate medical care is provided to the subject for treatment of adverse events. b. Assessment of Event – The Principal Investigator should assess the risk, expectedness, and relation of the event to the study. c. Reporting of Event – The Principal Investigator must report the events to the DSRB. For more information Refer to Chapter 4.4 Unanticipated Problems Involving Risks To Subjects Or Others (UPIRTSO).8.3 RISK / BENEFIT ASSESSMENT
  • 97. 8.4 DATA AND SAFETY MONITORINGOne of the review criteria for DSRB approval at initial review is that thereis an adequate data and safety monitoring plan. All research proposalsshould include adequate provisions for monitoring of data collected forscientific validity and safety of research subjects. The monitoring plan for aparticular research study would depend on the complexity of the researchstudy and the possibility of potential harm to subjects. Determination of Research Study Risk Determination of risk should include a consideration of both the interventions being performed and the research study population. Risk assessments must also take into account special circumstances that are unique to the research study such as disclosures of HIV status or risks of results of genetic studies. 79 MINIMAL RISK – A research study is said to be minimal risk when the probability and magnitude of harm and / or discomfort are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Minimal risk studies generally include research involving surveys, questionnaires, blood samples, MRI scans, exercise testing in low risk populations, ECGs, and other such non-interventional studies. MODERATE RISK – A moderate risk research study exceeds minimal risk, would be less risky to the subject than high risk research studies. Moderate risk studies may include a Phase IV trial, research studying efficacy of drugs for their indicated use etc. HIGH RISK – High risk research studies include clinical trials using new drugs, drugs for off label use, new devices, new surgical procedures, etc. 8.4 DATA AND SAFETY MONITORING
  • 98. Who Performs Safety Monitoring The Data Safety Monitoring Plan should state who would assume monitoring responsibility. This will depend on the type and risk of the research study and may include the investigator, experts within the department or institution, independent consultants or a combination of the above. Some examples: PRINCIPAL INVESTIGATOR - For a research study involving minimal risk to the subjects, it may be appropriate for the Principal Investigator to manage the data and safety monitoring. Continuous close monitoring by the Principal Investigator may be an adequate and appropriate format for monitoring with prompt reporting of serious adverse events to DSRB. For minimal risk research study involving multiple sites, this function could be managed by the team of Principal Investigators for each site or the lead or overall Principal Investigator for the entire research study.80 INDEPENPENT EXPERT(S) – For a moderate risk research study or investigator initiated clinical trial involving single or multiple sites, it is recommended that the data safety monitoring be performed by an expert or group of experts in the disease and familiar with the agent being studied. Using an independent expert or team of experts is particularly helpful in monitoring of unblinded data for a double blind research study as this will help ensure a meaningful review by independent experts while maintaining the blind amongst the research staff. DATA SAFETY MONITORING BOARD (DSMB) – This is a committee that is established specifically to monitor data throughout the life of a research study to determine if it is appropriate, from both scientific and ethical standpoints to continue the research study as planned. For high risk studies and for sponsor initiated large, blinded studies, involving multiple sites, it is recommended that a formal DSMB be appointed.8.4 DATA AND SAFETY MONITORING
  • 99. Frequency and Extent of MonitoringThis might be planned to occur at specific points in time, such as quarterly,or every six months or annually or after a specific number of participantshave been enrolled, or upon recognition of harm. The plan should statehow often monitoring will be performed. The plan should also state whatdata will be reviewed for safety monitoring.Safety MonitoringThe safety monitoring plan should include: a. Details of the assessments (laboratory tests, physical examinations, etc.) used to monitor for adverse events and the schedule of these evaluations. b. Description of anticipated events including character and expected incidence. 81 c. Plan for grading events as serious / not serious. d. Plan for grading events as reasonable causal relationship or not related. e. Persons responsible for grading events. f. Persons responsible for managing events - plan should identify the PI and other key personnel who is medically trained in the disease under research study and / or procedures that impart more than minimal risk to subjects. The plan should provide assurance that the PI will be located on site to monitor research study subjects’ safety on a day-to-day basis. g. Persons responsible for reporting events according to DSRB guidelines. 8.4 DATA AND SAFETY MONITORING
  • 100. Data accuracy and compliance The Principal Investigator should describe the measures that will be taken to ensure accuracy of data and compliance to protocol. The extent and nature of monitoring should be based on considerations such as objective, purpose, design, complexity, blinding, size, and endpoints of the research. In general, there should be monitoring before, during and after the research. For investigator initiated minimal risk studies, monitoring for data accuracy and compliance would entail – checking for completeness of the investigator file prior initiation and self assessment of all or randomly selected data collection forms. For investigator initiated trials that involve high risk, monitoring should be in accordance with SGGCP. In the event of inadequate resources to conduct monitoring, the investigator may contact the NHG Research QA82 for assistance with monitoring. Sponsor initiated clinical trials should outline a plan consistent with SGGCP guidelines for monitoring. Stopping Criteria An effective data and safety monitoring plan should be able to detect signals to decide when the research study should be stopped. Usually stopping criteria are based on one or more reasons such as: a. Efficacy – With high certainty, the research question has been answered. For example, when it is clear that one group is doing better than the others, or no group is likely to do better than any other. b. Futility – When it is evident that the research question will not be answered when the study is completed, for example, because too many subjects have withdrawn from the research study. c. Safety – The risks of continued participation to subjects is too high.8.4 DATA AND SAFETY MONITORING
  • 101. Special ConsiderationsCONFIDENTIALITY ISSUES – The proposal should include details onhow the security of the research data will be maintained. For example, theuse of password protection on research study databases and scheduledchanges to passwords and access to research study databases restrictedto an “as-needed” basis.DOCUMENTATION OF PARTICIPATION IN MEDICAL RECORDS – Ingeneral a copy of the informed consent document should be placedin the medical records. If a medical record will be created because ofparticipation in a research study, the research subject should also beinformed of this. For any research study with more than minimal riskand all intervention research, the subject should be requested to informhis or her attending doctor of participation in the research study. If dueto confidentiality reasons the informed consent document is not placedin the medical records, the investigator should place a statement in themedical records indicating the subject’s participation in research study. 83If the research protocol may impact the research subject’s health, thestatement in the chart must include enough description of the interventionfor other health care professionals to deal with any medical problemswhich may arise.STORAGE OF BIOLOGICAL SPECIMENS – In studies involvingstorage of biological specimens, the original signature copy of eachsubject’s informed consent document should be maintained if identifyinginformation is included with the specimen. There should be writtenprocedures related to access to the research samples. 8.4 DATA AND SAFETY MONITORING
  • 102. 8.5 PRIVACY AND CONFIDENTIALITY PRIVACY is the act of maintaining respect for the patients. To protect a patient’s privacy, only healthcare professionals who have access to the patient for their clinical care should make contact with the patient, for the purpose of inviting him / her to participate in a research. CONFIDENTIALITY refers to respecting the patient’s data. To avoid breaches in confidentiality, the Principal Investigators should store identifiable data in a secured location with access control to only members of the research team. The Principal Investigator must ensure that persons without ethically permissible access should not be allowed to access medical records for research without the patient’s explicit consent unless the DSRB has granted waiver. Only persons with ethically permissible access may be allowed to make the first contact with patients.848.5 PRIVACY AND CONFIDENTIALITY
  • 103. 8.6 CONFLICT OF INTERESTCONFLICT OF INTEREST – A conflict of interest can be broadly definedto refer to any interest of the Principal Investigator or immediate family(including his or her spouse and each dependant child) that competes withthe Principal Investigator’s obligation to protect the rights and welfare ofresearch subjects.FINANCIAL INTEREST – A significant financial interest refers to anyownership of monetary value, including but not limited to, salary orpayments for services (e.g., consulting fees or honoraria); equity interests(e.g. stocks, stock options or other ownership interests); intellectual propertyrights (e.g., patents, copyrights and royalties from such rights), and boardor executive relationships.The Principal Investigator must take special care to avoid any form ofconflict of interest, whether actual, potential, or merely an appearanceof conflict as such. Where such actual, potential or apparent conflict 85arises, the Principal Investigator must reveal to the DSRB whether he / she,research personnel or their immediate family members have any financialinterests related to the research study.The declaration should give full disclosure of the facts giving rise to thefinancial interest and to detail the steps proposed to eliminate any conflictof interest that arises from the financial interest.Possible resolution of the conflict may include, but is not limited to: a. Disclosure of the conflict in the consent document, b. Modification of research plan, c. Divestiture of financial interest, and / or d. Severance of the relationship that created the conflict. 8.6 CONFLICT OF INTEREST
  • 104. The Principal Investigator must also comply with the NHG Cluster HR Policy NHG-HR-S11 to S13 which offer guidelines on managing gifts, sponsorship and entertainment when dealing with industry sponsors of research projects. Conflicting interests may arise during the conduct of the study. If such interests arise, the investigator should declare these to DSRB.868.6 CONFLICT OF INTEREST
  • 105. 8.7 RESEARCH IN VULNERABLE POPULATIONResearch Involving ChildrenThe DSRB regards children as a vulnerable population and requiresadditional protections to be in place when children are to be included inresearch. ASSENT - A child’s affirmative agreement to participate in research. Mere failure to object should not be construed as assent. CHILDREN – Persons who have not attained the legal age for consent to treatments or procedures involved in the research, who under Singapore law is an individual under the age of 21 years, excluding persons who are below the age of 21 but are married. GUARDIAN – An individual who is authorized under law to give permission on behalf of a child to general medical care. 87 PARENT – The child’s biological or adoptive parent. PERMISSION – The agreement of the parent(s) or guardian to the participation of their child or ward in research. WARD – A child who is placed in the legal custody of the State or other agency, institution, or entity. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 106. Conditions for Research Involving Children Children can be included in research only if the research fulfils any of the following three categories: a. CATEGORY 1 – Research that does not involve more than minimal risk. b. CATEGORY 2 – Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subject and the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by alternative approaches. c. CATEGORY 3 – Research involving greater than minimal risk and no prospect of benefit to the individual subject. In order to approve research in this category, the DSRB must determine that: i. The risk of the research presents no more than a minor increase88 over minimal risk. ii. The intervention or procedure presents experiences to the subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations. iii. The intervention or procedure is likely to yield generalisable knowledge about the subject’s disorder or condition which is of vital importance for the understanding or the amelioration of the disorder or condition. Consent In Research Involving Children Under the Medicines (Clinical Trials) Regulations, the Principal Investigator shall not use a child as a subject in a clinical trial, unless the following conditions are met:8.7 RESEARCH IN VULNERABLE POPULATION
  • 107. a. A child below the age of 21 years who is married, with the consent of that person. b. In the case of a child below the age of 21 years who is not married, the consent of the child is obtained, unless the child lacks sufficient understanding to give such consent and there is a reasonable prospect that participation in the clinical trial will directly benefit that child AND the consent of the child’s parent or guardian (if no parent) is obtained.Special Considerations (Singapore Context) a. When the parents are divorced, the parent who has legal custody has sole legal responsibility for the care and custody of the child. The parent who has legal custody is the legally acceptable representative for the child. b. When the child is illegitimate, the mother has sole legal responsibility 89 for the care and custody of the child. The mother is the legally acceptable representative for the child. c. The following individuals are legally acceptable representatives as they have the same rights as a parent to consent on behalf of the child to general medical care – (a) A guardian appointed under the Guardianship of Infants Act and (b) A person to whom the care of a child is committed under the Children and Young Persons Act.For the purposes of research governance in NHG and all Institutionsunder the oversight of NHG DSRB, the terms ‘consent’ is the same as‘assent’ by the child and ‘parental permission’ by the parent / legalguardian.PARENTAL PERMISSION – Since children have not reached their fullintellectual and emotional capacities and are legally unable to givea valid informed consent, involving children in research requires the 8.7 RESEARCH IN VULNERABLE POPULATION
  • 108. permission of their parents or legally authorized representatives. The DSRB will use the following guidelines to determine consent / assent requirements: a. If both parents are available and willing to provide permission, the Principal Investigator should obtain consent from both parents. b. For research approved under Category 1 and 2 as listed under Conditions for Research Involving Children, permission from at least one parent or legal guardian must be obtained. c. For research approved under Category 3, permission must be obtained from both parents, unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. WAIVER OF PARENTAL PERMISSION – Parental permission may not be appropriate in cases such as in research involving child abuse or neglect.90 The DSRB may waive parental permission, provided the following are adequately met: a. The research is designed for conditions or for a participant population for which parental or guardian permission is not a reasonable requirement to protect the participants. b. An appropriate mechanism for protecting the children who will participate as participants in the research is substituted. c. The research is not US FDA-regulated. In such cases, the DSRB should work with the Principal Investigator to devise alternative procedures for protecting the rights and interests of children asked to participate such as appointment of special guardians for the children. ASSENT BY THE CHILD – While children may be legally incapable of giving consent, they may possess the ability to assent to or dissent from participation. Out of respect for children as developing persons, children should be asked whether or not they wish to participate in8.7 RESEARCH IN VULNERABLE POPULATION
  • 109. the research particularly if the research does not involve interventionslikely to be of benefit to the subjects and the children can comprehendand appreciate what it means to be a volunteer for benefit of others. Ingeneral, the DSRB recommends that assent be obtained from childrenwho are over six years old. The DSRB will determine whether all or someof the children are capable of assent by considering the following: a. The nature of research, b. The age, status, condition of the proposed subjects, and / or c. Maturity and psychological state of proposed subjects.Primary school aged children (6 – 12 yrs old) should be providedwith a short assent document that clearly explains discomforts andinconveniences that the child may experience if he or she agrees toparticipate. The document should also emphasize the voluntary natureof the research and that the child may refuse to participate without anyconsequences. 91For research involving children of secondary school age and olderchildren (aged 13 to 20 yrs old), provision may be made in the sameconsent document that will be signed by the parents for the signature ofthe child.The DSRB must review and approve the assent document and the consentdocument prior to initiation of the study.WAIVER OF ASSENT BY THE CHILD – The DSRB may determine thatthe assent of the child is not necessary when either of the following istrue: a. The children are not capable of providing assent based on the age, maturity, or psychological state. b. The capability of the children is so limited that they cannot reasonably be consulted. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 110. c. The intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well being of the children and is available only in the context of the research. d. The assent can be waived using the criteria for waiver of the consent process even when the children are capable of assenting, if the criteria set out in Chapter 8.1 Informed Consent - Waiver of Informed Consent are met. Special Circumstance – Wards of State Additional protections need to be in place when a research involves children who are wards of state or any other institution or entity. Where the research involves greater than minimal risk to the subjects with no prospect of direct benefit to the individual subjects, (i.e. Category 3) the research must either be related to their status as wards, or else be conducted in schools, hospitals, institutions, or similar settings where92 majority of the children involved as subjects are not wards. For such research, the DSRB will require the appointment of an advocate in addition to any other individuals who are acting on behalf of the child as a guardian. The advocate must be an individual who has the background and experience to act in, and agrees to act in, the best interest of the child for the duration of the child’s participation in the research. This individual must not be associated in any way (except in the role of advocate or member of the DSRB) with the research, investigator or the guardian organisation. Research Involving Pregnant Women, Fetuses and Neonates The DSRB regards pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates as a vulnerable population and requires additional protections to be in place when pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates are included in research.8.7 RESEARCH IN VULNERABLE POPULATION
  • 111. Conditions for Research Involving Pregnant Women,and FetusesPregnant women and fetuses may be involved in research if all of thefollowing conditions are met: a. Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses. b. The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means. c. Any risk is the least possible for achieving the objectives of the 93 research. d. If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, and her consent is obtained. e. If the research holds out the prospect of direct benefit solely to the fetus, then the consent of the pregnant woman and the father is obtained, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy had resulted from rape or incest. f. Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 112. g. For children who are pregnant, assent and permission are obtained. h. No inducements, monetary or otherwise, will be offered to terminate a pregnancy. i. Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy. j. Individuals engaged in the research will have no part in determining the viability of a neonate. Conditions for Research Involving Neonates These may be involved in research under the following circumstances: NEONATES OF UNCERTAIN VIABILITY AND NONVIABLE NEONATES94 These may be involved in research if all of the following conditions are met: a. Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates. b. Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the neonate. c. Individuals engaged in the research will have no part in determining the viability of a neonate. NEONATES OF UNCERTAIN VIABILITY – Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions are met: a. The DSRB determines that: i. The research holds out the prospect of enhancing the probability8.7 RESEARCH IN VULNERABLE POPULATION
  • 113. of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or ii. The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate from the research. b. The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.NONVIABLE NEONATES – After delivery nonviable neonate may notbe involved in research covered by this subpart unless all of the followingadditional conditions are met: 95 a. Vital functions of the neonate will not be artificially maintained. b. The research will not terminate the heartbeat or respiration of the neonate. c. There will be no added risk to the neonate resulting from the research. d. The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means. e. The legally effective informed consent of both parents of the neonate is obtained, except that the waiver and alteration provisions do not apply. i. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the requirements of this paragraph, except that the consent of the father need not be obtained if the pregnancy had resulted from rape or incest. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 114. ii. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph. VIABLE NEONATES – A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accordance with the applicable requirements. OTHERS – Research that involves, after delivery, the placenta, the dead fetus or fetal material: a. Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accordance with any regulations regarding such activities. b. Where information associated with material described is recorded for research purposes in a manner that living individuals can96 be identified, directly or through identifiers linked to those living individuals, those individuals are research participants. Research Involving Cognitively Impaired Persons The DSRB regards cognitively impaired persons as a vulnerable population and requires additional protections to be in place when cognitively impaired persons are to be included in research. COGNITIVELY IMPAIRED – Having either a psychiatric disorder (e.g. psychosis, neurosis, personality or behavior disorders), an organic impairment (e.g. dementia) or a development disorder (e.g. mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. Others, including persons under the influence of or dependant on drugs or alcohol, those suffering from degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests.8.7 RESEARCH IN VULNERABLE POPULATION
  • 115. COMPETENCE – Technically, a legal term, used to denote capacity to acton one’s own behalf; the ability to understand information presented, toappreciate the consequences of acting (or not acting) on that information,and to make a choice.Competence may fluctuate as a function of the natural course of a mentalillness, response to training, effects of medication, general physicalhealth, and other factors. Therefore, mental status should be re-evaluatedperiodically.INCAPACITY – Refers to a person’s mental status and means inabilityto understand information presented, to appreciate the consequences ofacting (or not acting) on that information, and to make a choice. Oftenused as a synonym for incompetence.INCOMPETENCE – Technically, a legal term meaning inability tomanage one’s own affairs. Often used as a synonym for incapacity. 97INSTITUTION – A residential facility that provides food, shelter, andprofessional services (including treatment, skilled nursing, intermediateor long term care, and custodial or residential care).Conditions for Research Involving CognitivelyImpaired PersonsDEGREE OF RISK – Research that presents more than minimal riskshould involve cognitively impaired persons only when the researchholds prospects of direct benefit to these individuals. A minor increaseover minimal risk may be permitted in research involving institutionalizedindividuals only where research is designed to evaluate an interventionof foreseeable benefit to their care. If a research study possesses morethan minimal risk and no prospect of direct benefit to the individuals, theDSRB should obtain advice from experts regarding the appropriatenessof the research study.SELECTION OF SUBJECTS – Research involving persons whoseautonomy is compromised by disability or restraints on their personalfreedom should bear some direct relationship to their condition or 8.7 RESEARCH IN VULNERABLE POPULATION
  • 116. circumstances. Persons who are institutionalized should not be chosen for studies that bear no relation to their situation just because it would be convenient for the researcher. LIMITING RISKS – The DSRB should ensure that investigators have included a description of appropriate psychological or medical screening criteria to prevent or reduce adverse reactions to the therapeutic and research procedures. When appropriate, the DSRB might require other health care providers involved in the care of these patients to be consulted to ensure that the research will not be detrimental to ongoing therapeutic regimens. Assessing Competence As a general rule, all adults, regardless of their diagnosis or condition, should be presumed to be competent to consent unless there is evidence of a serious mental disability that would impair reasoning or judgment.98 Even those who do have a diagnosed mental disorder may be perfectly able to understand the matter of being a research volunteer, and quite capable of consenting to or refusing participation. Mental disability alone should not disqualify a person from consenting to participate in research; rather, there should be specific evidence of individuals’ incapacity to understand and to make a choice before they are deemed unable to consent. DOCUMENTING CAPACITY – For all research, regardless of study population, the person who obtains the subjects’ consent must determine that the person has sufficient capacity to give consent. This is documented by the signature in the consent form of the person obtaining consent. In research that involves cognitively impaired persons, the DSRB should consider the need for independent assessment of capacity. For participation in clinical trials, it is required to have an independent assessment of capacity by a doctor. The DSRB may set qualifications for the person making assessment such as requiring a psychiatrist or geriatrician to make this assessment. The independent assessment should be documented by a formal note that is dated and signed.8.7 RESEARCH IN VULNERABLE POPULATION
  • 117. Consent In Research Involving Cognitively ImpairedPersonsInformed consent is required unless waived under the followingapplicable criteria: a. Research that poses no more than minimal risk: i. Family members of cognitively impaired persons may consent to research when the research poses no more than minimal risk to the subjects. b. For research involving more than minimal risk and for clinical trials (under Medicines (Clinical Trials) Regulations), the consent of a person who is incapable of exercising rational judgment shall not be required if: i. The Principal Investigator and a doctor who is not otherwise participating in the clinical trial certify in writing that – • the person is incapable of exercising rational judgment; and 99 • it is not likely that the person will be capable of exercising rational judgment within the window period; ii. Consent has been obtained from – • that person’s spouse, parent, guardian (if there is no parent) or any other person having charge of him; and • if different from (i) above, that person’s legal representative; and iii. There is a reasonable prospect that participation in the clinical trial will directly benefit that person and iv. The trial cannot be practicably carried out in subjects who can give their own consent. c. For non therapeutic trials (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), the trial may be conducted with the consent of a legally acceptable representative provided that the following conditions are fulfilled: 8.7 RESEARCH IN VULNERABLE POPULATION
  • 118. i. The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally. ii. The foreseeable risks to the subjects are low. iii. The negative impact on the subjects well-being is minimized and low. iv. The trial is not prohibited by law. v. The approval of MCRC and DSRB is expressly sought on the inclusion of such subjects, and the written approval covers this aspect. vi. Principal Investigator has made provisions in the study so that the subjects are closely monitored and are withdrawn if they appear to be unduly distressed. The Principal Investigator should ascertain to the best of his ability that any persons making a decision on behalf of the subject, acts in the best100 interest of the subject and has regard, to the subject’s past and present wishes and feelings and any factors which the subject would consider if he were able to do so. The DSRB would consider whether investigators must solicit prospective subjects’ assent (i.e., the willing and, to the extent possible, knowledgeable participation of those unable to give legally valid consent). Special Circumstances PERSONS WHO ARE INSTITUTIONALISED – When the research poses more than minimal risk and has no prospect of direct benefit to the individuals. a. Persons formally adjudged incompetent who have a court appointed guardian may consent on their behalf. b. Officials of the institution in which incompetent patients reside (even if they are the patient’s legal guardian) are not generally 8.7 RESEARCH IN VULNERABLE POPULATION
  • 119. considered appropriate, since their supervisory duties may give rise to conflicting interests and loyalties. c. Family members or others financially responsible for patient may also be subject to conflicting interests because of financial pressures, emotional distancing, or other ambivalent feelings common in such circumstances.EXCEPTIONS – As a general principle, incapable persons should notbe involved in research that can be conducted with capable subjects.Inclusion of cognitively impaired persons may be permitted by MCRC(for clinical trials) and DSRB if such a research provide access to animportant benefit, particularly one that is not otherwise available outsideof the research setting.DSRB RequirementsOne of the review criteria for DSRB approval at initial review is that there 101is an adequate data safety monitoring plan. All research proposalsshould include adequate provisions for monitoring of data collected forscientific validity and safety of research subjects. The monitoring planfor a particular research study would depend on the complexity of theresearch study and the possibility of potential harm to subjects.Research Involving PrisonersThe DSRB regards prisoners as a vulnerable population and requiresadditional protections to be in place when prisoners are to be includedin research.PRISONER – An individual involuntarily confined in a penal institution,including persons: (1) sentenced under a criminal or civil statute; (2)detained pending arraignment, trial, or sentencing; and (3) detained inother facilities (e.g., for drug detoxification or treatment of alcoholism)under statutes or commitment procedures providing such alternatives tocriminal prosecution or incarceration in a penal institution. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 120. Criteria for Research Research involving prisoners should bear some direct relationship to their condition or circumstances. Prisoners should not be chosen for studies that bear no relation to their situation just because it would be convenient for the researchers. The two main issues surrounding the participation of prisoners in research are: a. Whether prisoners have a real choice regarding their participation on research or whether their situation prohibits them from exercise of free choice and b. Whether confidentiality of participation and of data can be adequately maintained. Prisoners should neither bear an unfair share of the burden of participating in research, nor should they be excluded from its benefits, to the extent that voluntary participation is possible.102 Only certain kinds of research may involve prisoners as subjects: a. Studies (involving no more than minimal risk or inconvenience) of the possible causes, effects, and processes of incarceration and criminal behaviour; b. Studies (involving no more than minimal risk or inconvenience) of prisons as institutional structures or of prisoners as incarcerated persons; c. Research on particular conditions affecting prisoners as a class; and d. Research involving a therapy likely to benefit the prisoner subject. 8.7 RESEARCH IN VULNERABLE POPULATION
  • 121. 8.8 COMPENSATION FOR RESEARCH RELATED INJURIESGeneral Principles a. The CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects states that Investigators are responsible for ensuring that research subjects who suffer injury as a result of their participation should be entitled to free medical treatment for such injury and to such financial or other assistance as would compensate them equitably for any resultant impairment, disability or handicap. b. The NMEC Ethical Guidelines on Research Involving Human Subjects states that, ‘in the event of any significant injury, the subject must be entitled to receive compensation regardless of whether there may or may not have been legal negligence of legal liability on any other basis (i.e. no fault basis). 103 c. The DSRB’s stand is that lack of compensation for medical care to individuals who are injured as a result of their involvement in a research project is indefensible because it is against the ethical principle of justice. Thus, in good faith, compensation (i.e. medical treatment of research related injuries) should be provided for all research participants who suffer a research-related injury. The Investigator’s institution may purchase clinical trial insurance and medical malpractice insurance to provide for such compensation. 8.8 COMPENSATION FOR RESEARCH RELATED INJURIES
  • 122. Guidelines for compensation of research-related injuries a. In general, institutions (and / or sponsors) should pay for medical treatment of any injuries arising from participation in the research as long as the injury is related to participation in the research and the injury is not a consequence of an existing condition or standard clinical care and standard diagnostic procedures. b. Several exclusions may be acceptable, depending on the nature of injury, study, participants etc. For example: i. Compensation may be paid for only serious injury of an enduring and disabling character and not for exacerbation of an existing condition or temporary pain or discomfort, or less serious or curable complaints. ii. Compensation need not be paid for the failure of a medicinal product to have its intended effect or to provide any other benefit to the patient; or to patients receiving placebo in consideration104 of its failure to provide a therapeutic benefit. iii. Compensation need not be paid when injuries arise due to non- compliance with the trial protocol on the part of the subject. c. The institution must remain responsible to compensate for injuries resulting from negligence / non-compliance by the research team. d. For the avoidance of doubt, these recommendations are not intended to discourage or prevent investigators (and / or Sponsors) from providing further or additional compensation to subjects if they feel that it is appropriate to do so. 8.8 COMPENSATION FOR RESEARCH RELATED INJURIES
  • 123. Sponsor-Initiated Studies a. Sponsor-initiated studies often follow the Association of the British Pharmaceutical Industry (ABPI) guidelines for compensation of research-related injuries. i. ABPI’s Guideline for Medical Experiments in Non-Patient Human Volunteers (for Phase I studies). ii. ABPI’s Clinical Trial Compensation Guidelines (for Phase II and III studies). b. The DSRB may accept alternative guidelines of compensation to research participants, if the terms provide equal to or more protection than that provided by the ABPI guidelines. c. Research participants should be adequately informed of compensation guidelines applicable to them and the limitations (if any). In addition, the Principal Investigator is encouraged to actively provide a copy of the ABPI guidelines to the research 105 participants. d. Depending on the nature of the study, risks and population involved, the DSRB may require additional provisions of compensation.Informed Consent Process and Consent DocumentLanguage a. Research participants should be adequately informed of compensation guidelines applicable to them and the limitations (if any). b. It is recommended that compensation statement in the consent document should be worded as follows: 8.8 COMPENSATION FOR RESEARCH RELATED INJURIES
  • 124. If you follow the directions of the doctors in charge of this study and you are physically injured due to the trial substance or procedure given under the plan for this study, the (Name of Institution and / or Sponsor) will pay for the medical expenses for treatment of that injury. Payment for management of the normally expected consequences of your treatment will not be provided by the (Name of Institution and / or Sponsor) – Remove if it is a healthy volunteer study. Compensation for the research related injury shall be paid by (Name of Institution and / or Sponsor) according to the Association of the British Pharmaceutical Industry’s Clinical Trial Compensation Guidelines. Broadly speaking, the ABPI guidelines recommend that without legal commitment, subjects should be compensated by (Name of Institution and / or Sponsor) without having to prove that Institution / Sponsor Name is at fault. There are limitations to106 compensation in the ABPI guidelines. A copy of the ABPI guidelines will be provided to you upon request. – Insert if it is a sponsor- initiated study / ABPI Guidelines. (Name of Institution) without legal commitment will compensate you for the injuries arising from your participation in the study without you having to prove (Name of Institution) is at fault. – Insert if this is a PI-initiated study. By signing this consent form, you will not waive any of your legal rights or release the parties involved in this study from liability for negligence. c. NHG policy does not allow for sponsor or institution to first utilise subject’s own health insurance to pay for costs related to research related injuries. 8.8 COMPENSATION FOR RESEARCH RELATED INJURIES
  • 125. 8.9 STANDING DATABASE & TISSUE BANKING“Standing databases” contain electronic data stored for the purposes ofpatient care / services and / or as a potential resource for future research.For the purposes of these guidelines, any collected and arranged privateinformation stored electronically will be considered a database.“Tissue Banks” contain tissue specimens stored for the purposes of patientcare / services and / or as a potential resource for future research. Tissuespecimens include all kinds of human biological materials derived fromliving or cadaveric donors, including solid body tissues, organs, fetuses,blood and other body fluids and their derivatives, cord blood, embryos,gametes (sperm or eggs) or any part or derivative thereof.This policy is applicable to NHG Institutions only. Good Practice Guidelines For Standing Database and Tissue Banks for Research 107 Registration of Standing Databases / Tissue Banks As part of patient care, clinical quality assurance or improvement, hospital or institution operations, many databases are created. Similarly, tissue samples are collected and stored in hospital pathological departments. Though such databases and tissue collections are created and maintained primarily for clinical / service-related purposes, they serve as a valuable resource for future research projects. Where there is a possibility for such clinical / service-related databases / tissue banks to be used for research (in parts, or in future), such databases / tissue bank should be registered. Databases and tissue banks that are created primarily for the purposes of possible future research, e.g. database of names, contact information, diagnoses for the purposes of identifying potential research subjects, or tissue repositories should be registered. 8.9 STANDING DATABASE & TISSUE BANKING
  • 126. Databases and tissue banks that are created as part of a previous DSRB- approved research project that has since completed, may be stored for possible future research. Such databases / tissue banks should be registered upon completion of the DSRB project. If the data / tissue specimens are collected for a specific research project, approval from the NHG Domain Specific Review Board (DSRB) is required. Prior permission must be sought from the relevant institutional authorities before the setting up of the database / tissue bank. These databases / tissue banks should then be registered with NHG RDO. Owner and Custodian of Standing Database / Tissue Banks The respective institutions shall own the databases / tissue banks set up108 by their staff members (“Owner”). The owners of the database / tissue banks shall appoint a suitable staff member as the overall responsible for the set up and maintenance (including security and access) of the database / tissue bank (“Custodian”). For large IT systems the “Custodian” shall be synonymous with the appointed “System Owner”. Where there is shared ownership of a database / tissue banks amongst various NHG institutions, the owners should agree upon the most suitable custodian. Should a database / tissue bank be set up with an external institution, institutions within NHG should appoint an NHG custodian to protect NHG’s interest in the joint database. The custodian does not possess any ownership of database / tissue banks. Should the custodian later leave the employment of the institution, another employee should be appointed as the new custodian by the institution. The custodian should inform the owner(s) when the database that has ceased to be useful and therefore “shut down”. 8.9 STANDING DATABASE & TISSUE BANKING
  • 127. These guidelines apply to the owner(s), the appointed custodian andany staff who have been granted access to a standing database / tissuebank.Setting up of Standing Database / Tissue BankThe procedure for setting up the database / tissue bank and subsequentacquisition of data / tissue specimens should be written and adhered to.This written procedure should include: a. A description of the types, origin, method of collection, and storage location of the data / tissue specimens. b. A list of names and designation of personnel given access to the database / tissue bank. This “access list” should be updated regularly. Access to the database / tissue bank should be restricted to authorised personnel only and should be supervised closely by the appointed custodian and kept to a justifiable minimum. 109 c. A description of the process to ensure that individual research projects utilizing the database / tissue banks will not be conducted without prior DSRB review. d. Security measures used to maintain confidentiality of data.Informed Consent For the Setting up of StandingDatabase / Tissue BankINFORMED CONSENT IS IMPLIED – For databases / tissue banksthat are created primarily for patient care, clinical quality assuranceor improvement, hospital or institution operations, informed consent isconsidered implied.Should additional information not directly relevant to patient care orservice be collected, informed consent is required, unless the process orany part thereof has been waived by the DSRB. 8.9 STANDING DATABASE & TISSUE BANKING
  • 128. Such implied consent does not remove or diminish the obligation of all staff that has access to the standing database / tissue bank to use it in a responsible and appropriate manner. INFORMED CONSENT IS REQUIRED – For databases / tissue banks that are intended for use in possible future research (regardless of whether the primary function is for research or not), informed consent from patients is required. Custodians are strongly advised to use the NHG Standard Informed Consent Form for Tissue / Data Banking to ensure that all required elements of an informed consent are present. INFORMED CONSENT IS WAIVED – In certain circumstances the requirement to obtain informed consent may be waived. The custodian should be able to justify the following four criteria, which are similar to the NHG DSRB’s requirements for waiver of informed consent for research. The justifications for waiver of informed consent should be submitted110 to the NHG RDO in the application for registration of the standing database / tissue bank. Refer to Chapter 8.1 Informed Consent, Waiver of Consent. INFORMED CONSENT REQUIREMENTS ARE ALTERED – In certain circumstances the requirement to obtain a signed consent form (e.g. verbal consent and documentation of verbal consent in medical records) may be waived provided that: a. The research presents no more than minimal risk of harm to subjects, and b. The research involves no procedures for which written consent is normally required outside of the research context. 8.9 STANDING DATABASE & TISSUE BANKING
  • 129. ConfidentialityHarms that may occur as a result of such data and tissue bankingactivities are mostly related to threats to privacy and breaches inconfidentiality. There should be adequate policies and procedures inplace to ensure adequate protections for privacy and maintenance ofconfidentiality. Such procedures should be regularly reinforced by theappointed custodian to all staff who have been granted access to thestanding database / tissue banks. Owners and appointed custodians ofstanding databases / tissue banks may undertake regular internal auditsto monitor compliance with these guidelines and to ensure that there areadequate protections for privacy and maintenance of confidentiality.The confidentiality of the private information contained in the databases/ tissue banks is primarily the responsibility of their respectivecustodians. Custodians need to put in place data security features toprevent and to monitor regularly for unauthorised access to the database/ tissue banks. Such precautions could range from structural or IT-basedsolutions features (e.g. firewalls, password protection) to organisational 111and administrative measures (e.g. regular audits).Databases should be stored in secured computers / storage media. Thesecomputers / storage media must be password-protected, and storedunder lock & key (e.g. in a locked cupboard / office). There should bescheduled changes (at least every 6 months) to the password.Standing databases / tissue banks that are for the purposes of patientcare or service, often contains identifiers. The custodian shoulddemonstrate that when utilizing such stored data / tissue specimens, thepatient’s rights for confidentiality had been maintained.For standing databases / tissue banks that are for the purposes ofpossible future research, patient identifying information should bestored separately in a different location with links maintained in themain database / tissue specimens. The custodian should oversee andcontrol access to the identifying links on a strictly need-to-know basis, tomaintain the confidentiality of the data. 8.9 STANDING DATABASE & TISSUE BANKING
  • 130. Owners and Custodians are responsible for taking active steps to ensure that all staff who are given access to the database / tissue bank as part of their work, maintain the confidentiality at all times. Utilisation of Stored Data / Tissue Specimens Each subsequent research project (including research projects initiated by the custodian and all staff listed in the “access list”) utilising any standing database / tissue specimens, will require prior approval from NHG DSRB before project initiation. The concurrence of the custodian should also be obtained. Depending on the nature of the study, the DSRB will determine if access to the standing database / tissue bank may require additional consent. Some considerations by the DSRB will include whether any patient contact is proposed, the practicability of getting informed consent for the research, and whether the data extracted and used for the research will112 be de-identified or aggregated etc. In general, recipients of the data / tissue specimens should not be provided with identifiable information or to information through which identities of patients or subjects may be readily ascertained. Disposal of Stored Data / Tissue Specimens When the database / tissue bank is no longer required and the institution so agrees, all data / tissue specimens and identifying links must be destroyed immediately. Should the owner deem it necessary to archive a database for future reference, the owner should continue to comply with the guidelines on storage of data. The owner shall be responsible for the safekeeping of archived databases. A notification should be sent to DSRB when the custodian do not wish to maintain the standing database / destroy the data / tissue transfer the custodian. 8.9 STANDING DATABASE & TISSUE BANKING
  • 131. 9.0MINIMUM QUALIFICATIONSAND TRAINING TO BE ANINVESTIGATOR9.1 Who Can Be A Principal Investigator?9.2 Minimum Training Requirements 9.0
  • 132. 9.1 WHO CAN BE A PRINCIPAL INVESTIGATOR?The minimum requirements of being a Principal Investigator (PI) for aresearch study is based on the risks involved in the research project.MINIMAL RISK STUDIES - The research proposals that qualify for exempt /expedited review will be considered to be minimal risk studies. To be a PIfor a minimal risk study, the individual should at least be a: a. Fully registered medical practitioner, b. Fully registered nurse or c. Fully registered allied health practitioner.GREATER THAN MINIMAL RISK - The research proposals that do notqualify for exempt / expedited review and are reviewed by the full boardare considered to be greater than minimal risk. To be a PI for a greaterthan minimal risk study, the individual should at least be a: 113 a. Fully registered medical practitioner who is an Associate Consultant and above, b. Senior Staff Nurse and must have an Associate Consultant or above on the research team or c. A senior therapist / pharmacist and must have an Associate Consultant or above on the research team.For research conducted in NHG, the PI should be a NHG staff. Thisrequirement is not solely for the purpose of the application to DSRB, as thePI has the responsibility for ensuring that the conduct of the research withinNHG is in compliance with SGGCP and all other applicable guidelinesand regulations. 9.1 WHO CAN BE A PRINCIPAL INVESTIGATOR?
  • 133. Special Considerations VISITING CONSULTANTS – If the PI holds a Visiting Consultant position within NHG, there should be at least one full time NHG staff who is a study team member for that study (the designation of the collaborator should follow the guidelines outlined above). MULTI-CENTRE BETWEEN TWO CLUSTERS – If the research project involves both clusters and the PI for the project is from SingHealth; it is necessary to have a PI from NHG. MULTI-CENTRE WITHIN NHG – If the research study is going to be conducted in more than one site, each site should have a Site PI who is responsible for the conduct of the study in his / her institution. One of the Site PIs should be designated as PI for the study, who is responsible for the coordination of investigators at different institutions participating in the multi-centre study, including but not limited to communication with114 the DSRB. Change of Principal Investigator / Study Team Members If the Principal Investigator is resigning from NHG or is going away for an extended duration of time, the research project should be formally transferred to another Investigator. This Investigator assumes all the responsibilities as the Principal Investigator for the conduct of the research project until the original Principal Investigator returns. This change should be reviewed and approved by the DSRB. The above also applies to any change in the study team member list. The DSRB must be informed and approval sought before any new addition or change is made to the study team member list. The existing Principal Investigator must submit a Protocol Amendment Cover Note, along with the relevant documents, to the DSRB for approval. The relevant document may include, but is not limited to: a. For a change in Principal Investigator, the prospective Investigator’s latest CV (most recent, at least up to the past one year). 9.1 WHO CAN BE A PRINCIPAL INVESTIGATOR?
  • 134. 9.2 MINIMUM TRAINING REQUIREMENTSThe intent of having minimum training requirements is for Investigators toappreciate and apply the ethical principles underlying research to the dayto day practice of research. Courses COLLABORATIVE INSTITUTIONAL TRAINING INITIATIVE (CITI) – This is a web based training program that consists of 7 core modules and 5 elective modules, on the protection of human subjects in research. It is essential for all Principal Investigators and Co-Investigators to complete this training program. SINGAPORE GUIDELINE FOR GOOD CLINICAL PRACTICE (SGGCP) COURSE – Principal Investigators And Co-Investigators who have completed the SGGCP course conducted by NUS do not need to 115 complete the CITI program. The SGGCP course may be used as an alternate minimum requirement. Waiver of Minimum Training Requirement If the PI or Co-I have attended any other course relevant to research ethics, the PI or Co-I may apply for waiver of requirement to complete the CITI or SGGCP course program. This will be reviewed for approval by the DSRB and the waiver may be granted on a case by case basis. 9.2 MINIMUM TRAINING REQUIREMENTS
  • 135. CRITERIA TO QUALIFY FOR WAIVER – Any program that qualifies as a research ethics training equivalent of CITI should be at minimum, an 8 hour program. The program should be organised and conducted by a reputed body – for example NUS, NHG Institutions and HSA and should address most of the following topics: a. History Principles of Research Ethics b. Regulatory Framework and Guidelines in Singapore c. Informed Consent d. Privacy and Confidentiality Issues For more information The CITI Program is available online at http://www.citiprogram.org116 9.2 MINIMUM TRAINING REQUIREMENTS
  • 136. 10.0RESPONSIBILITIES OFINVESTIGATOR 10.0
  • 137. 10.0 Responsibility and AccountabilityTHE PRINCIPAL INVESTIGATOR is the person primarily responsible forthe conduct of the research study. If a team of individuals is involved inthe research, the Principal Investigator is the leader of the team.The responsibility of filling up the B2BResearch Online DSRB ApplicationForm rests solely on the Principal Investigator even if the task is delegated.The rights, safety and well being of the research subjects are of utmostimportance and hence the research proposal should demonstrate thatthere are adequate provisions to protect rights, safety and wellbeing ofresearch subjects.If the research study is going to be conducted in more than one site, eachsite should have a Site PI who is responsible for the conduct of the studyin his / her institution. One of the Site PIs should be designated as PIfor the study, who is responsible for the coordination of investigators atdifferent institutions participating in the multi-centre study, including but 117not limited to communication with the DSRB.The Principal Investigator must adhere to the following declarations: a. The Principal Investigator will not initiate the study until he / she has received notification of the DSRB Approval and the regulatory authority approval (if applicable). b. The Principal Investigator will not initiate any change in protocol without prior written approval from the DSRB except when it is necessary to reduce or eliminate immediate risk to the subjects. Thereafter, the Principal Investigator will submit the proposed amendment to the DSRB and other relevant authority for approval. c. The Principal Investigator will promptly report any unexpected or serious adverse events, unanticipated problems or incidents that may occur in the course of the study. 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 138. d. The Principal Investigator will maintain all relevant documents and recognize that the DSRB and other regulatory authorities may inspect these records. e. The Principal Investigator understands that failure to comply with all applicable regulations, institutional and DSRB policies and requirements may result in the suspension or termination of this study. f. The Principal Investigator declares that there are no conflicting interests for any of the research personnel participating in the study. Should there be any conflict of interest, the Principal Investigator must complete and submit Annex B – Conflict of Interest Declaration Form for each individual having the conflict. CO-INVESTIGATORS / COLLABORATORS are individual members of the research / clinical trial team, who are designated and supervised by the Principal Investigator at the institution site to perform research118 / trial-related procedures and / or to make important research related decisions (e.g. associates, residents, research fellows). Qualifications And Agreements The Investigator must be qualified by education, training and experience to assume responsibility of the proper conduct of a research study and should meet all qualifications specified by the applicable regulatory requirements. The Investigator should be thoroughly familiar with the study protocol. When conducting clinical trials, the investigator should be thoroughly familiar with the investigational product(s) as described in the Investigator’s Brochure, in the product information and other sources. The Principal Investigator should maintain a list of appropriately qualified persons to whom the Principal Investigator has delegated significant research related responsibilities. 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 139. Adequate ResourcesThe Principal Investigator should have sufficient time and adequatequalified personnel (including Co-Investigators, Collaborators, and allother research staff) to properly conduct and complete the research.The Principal Investigator should ensure that all persons assisting with theresearch are adequately informed about the protocol, the investigationalproduct(s) and their research related duties.Care Of SubjectsAny qualified physician (or dentist, when appropriate) who is aninvestigator or a co-investigator for the research study should beresponsible for all research related medical (or dental) decisions.The Investigator should ensure that adequate medical care is providedto a subject for any adverse events, including clinically significant 119laboratory values, related to the research.The Investigator is to inform the subject’s primary physician about thesubject’s participation in the trial if the subject has a primary physicianand if the subject agrees to the primary physician being informed. 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 140. Communication With DSRB The Principal Investigator should obtain DSRB approval before initiating a research project if the research involves patients, staff, premises, or facilities of NHG institutions and all Institutions under the oversight of NHG DSRB. Safety Reporting The Investigator must report all unanticipated problems involiving risks to subject or others (UPIRTSO) that occur during the conduct of a research project to the DSRB in accordance with the timelines set by DSRB and relevant regulatory authorities. Study Status Report120 The Principal Investigator should submit a status report of the trial to DSRB and relevant regulatory authorities annually or more frequently, if requested. Compliance With Protocol The Investigator should conduct research in compliance with the approved protocol and all applicable regulations. The Investigator should not implement any deviation from or changes to the protocol without agreement by the sponsor and prior review and documented approval from the DSRB of an amendment, except where necessary to eliminate an immediate hazard(s) to subjects, or when the change(s) involve only logistical or administrative aspects of the study. The Principal Investigator bears direct responsibility for the conduct of the research study. The Principal Investigator should employ sound study design in accordance with standards of the discipline. The study design should minimize risks and maximize benefits. In studies involving greater 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 141. than minimal risks to participants, the Principal Investigator must submita data safety monitoring plan for review and approval by the DSRB andcomply with the plan.Informed Consent Of Trial SubjectsThe Investigator or research staff must recruit participants in a fair andequitable manner, weighing the potential benefits of the research to theparticipants against their vulnerability and risks involved.The Principal Investigator must ensure that informed consent is obtainedfrom subjects prior to their enrollment into the research, unless waivedby the DSRB. The Principal Investigator must use the latest approvedversion of the consent documents approved by the DSRB.Records & Reports 121The Principal Investigator must maintain all essential study documentsand recognize that the DSRB staff and applicable regulatory authoritiesmay inspect these documents. The Principal Investigator can refer tothe Investigator file content template to ensure that all relevant studyessential documents are filed accordingly.The Principal Investigator must ensure the accuracy and completeness ofdata in all case report forms and study reports.Essential documents should be retained for at least 2 years after the lastapproval of a marketing application and until there are no pending orcontemplated marketing applications, or for at least 2 years beyondthe formal discontinuation of clinical development of the investigationalproduct or 6 years after the completion of the clinical trial. Thesedocuments should be retained for a longer period however if requiredby the applicable regulatory requirements or by an agreement with thesponsor. 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 142. Reporting Requirements The Principal Investigator must report to relevant authorities if any research subject is suspected of having a notifiable disease according to relevant regulations and institutional requirements. If abuse or neglect of a child or an elderly person is detected, the Principal Investigator must ensure that this is reported to relevant authorities and in accordance to institutional requirements. Investigational Product The Principal Investigator is responsible for the investigational product accountability at the study site. The Principal Investigator may assign some or all of the Principal Investigator’s duties for investigational product accountability at the study site to an appropriate pharmacist or another appropriate individual who is under the supervision of the122 Principal Investigator. The Principal Investigator should maintain an investigational product accountability log that accurately documents the receipt, storage, use and destruction of the investigational product. The Principal Investigator should also ensure that the investigational product is stored and dispensed in compliance with the approved protocol. Randomisation Procedures And Unblinding The Principal Investigator should follow the study randomization procedures, if any, and ensure that the randomization code is broken only in accordance with the protocol. If the study is blinded, the Principal Investigator should promptly document and explain to the sponsor, if applicable, any premature unblinding (eg. accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s). 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 143. Premature Termination Or Suspension Of A Trial The Principal Investigator should promptly inform the trial subjects and assure appropriate therapy and follow-up for the subjects if the study is prematurely terminated or suspended for any reason. The Principal Investigator should inform DSRB and the relevant regulatory authorities if the study is prematurely terminated or suspended for any reason. Conflict Of Interest The Principal Investigator must declare on the application to the DSRB whether the research personnel or their immediate family members have any financial interests related to the research study. The declaration should give full disclosure of the facts giving rise to the financial interest and to detail the steps proposed to eliminate any conflict of interest that 123 arises from the financial interest. Conflicting interests may arise during the conduct of the study. If such interests arise, the Investigator should declare these to DSRB. Sponsored Clinical Trials The Principal Investigator and the sponsor must sign a Clinical Trial Agreement. The Principal Investigator should ensure that the clinical trial is conducted according to the signed Agreement.For more informationRefer to Chapter 8.6 Conflict of Interest.Refer to Chapter 13 Appendices for ‘The Investigator File ContentTemplate’. 10.0 RESPONSIBILITY AND ACCOUNTABILITY
  • 144. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 145. 11.0PREPARING FOR AUDIT 11.0
  • 146. 11.0 Preparing for AuditUpon receiving notice that an audit / inspection is to be scheduled, whereappropriate, the Investigator should inform the Director of Research asappropriate, the purpose, time and date of the audit. If the research teamreceives a notice for an inspection, the Investigator should inform thesponsor of the study, if any, as soon as possible.The clinical research coordinator should ensure that all documentation,including informed consent forms, source documents, CRFs and theInvestigator file for the study are accurate, complete and available forreview by the auditor.The clinical research coordinator / study pharmacist should ensure that thestudy drug dispensing records are accurate, complete and available forreview and if there were any instances in which an emergency breaking ofthe blind was required, the documentation would have to be available. 124The research manager or designee should ensure that records of staffqualifications and training and research SOPs are available for review bythe auditor.The Investigator should ensure that key study team members are availablefor a meeting with the auditors on the day of the audit.For more informationRefer to Chapter 13 Appendices for ‘Pre-Audit Checklist’. 11.0 PREPARING FOR AUDIT
  • 147. During The Audit The Investigator should meet with the auditors, and provide orientation and access to the study records and files and provide copies of requested study- related documents. The Investigator should ensure that questions posed by the auditor or inspector are answered by the appropriate study personnel. For more information Refer to Chapter 13 Appendices for ‘Possible Questions During An Audit’. Follow Up To Audit The Investigator should participate in the exit interview with the auditor or125 inspector. The Investigator must respond to the audit report as soon as possible after its receipt and reply to each item in the report, providing clarifications or indicate steps that will be taken to institute corrective action. QA Study Review Checklist for Investigator (Investigator Self Assessment) The Self-Assessment tool is an effective way for Investigators to ensure that the research is conducted in compliance with the applicable guidelines. The Investigator Self Assessment Checklist is easy to complete. This checklist will assist the investigator in familiarizing with the requirements for proper conduct of research and also help in the identification of areas that require corrective action. 11.0 PREPARING FOR AUDIT
  • 148. Investigators will be required to submit this self assessment checklist along with the annual Study Status Report Form to DSRB. Once the Investigator has completed the checklist, the checklist can either be faxed or scanned along with the study status report form to the DSRB / NHG QA department. The NHG QA department will review the Investigator Self Assessment Checklist and make recommendations, where required. Once the Investigator has received these written recommendations, he or she is required to respond to NHG QA department within the indicated timeline.For more informationRefer to Chapter 13 Appendices for ‘Study Review Checklist’. 126 11.0 PREPARING FOR AUDIT
  • 149. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 150. 12.0SUGGESTED READINGS 12.0
  • 151. 12.0 SUGGESTED READINGSa. Proper Conduct Of Research Standard Operating Procedures – This document is available online at http://www.b2bresearch.nhg.com.sgb. Belmont Report – This document is available online at http://www.hhs.gov/ohrpc. Declaration of Helsinki – This document is available online at http://www.wma.netd. SGGCP – This document is available for purchase from the Health Products Regulation Group, Health Sciences Authority.e. Guidances by the Bioethics Advisory Committee (BAC) – Guidance documents by the BAC are available online at http://www.bioethics-singapore.org 127f. Medicines Act (Chapter 176) - This document is available online at http://statutes.agc.gov.sgg. Medicines (Clinical Trial) Regulations 2000 – This document is available for purchase from SNP Corporation Ltd (Legal Publications) or contact http://www.snpcorp.comh. Ethical Guidelines on Research Involving Human Subjects by National Medical Ethics Committee - This document is available online at http://www.moh.gov.sgi. Code of Ethical Practice in Human Biomedical Research – This document is available online at http://www.moh.gov.sg 12.0 SUGGESTED READINGS
  • 152. Today, the world benefits greatly from major advances in medicine throughthe conscientious and concerted efforts of the research community to translateresearch knowledge into feasible clinical applications. As we benefit from thefruits of research, and recognize the effort by the research community, noless appreciation goes to the contribution of research participants. To ensurethat research is continually conducted in a scientifically and ethically robustmanner, guidelines and principles are developed and adhered to widely.These include the Nuremberg Code (1946), Declaration of Helsinki (1964),the Belmont Report (1979) and the Singapore Guidelines to Good ClinicalPractice (1998), all unanimously created to facilitate scientifically and ethicallyapplauded research, that promote respect, beneficence and justice in humansubject research.In parallel with the demands of excellence in research and research ethics,the Investigator Manual is written to guide investigators and research teammembers on the ethical conduct of research conducted under the oversight ofthe National Healthcare Group Domain Specific Review Board (NHG DSRB).The Manual serves as an essential resource for investigators to carry outresearch responsibly. A comprehensive toolkit for best research ethics practice,this Manual outlines the overall governance of research, provides proceduralguidelines for meeting ethical requirements in research, and offers guidanceon key ethical issues.
  • 153. 13.0APPENDICESa Participant Information Sheet e Investigator File Content Checklist f Pre Audit Checklistb Short Form Consent - g Possible Questions During An Example An Auditc Waiver Of Documentation h Study Review Checklist Of Consent - Examples i Applicable Feesd Waiver Of Consent – Examples 13.0
  • 154. a. PARTICIPANT INFORMATION SHEET CHECKLIST CHECKLIST Yes No1 Is the language and documentation of the Information Sheet appropriate?2 Do the explanations of the research provide an accurate assessment of the risks and anticipated benefits?3 Study Information A full title of the research study. The name and contact number of the Principal Investigator. The name of the Sponsor of the study, if any. 1284 Purpose Of The Research Study A statement that mentions that the study involves research. A statement describing why the subject was invited to participate. An explanation of the purpose of the research. Target recruitment from institution, Singapore and total. Expected duration of study period is mentioned.5 Procedures To Be Followed In This Study Probability of randomization to study arms. A description of visits and procedures to be followed by the protocol.6 Subject’s Responsibilities In This Study List of responsibilities of the subject. PARTICIPANT INFORMATION SHEET CHECKLIST
  • 155. CHECKLIST Yes No 7 Non Standard Care Or Experimental In This Study A description of all the aspects of the study that are being done specifically for the research and that are experimental. 8 Possible Risks And Side Effects Description of side effects and risks is adequate. 9 Possible Benefits From Participating In The Study A description of the potential benefits of participating in the study. 10 Important Information For Women Subjects Risks to embryo or fetus for subjects who may become pregnant while on the study.129 11 Alternatives To Participation A description of alternate treatment options available. 12 Costs And Payments If Participating In The Study List of procedures that will be performed at no cost. Reimbursement / Compensation for transport and time. Additional costs that the patient might have to bear as a result of participation in the study. A statement that the institution/doctor is being paid by sponsor (for sponsor initiated studies) for conducting this trial. 13 Voluntary Participation Assurance that participation is voluntary and the subject can discontinue from the study without being penalized. If appropriate, a description of the consequences of subject withdrawal and procedures for orderly termination. PARTICIPANT INFORMATION SHEET CHECKLIST
  • 156. CHECKLIST Yes No A statement that significant new findings developed during the course of the study that might relate to the subject’s willingness to participate in the study will be conveyed to the subject.14 Compensation For Injury A statement that medical expenses for treatment of research related injuries will be paid for. The information being communicated to the participant or the legally acceptable representative during the consent process would not include exculpatory language through which the participant or the legally acceptable representative is made to waive or appear to waive any of the participant’s legal rights. The information being communicated to the participant or the legally acceptable representative during the 130 consent process would not include exculpatory language through which the participant or the legally acceptable representative released or appeared to release the investigator, the sponsor, the institution, or its agents from liability for negligence.15 Confidentiality Of Study And Medical Records A description of how confidentiality will be maintained – a declaration that records might be inspected by sponsor/ regulatory bodies (including FDA) /DSRB.16 Contact Information An explanation of whom to contact for questions about the research issues. An explanation of whom to contact for questions about the research related injuries and compensation issues. PARTICIPANT INFORMATION SHEET CHECKLIST
  • 157. CHECKLIST Yes No An explanation of whom to contact for questions about the ethical issues. 17 Signature Provision for Subject to sign. Is there provision for legally acceptable representative to sign? If yes, is this approved by DSRB?131 PARTICIPANT INFORMATION SHEET CHECKLIST
  • 158. b. SHORT FORM CONSENT – AN EXAMPLEStudy Title:You are being invited to participate in the above research study. Before youagree, the investigator must tell you about: i. the purpose, procedures and duration of the research; ii. any procedures which are experimental; iii any reasonably foreseeable risks or discomforts, iv. any potential benefits of the research; v. any alternative procedures or treatments; and vi. how confidentiality will be maintained. 132Where applicable, the investigator must also tell you about: i. any available compensation or medical treatment if injury occurs; ii. the possibility of unforeseeable risks; iii. circumstances where the investigator may halt your participation; iv. any added costs to you; v. what happens if you decide to stop participating; vi. when you will be told about new findings which may affect your willingness to participate; and vii. how many people will be in the study. If you agree to participate, you must be given a signed copy of this document and a written summary of the research.You may contact at any time you havequestions about the research SHORT FORM CONSENT – AN EXAMPLE
  • 159. You may contact at if you have questions about your rights as a research subject or what to do if you are injured. Your participation in this research is voluntary, and you will not be penalized or lose benefits if you refuse to participate or decide to stop. Signing this document means that the research study, including the above information, has been described to you orally, and that you voluntarily agree to participate. Name of participant Signature of participant Date133 Name of witness Signature of witness Date For more information Refer to http://www.b2bresearch.nhg.com.sg (Downloads) for the ‘Short Form Consent’ in Chinese, Malay and Tamil. SHORT FORM CONSENT – AN EXAMPLE
  • 160. c. WAIVER OF DOCUMENTATION OF CONSENT – EXAMPLESExamples where a waiver of documentation of consentmay be approved: a. When the identities of subjects will be completely anonymous and there is minimal risk involved in the study. The signed informed consent would be the only record linking the subject to the study therefore it would be the only identifier in the study. b. When there is a possible legal, social or economic risk to the subject entailed in signing the consent form, e.g., for immigrants who might be identified as being illegal aliens, or for HIV antibody-positive individuals who might be identified as such by signing the consent form. c. When the study involves only a telephone interview.Scenario 1: 134 A researcher plans to evaluate the effectiveness of a smoking cessation programme with women who are receiving prenatal care at the local health clinic. During a prenatal visit, any women who are already participating in the smoking cessation programme will be asked to complete a written questionnaire about the program. The one-time written questionnaire includes questions about how well the women are complying with the program and how they feel about their progress. There is no identifying information about the subjects on the questionnaire and whether the subjects complete the questionnaire has no effect on the care they may receive at the clinic. WAIVER OF DOCUMENTATION OF CONSENT – EXAMPLES
  • 161. How the above example satisfies the criteria for Waiver of Documentation of Consent. a. Minimal risk: The anonymous questionnaire fits definition of minimal risk, and the only potential harm comes from the breach of confidentiality. b. Linkage: The consent document is the only record linking the subject and the research activity. c. Implied consent: By the virtue of completing the questionnaire, the subjects have consented to participate in the research. Use of Verbal Consent Investigators may wish to replace signed consent with verbal consent. The DSRB will consider approving such requests in limited circumstances, and will usually require use of an information sheet. If this is not feasible (for example, the only contact is by phone), the DSRB may ask to see a script of what would be said to prospective subjects to evaluate the consent process.135 Use of Information Sheets In cases where the documentation requirement is waived, the DSRB may require the investigator to provide subjects with a written statement regarding the research. The DSRB will usually call for use of an information sheet that includes most or all of the elements of a consent form but not the subject’s signature. Acknowledgements • Institutional Review Board: Management and Function, R. Amdur and E. Bankert. • NYU SoM Guidance Document - Guidelines of Requests for Waiver of Consent - Version 1 – 07/07. WAIVER OF DOCUMENTATION OF CONSENT – EXAMPLES
  • 162. d. WAIVER OF CONSENT – EXAMPLESScenario 1: Review of medical records of all patients who have undergone abdominal surgery in the past two years and correlate the data with blood chemistry values kept by pathology. Researchers are collecting limited data that will be assigned a random code # and the link is known only to the researchers. Results of the research will not affect clinical care of the individuals, since they have left the hospital. How the above example satisfies the criteria for Waiver of Informed Consent. a. Minimal risk: Evaluating non-sensitive data from patient records fits the definition of minimal risk. 136 b. Would not adversely affect rights and welfare of subject: Surgery and associated blood chemistry values are clinically indicated, therefore would be done regardless of the research. No study results would affect clinical decisions about the individual’s care. c. Research could not be practicably carried out without the waiver: Identifying and contacting thousands of potential subjects, while not impossible, would not be feasible for a medical record review where results would not change the care which the individuals have already received. (Note: In smaller studies, it is harder to argue that obtaining consent is not feasible, especially if subjects have not yet been treated or are still being seen.) d. Whenever appropriate, subject will be provided with additional pertinent information after participation: Not appropriate in this case, since results of research would have no effect on the subjects; there is no anticipated benefits to subject that would change what has already occurred. WAIVER OF CONSENT – EXAMPLES
  • 163. Scenario 2: A researcher plans to review the medical records using the same procedures in the previous example. However in this research, the hypothesis is that there is a correlation between a particular drug intervention and development of neurology problems several years later. As with the previous example, the DSRB may find that a waiver of informed consent is appropriate for the same reasons (part a, b and c) as outlined in the example. However, there is one important difference. Providing Additional Pertinent Information In this example, the DSRB may determine that it would be appropriate to provide these subjects with additional information about the results of the study. For the DSRB to make this determination, the DSRB may require the researcher to submit the results of the research, along with an assessment of whether subjects should be provided additional pertinent information, to the DSRB for review. The DSRB may require the researcher to outline a137 process that would include how the information about the research results would be communicated to the subjects, what the results might mean and what to do if there are any questions. Acknowledgements • Institutional Review Board: Management and Function, R. Amdur and E. Bankert, Chap. 6-6, “Research without Consent or Documentation Thereof,” M. M. Elliott. WAIVER OF CONSENT – EXAMPLES
  • 164. e. INVESTIGATOR FILE CONTENT ESSENTIAL DOCUMENT Yes No Remarks 1. STUDY TEAM Contact details of study team Study responsibilities log CVs of Study Team Members Financial Disclosure (if required) 2. PROTOCOL Study protocol + amendments Patient Information Sheet + amendments PIS translations (with certificate) 138 Advertisements Investigator’s Brochure (IB) Safety update letters for inclusion in IB Sample of Questionnaires/survey forms Sample of Diary cards Sample of Memory aids for study procedures Any other written information given to the patient Sample of CRF 3. REGULATORY Domain Specific Review Board (DSRB) Copy of submission to DSRB DSRB Approval letters DSRB Acknowledgement letters INVESTIGATOR FILE CONTENT
  • 165. ESSENTIAL DOCUMENT Yes No Remarks Study Status Reports Renewals Correspondence with DSRB Health Sciences Authority (if applicable) Copy of submission to HSA Clinical Trial Certificate Progress Reports Renewals Correspondence with HSA 4. SUBJECT LOGS Screening log139 Enrollment log Subject Visit Schedule Log Signed Informed Consent Forms 5. UPIRTSO Copies of UPIRTSO reports if not included in CRF UPIRTSO log for events in non-site subjects UPIRTSO log for events in site subjects 6. DRUG ACCOUNTABILITY Prescribing information Order / Delivery note Study drug accountability records INVESTIGATOR FILE CONTENT
  • 166. ESSENTIAL DOCUMENT Yes No Remarks Study drug dispensing records Study drug disposal records Sealed unblinding envelopes Individual treatment codes7. LABORATORY Logistic Arrangements with lab (if local lab is used) Lab results Lab certifications and normal ranges Biological specimen sampling, labelling, storing and shipping procedure Biological specimen log 140 Shipping records (if central lab is used)8. MONITORING Monitoring log Monitoring reports Investigator meeting agenda, minutes Initiation meeting agenda, minutes Correspondence9. ADMINISTRATIVE DOCUMENTS Investigator agreement if any Insurance records Budget Financial expenditure records INVESTIGATOR FILE CONTENT
  • 167. ESSENTIAL DOCUMENT Yes No Remarks Billing statements 10. Other Documents Completed CRF Study completion report Publications, presentations, manuscripts, etc PLEASE USE THIS SPACE FOR ADDITIONAL EXPLANATION / COMMENTS141 INVESTIGATOR FILE CONTENT
  • 168. f. PRE AUDIT CHECKLIST 1. ORGANIZATION CHECK COMMENTS Notify all parties involved with the clinical study • Sponsor (if an inspection) • CRU / OBR • Co-investigators • Pharmacy • Laboratories • Medical Records Office • Administration Office • Legal counsel • Others: 142 General overview of the study • Prepare a general overview of the study • List all personnel and responsibilities delegated Reserve work space for the auditor 2. FILES MANAGEMENT (also refer to Investigator File Content Checklist) Organize study file (not limited to the following) Study Team / Protocol • Protocol (all versions) • Investigator’s Brochure (all versions) PRE AUDIT CHECKLIST
  • 169. CHECK COMMENTS • Protocol amendments • Form FDA 1572 (all versions) if applicable • CVs for PI and co investigators listed on all versions of Form FDA 1572 (if present) IRB documents • Approval letter (initial) for initial protocol with original informed consent • Amendment approval(s) with approved informed consent (if applicable) • Informed consent forms (originals) for enrolled subjects143 • Informed consents for screened subjects • Reports to IRB – renewals, UPIRTSO, etc List of subjects • List all subjects enrolled including name, address, and/or phone number, date enrolled, medical record number (to be kept as a reference for site research staff ) • List all subjects screened/enrolled Communications • Sponsor correspondence • CRO correspondence • Monitoring log PRE AUDIT CHECKLIST
  • 170. CHECK COMMENTS Laboratory • Laboratory certification and normal ranges • Drug accountability log to include: receipt, dispensing, return, disposition Subject documents • Completed CRFs for each subject enrolled • Source documents for each subject enrolled3. REVIEW Retrieve and review for each subject enrolled • CRFs completed for each subject enrolled • Data correction forms for CRFs Medical records – The following are 144 documented for each enrolled subject, but not limited to: • Subject enrollment in the study and signed consent document given to subject • Condition of subject at time of entry into the study (i.e. all inclusion/exclusion criteria are met) • Exposure to test article • Concomitant medications • Clinical assessments of the subject during the course of the study • Laboratory reports • Diagnostic tests • Dose modifications PRE AUDIT CHECKLIST
  • 171. CHECK COMMENTS • Adverse events / UPIRTSO / death • Protocol exemptions • Early termination145 PRE AUDIT CHECKLIST
  • 172. g. POSSIBLE QUESTIONS DURING AN AUDIT 1. What is your research topic? 2. How are prospective subjects identified for the project, i.e. what are your recruitment strategies? 3. Describe the screening method used to determine the first stage of eligibility and who implements the screening process. 4. Describe the mechanisms you have in place to ensure that each subject meets the stated inclusion / exclusion criteria and that all study procedures are implemented as written. 5. Once a prospective subject is identified, describe step-by-step the procedures implemented to inform the subject prior to obtaining a signature on the informed consent document. Who implements the informed consent process in depth? 146 6. Who addresses questions presented by the subject or subject’s family? 7. Is the principal investigator usually present for the informed consent process? 8. What is the time interval between the presentation of the research study information and the actual signing of the consent form? 9. Who are the study team members and what are their responsibilities in the study? 10. What are the study procedures and how are they performed? 11. What is the procedure for investigational product accountability? 12. What is the procedure for randomization and unblinding? 13. How are the biological samples handled? 14. Do you maintain an Investigator / Study File for this study? 15. Do you have case report forms / data collection tools developed for this study? POSSIBLE QUESTIONS DURING AN AUDIT
  • 173. 16. How do you handle the data collected? 17. Where are your research records stored? 18. What mechanisms do you have in place to protect the confidentiality of your subjects? 19. How frequently is the study data reviewed, i.e. per subject, per month etc? 20. How would you handle an unexpected event such as the loss of research records or study data? 21. How do you deal with unanticipated problems involving risks to subjects and others? 22. What additional mechanisms do you have in place to protect subjects in your research? 23. What do you do if you receive a complaint from a subject? If you are unable to resolve the issue – what do you do?147 24. Describe your oversight of the study and the communications that occur regarding this study, i.e. do you have weekly meetings? 25. Who is responsible for preparing and submitting DSRB correspondence? 26. Do you have adequate resources to perform your duties? POSSIBLE QUESTIONS DURING AN AUDIT
  • 174. h. STUDY REVIEW CHECKLISTProtocol Title :Principal Investigator :DSRB Protocol Number: DSRB- / /All the questions should be ticked as Yes (or NA) to indicatecompliance to study and guidelines. If No is ticked, pleaseindicate the reason and any follow up actions done in thespace provided at the end of this checklist.1. INITIAL REVIEW Yes No NA1.1 Is the Initial IRB Approval letter on file?1.2 Are the current approved documents and correct version used for the study? 1482. CONTINUING REVIEW [Check here if not applicable and proceed to next section] Yes No NA2.1 Has the study undergone Continuing Review?2.2 Was the DSRB Study Status Report Form submitted on time?2.3 There was no lapse between Expiry date and continuing review date.2.4 There were no subject enrolled and study procedures done (if there was a lapse period).2.5 DSRB was informed of any subject enrolled and study procedures done (if there was a lapse period).3. PROTOCOL AMENDMENT [Check here if not applicable and proceed to next section] Yes No NA3.1 Have there been any amendments to the protocol and/or Participant Information Sheet/Informed STUDY REVIEW CHECKLIST
  • 175. Yes No NA Consent Form & other documents eg. Data Collection Form or Case Report Forms? 3.2 If yes, do all amendments have DSRB documented approval? 3.3 Are the amended documents used only after DSRB approval? 3.4 If NO to No. 3.3, was DSRB informed? 4. STUDY COMPLETION [Check here if not applicable and proceed to next section] Yes No NA 4.1 Has the study been completed? 4.2 If yes, has DSRB been informed? 5. PREMATURE TERMINATION / SUSPENSION OF THE STUDY [Check here149 if not applicable and proceed to next section] Yes No NA 5.1 Has there been a premature termination/ suspension of the study? If yes, please give reason: 5.2 If yes to No. 5.1, have the subjects/institution/ sponsor/regulatory bodies/DSRB been informed? 6. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS (UPIRTSO) REPORTING [Check here if there is No UPIRTSO and proceed to next section] Yes No NA 6.1 Have there been any UPIRTSOs reported to DSRB? 6.2 If yes, are UPIRTSOs reported within acceptable timelines? STUDY REVIEW CHECKLIST
  • 176. 7. HSA REGULATED STUDY (Clinical drug trial) [Check here if not applicable and proceed to next section] Yes No NA7.1 Is there a Clinical Trial Certificate (CTC)? Is the CTC still valid (see CTC Expiry date)?7.2 Is there a Clinical Trial Medication (CTM) certificate for the investigational product? If yes, is it still valid?8. INVESTIGATIONAL PRODUCT (IP) / DEVICE ACCOUNTABILITY Yes No NA8.1 Is the IP / Device dispensing and accountability log maintained?8.2 Is there proper documentation like temperature and accessibility log on IP / Device storage?9. GENETIC RESEARCH [Check here if not applicable and proceed to next section] Yes No NA 1509.1 Are subject identifiers maintained?9.2 If yes, are identifiers stored and maintained in a secure location with limited access?9.3 Are the samples coded?9.4 If there is secondary use of samples to 3rd parties, are these samples de-identified?10. BIOLOGICAL SAMPLES [Check here if not applicable and proceed to next section] Yes No NA10.1 Are samples collection methods in compliance with approved protocol?10.2 If the samples are stored, is the storage area secure with access control?10.3 Is a temperature log maintained?10.4 If samples are shipped, are records on file?10.5 If samples are to be destroyed after the completion of the study, will destruction records be maintained? STUDY REVIEW CHECKLIST
  • 177. 11. DATABASE Yes No NA 11.1 Is there a list of individuals who have access to the database? 11.2 Is the database password protected? 11.3 Patient identifiers are not stored together with the data. 12. INFORMED CONSENT FORM (ICF) Yes No NA 12.1 Was correct approved version of the consent document used? 12.2 Did Subject / Legally Acceptable Representative sign and date the PIS personally? 12.3 Did the person taking consent sign and date the PIS personally? 12.4 Only site personnel listed on study responsibility151 log took consent from subject. 12.5 Is the consent process documented in the medical records and a copy of the signed consent form given to subject? 13. SUBJECT SELECTION CRITERIA Yes No NA 13.1 Is there a checklist to assess the eligibility of the subject? 13.2 There is nil Non-Compliance to protocol. 13.3 If there is non-compliance to protocol (Answer No to No. 13.2), was it submitted to DSRB? If No, explain in the space below. STUDY REVIEW CHECKLIST
  • 178. 14. FILING OF STUDY DOCUMENTS Yes No NA14.1 Is there an Investigator file for filing of study documents? If the answer to any of the above questions is “No”, please indicate the reason and any follow up action done:Completed by: Date: PRINT NAME & SIGNATURE dd/mm/yy 152 STUDY REVIEW CHECKLIST
  • 179. i. APPLICABLE FEES For latest and most updated New Application Review Fees & Study Amendment Review Fees, please contact the DSRB. For industry sponsored trials, please forward a cheque made payable to ‘National Healthcare Group Pte Ltd’.153 APPLICABLE FEES
  • 180. Notes 154
  • 181. Notes155
  • 182. Research & Development Office (RDO)6 Commonwealth Lane, Level 4 GMTI BuildingSingapore 149547Tel: (65) 6471 3266 Fax: (65) 6496 6257Email: rdo@nhg.com.sgwww.b2bresearch.nhg.com.sg

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