Nhg+investigator+manual+ +1st+edition

INVESTIGATOR
MANUAL
All That An Investigator Needs To Know

1st Edition: August 2009

© National Healthcare Group, Research & Development Ofﬁce, Singapore
www.b2bresearch.nhg.com.sg

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system
or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise without the permission of NHG Research & Development Ofﬁce.

Participating Institutions
Tan Tock Seng Hospital • National University Health System • Institute of Mental Health •
National Skin Centre • Alexandra Hospital • National Healthcare Group Polyclinics •

Today, the world benefits greatly from major advances in medicine through
the conscientious and concerted efforts of the research community to translate
research knowledge into feasible clinical applications. As we benefit from the
fruits of research, and recognize the effort by the research community, no
less appreciation goes to the contribution of research participants. To ensure
that research is continually conducted in a scientifically and ethically robust
manner, 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 Clinical
Practice (1998), all unanimously created to facilitate scientifically and ethically
applauded research, that promote respect, beneficence and justice in human
subject research.

In parallel with the demands of excellence in research and research ethics,
the Investigator Manual is written to guide investigators and research team
members on the ethical conduct of research conducted under the oversight of
the National Healthcare Group Domain Specific Review Board (NHG DSRB).

The Manual serves as an essential resource for investigators to carry out
research responsibly. A comprehensive toolkit for best research ethics practice,
this Manual outlines the overall governance of research, provides procedural
guidelines for meeting ethical requirements in research, and offers guidance
on key ethical issues.

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 6

Chapter 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 17

Chapter 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 24

Chapter 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 44

Chapter 05: Review Process
5.1 Exempt Review 46
5.2 Non-Exempt Review 49
5.3 Criteria For Approval 55

Chapter 06: Outcome Of Review 57

Chapter 07: Appeals To DSRB Decision 58

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 107

Chapter 09: Minimum Qualifications And Training To Be
An Investigator
9.1 Who Can Be A Principal Investigator? 113
9.2 Minimum Training Requirements 115

Chapter 10: Responsibilities Of Investigator 117

Chapter 11: Preparing For Audit 124

Chapter 12: Suggested Readings 127

Chapter 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

1.0

1.0
RESEARCH GOVERNANCE
1.1 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

1.1 NHG HUMAN SUBJECTS PROTECTION
PROGRAM (HSPP)

NHG Human Subjects Protection Program (HSPP) aims to promote high
quality and ethical research, and to ensure protection of human subjects
participating in research in NHG, and all institutions under the oversight of
NHG DSRB (herein after referred to as “Institutions”). All parties engaging
in research involving human subjects have a part to play to ensure that
the 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 procedures
related to human subjects protection, including both the Domain Specific
Review Board (DSRB) and the Research Quality Assurance Program.

1

1.1 NHG HUMAN SUBJECTS PROTECTION PROGRAM (HSPP)

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 the
2 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)

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)

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.


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.

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).


1.4 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 Funds
6
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:


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 being
an instrument, apparatus or appliance) which is manufactured, sold,
supplied, imported or exported for use wholly or mainly in either or both
of 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 following
purposes:

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.


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 vices
8
(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 has


been provided for specific purposes by an individual and which the
individual 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 the
investigator or associated with the information) in order for obtaining
the 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 the
purposes of the research project obtain: (1) data about the subjects of the
research through intervention or interaction with them; (2) identifiable
private information about the subjects of the research; or (3) the informed
consent of human subjects for the research.

EMPLOYEE OR AGENT – An institution’s employees or agents refer
to individuals who: (1) act on behalf of the institution; (2) exercise
institutional authority or responsibility; or (3) perform institutionally
designated activities. “Employees and agents” can include staff, students, 9
contractors, and volunteers, among others, regardless of whether the
individual is receiving compensation.

Food and Drug Administration (FDA), USA

The definition of clinical investigation and other related terms under FDA:

CLINICAL INVESTIGATION is any experiment that involves a test article
and 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.


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:


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).
11
INDIRECT HUMAN BIOMEDICAL RESEARCH comprises any research
that 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);


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 and
12 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.


TISSUE REPOSITORIES – Operation of Human Tissue Repositories and
its data management centre are subjected to oversight by the DSRB. The
DSRB will review and approve protocols specifying the conditions under
which data and specimens may be accepted and shared, and ensuring
adequate provisions to protect the privacy of subjects and maintain the
confidentiality of data. The DSRB will also review and approve a sample
collection protocol and consent document.

QUALITY ASSESSMENT AND IMPROVEMENT (QA/QI) – Activities
designed to determine if aspects of medical practice are in line with
established standards are called quality assessment. When an activity is
designed to improve the performance of medical practice in relation to
an established standard, it is called quality improvement. These projects
involve systematic investigation and usually contribute to generalisable
knowledge. Any QA or QI activity where participants are subjected
to additional risks or burdens beyond usual clinical practice will be
reviewed as research.
13
OUTBREAK INVESTIGATIONS – Outbreak investigations are important
activities that benefit public health. Subjecting these to research standards
might compromise these activities. So such activities are not considered
to be research and hence do not require DSRB review. However any
interventional studies conducted during an outbreak would require
review and approval by the DSRB and / or other clinical Committees.
The DSRB will make an effort to expedite the review and approval
process for such protocols.

DISEASE MANAGEMENT – Disease Management projects that do not
require the participants to undergo additional burdens or risks do not
require review and approval by the DSRB.

INFECTION CONTROL – Investigations carried out as part of an
infection control program are not considered as research and these do
not require review by the DSRB.


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.

14


2.0

2.0
PRINCIPLES OF
RESEARCH ETHICS
2.1 Ethical Research
2.2 The Belmont Report
2.3 Code Of Ethical Practice In
Human Biomedical Research

2.1 ETHICAL RESEARCH

Ethical 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

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

2.3 CODE OF ETHICAL PRACTICE IN HUMAN
BIOMEDICAL RESEARCH (MOH)

The credibility of human biomedical research with society is dependent
upon the maintenance of the highest ethical standards in its conduct.
Research is ethically justifiable only if it is scientifically sound and does not
expose research subjects to unwarranted discomfort or risks without likely
benefit to the advancement of biomedical science. Research should also
abide by accepted moral standards within the community and be carried
out responsibly, in ways that respect and protect the research subjects, and
maintain scientific integrity to promote trust and accountability.

Researchers have a personal and non-delegable responsibility to ensure
the ethical conduct of their research. This Code lays down principles and
standards for ethical practice in human biomedical research in Singapore.
Researchers should use this Code as a yardstick for their conduct and
behavior. In addition, researchers should have an understanding of
research ethics, develop the knowledge, skills and attitude needed to 17
manage ethical conflicts, and to consult with colleagues, ethics committees
and other experts when ethical issues arise.

Researchers are to uphold the principles fundamental to the protection of
human 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

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.

18
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.sg

2.3 CODE OF ETHICAL PRACTICE IN HUMAN BIOMEDICAL RESEARCH

3.0
3.0

OVERVIEW OF APPLICATION
AND REVIEW PROCESS
3.1 Application Process
3.2 Review Process
3.3 Outcome Of Review
3.4 Post Approval Reporting Requirements

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.

Refer 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:


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.

Refer to Chapter 4.1 New Applications.

Details on how to complete the B2BResearch Online DSRB Application
20 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.


3.2 REVIEW PROCESS

All research studies submitted will be classified under one of the following
review categories:
a. Exempt Review

b. Expedited Review

c. Full Board Review

The determination of the review category is made by the DSRB. In general,
the determination is based on the level of risk in which research participants
is exposed to. Research studies that involve minimal or less than minimal
risk are reviewed under the Exempt or Expedited review categories, and
studies that involve more than minimal risk are reviewed under Full Board
Review 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.

Refer to Chapter 5.1 Exempt Review and Chapter 5.2 Non-Exempt Review.

3.2 REVIEW PROCESS

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.

Refer to Chapter 5.3 Criteria for Approval.

3.2 REVIEW PROCESS

3.3 OUTCOME OF REVIEW

Following the review of a research study, the DSRB will reach one of the
following decisions:

a. approve,

b. conditionally approve,

c. table for next convened meeting, or

d. not approve

A research study that is reviewed under Exempt or Expedited Review
category cannot be disapproved. Instead, it will be escalated to the next
level of review or approved with modifications.

Refer to Chapter 6.0 Outcome of Review. 23

3.3 OUTCOME OF REVIEW

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.

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.

Refer to Chapter 4.3 Continuing Review / Renewal.

3.4 POST APPROVAL REPORTING REQUIREMENTS

Unanticipated Problems Involving Risks To Subjects Or
Others (UPIRTSO)

The Principal Investigator is responsible for the accurate documentation,
investigation, follow-up and timely reporting of all UPIRTSOs. The criteria
for reporting are that the problems have to be (1) unexpected and (2)
related or possibly related to study. Special requirements are applicable
for reporting of events involving deaths of local research participants.

Refer to Chapter 4.4 Unanticipated Problems Invdving Risks To Subjects Or
Others (UPIRTSO).

Non–Compliance

All research should be conducted in compliance with the research study
approved by the DSRB, SGGCP, NHG DSRB requirements, institution 25

requirements, and applicable regulations. The Principal Investigator is
encouraged to report conduct of any non-compliance by him / herself,
members of the research team and others.

Refer to Chapter 4.5 Non-Compliance.

Study Closure

When a study is completed, the Principal Investigator should submit study
completion reports at least 4-6 weeks days after completion of the study.
Completion reports should be submitted using the Study Status Report
Form.

Refer to Chapter 4.6 Study Closure.

3.4 POST APPROVAL REPORTING REQUIREMENTS

4.0
SUBMISSIONS TO DSRB
4.0

4.1 New Applications
4.2 Study Amendments
4.3 Continuing Review / Renewal
4.4 Unanticipated Problems Involving Risks To
Subjects Or Others (UPIRTSO)
4.5 Non-Compliance
4.6 Study Closure

4.1 NEW APPLICATIONS

Each DSRB meets once a month, except December . The meetings are held
in the third / fourth week of the month. The submission deadline for new
applications is the first working day of each month, or the next working
day, if the first falls on a weekend or public holiday. For example, for an
application to be reviewed in the month of April, the application must
reach the DSRB office on 1st April.

Only completed applications will be considered for DSRB review.
The Principal Investigator is strongly encouraged to submit his / her
application well before the deadline for submission to allow some time for
the DSRB to check for any missing documents / information. Incomplete
applications that are submitted on the first working day of the month will
be scheduled for review in the following month.

Research studies that qualify for expedited review or applications requesting
for 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


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 (if
27
used).

h. Written information intended to be provided to subjects (if used).

i. Principal Investigator’s CV (the latest in the past one year).

Refer to Chapter 13 Appendices for ‘Applicable Fees’.


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.

Details on how to complete the B2BResearch Online DSRB Application
Form are available online at http://www.b2bresearch.nhg.com.sg
(Downloads) and in the Online Manual.


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.


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

Refer to Chapter 13 Appendices for ‘Applicable Fees’.


The above conditions are applicable to, but not limited to, amendments
made to the protocols, consent documents, study sites and research
personnel.

Details on how to complete the B2BResearch Online
DSRB Study Amendment Form are available online at
Online Manual.

31


4.3 CONTINUING REVIEW / RENEWAL

The DSRB will conduct continuing review of ongoing research at intervals
appropriate to the degree of risk, but not less than once per year. Continuing
DSRB review is required as long as individually identifiable follow-up data
are collected on subjects enrolled.

The Principal Investigator should submit a completed B2BResearch Online
DSRB Study Status Report Form at least 4-6 weeks before the study approval
period ends (as indicated in the approval letter of the study).

The Principal Investigator applying for renewal of approval of a study
must 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-

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.


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.


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.

Refer to Chapter 8.4 Data And Safety Monitoring.

DSRB Study Status Report Form are available online at
Online Manual.


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)

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.
36
e. 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


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 medicinal
37 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:


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 Considerations

In certain circumstances, for example, in studies whereby the study design
requires long term treatment-free follow up till death, the requirement to
report all local deaths, regardless of causality and expectedness of the
death event, within 24 hours of first knowledge by PI, does not provide
additional information that would add meaningfully to the protection of
the rights, safety and / or wellbeing of the subjects. The DSRB may alter


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).

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.


4.5 NON-COMPLIANCE

All research conducted in NHG institutions should be in compliance with
the research proposal approved by the DSRB, with SGGCP, with NHG
DSRB requirements, institution requirements, and applicable regulations.

COMPLIANCE is adherence to all the trial-related requirements,
good clinical practice requirements, and the applicable regulatory
requirements.

NON-COMPLIANCE is a failure by an Investigator to abide by the policies
and procedures of DSRB or applicable regulations governing the protection
of 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

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. If

4.5 NON-COMPLIANCE

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 or
continuing, the DSRB will conduct an inquiry and will provide an
opportunity to the Principal Investigator to respond in person at a
convened meeting, informal conference or in writing.

Outcome of DSRB Inquiry

If the DSRB accepts the Principal Investigator’s explanation, the DSRB will
inform the Principal Investigator within 30 days from the date the DSRB
receives the explanation.

If the DSRB rejects the Principal Investigator’s explanation, or if the
Principal Investigator fails to respond within the stipulated timeframe,
the DSRB will determine if the Principal Investigator should remain
42
eligible to continue to conduct research studies at institutions under
DSRB governance and make a recommendation for further actions that
include, 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

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.

Details on how to complete the B2BResearch Online DSRB Non
Compliance / Protocol Deviation Form are available online at
Online Manual.

4.5 NON-COMPLIANCE

4.6 STUDY CLOSURE
A research study is said to be completed when all of the following
criteria 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 study
completion reports 4-6 weeks after completion of the study. Completion
reports should be submitted using the B2BResearch Online DSRB Study
Status Report Form.

The DSRB will review the B2BResearch Online DSRB Study Status Report
Form and obtain any outstanding information or documentation from
44
the Principal Investigator. If there are inconsistencies or if clarification is
needed, 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

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.

DSRB Study Status Report Form are available online at
Online Manual.

4.6 STUDY CLOSURE

5.0
REVIEW PROCESS
5.0

5.1 Exempt Review
5.2 Non-Exempt Review
5.3 Criteria For Approval

5.1 EXEMPT REVIEW

The DSRB may determine that a research activity that falls under any of the
following 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

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, directly
47 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

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.

Details on h ow to complete the B2 BR e s e a rc h O n l in e
D 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 t
Online Manual.

5.1 EXEMPT REVIEW

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 to
49 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.


Categories of Research

CATEGORY 1 – Clinical studies of drugs and medical devices only when
one 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.


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.


CATEGORY 4 – Collection of data through noninvasive procedures (not
involving general anesthesia or sedation) routinely employed in clinical
practice, excluding procedures involving x-rays or microwaves. Where
medical devices are employed, they must be cleared / approved for
marketing. (Studies intended to evaluate the safety and effectiveness
of 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 solely
for non-research purposes (such as medical treatment or diagnosis).

CATEGORY 6 – Collection of data from voice, video, digital, or image
recordings made for research purposes.

CATEGORY 7 – Research on individual or group characteristics
or behavior (including, but not limited to, research on perception,
cognition, motivation, identity, language, communication, cultural


Nhg+investigator+manual+ +1st+edition

Nhg+investigator+manual+ +1st+edition

Recommended

Recommended

More Related Content

Viewers also liked

Viewers also liked (13)

Similar to Nhg+investigator+manual+ +1st+edition

Similar to Nhg+investigator+manual+ +1st+edition (20)

Nhg+investigator+manual+ +1st+edition