NIDCR Clinical Trial

Tool Summary Sheet
Tool: NIDCR Clinical Trial (Interventional) Protocol Template

Purpose: To provide an instructional template for use in development of a
protocol for studies using an intervention (biomedical or behavioral)
Audience/User: Principal Investigators and Study Staff
Details: This document is the National Institute of Dental and Craniofacial
Research (NIDCR) protocol template for a clinical trial.
The National Institutes of Health (NIH) defines a clinical trial as a

prospective biomedical or behavioral research study of human
subjects that is designed to answer specific questions about
biomedical or behavioral interventions (drugs, treatments, devices, or
new ways of using known drugs, treatments or devices). According to
the World Health Organization (WHO), a clinical trial is any research
study that prospectively assigns human participants or groups of
humans to one or more health-related interventions to evaluate the
effects on health outcomes. This protocol template is based on the
essential protocol elements in Section 6 of the ICH E6 guidance on
Good Clinical Practice. The template will assist investigators in
preparing a clinical trial protocol that meets NIDCR standards and
includes all elements required for an Institutional Review Board (IRB)
to assess study risks and benefits.
The IRB’s risk assessment and the size and complexity of the study
are used by the NIDCR to determine the resources needed to meet
the Institute’s study oversight responsibilities. Based on the potential
risk for subjects and the complexity of the clinical trial, the NIDCR
Medical Monitor will provide guidance on the appropriate level of data
and safety monitoring. Investigators should consult the NIDCR
Program Official when writing the protocol template sections on
Assessment of Safety and on Study Oversight.
The Grantee Institution may have an IRB-specified protocol format.

Use of that IRB format is acceptable to NIDCR, provided the
necessary elements (the section headings included in the template
table of contents) are included in the protocol. A grant application is
generally not acceptable as a protocol. Cutting and pasting from the
grant application will not usually meet the requirements for an
acceptable protocol.
Tool Summary Sheet Page 1 of 3

Changes to the protocol via an amendment cannot be implemented
until IRB approval is received.
Terminology has been consistently applied throughout this template.

For definitions and synonyms (e.g., case report form = data collection
form, subject = participant), please refer to the NIDCR Glossary of
Clinical Research Terms available on the NIDCR Toolkit for Clinical
Researchers website.
Best Practice  Refer questions regarding use of this protocol template to the
Recommendations: appropriate NIDCR Program Official or the NIDCR Office of
Clinical Trials Operations and Management (OCTOM).
 The Study Intervention section (Section 6) of this template
includes sub-sections for:
a) Study Product, such as an investigational or approved drug
or device (Sections 6.1 - 6.6);
b) Behavioral Intervention (Sections 6.7 - 6.10) and;
c) Procedural Intervention (Section 6.11 - 6.14).
Choose the appropriate section that matches the type of study
intervention planned and delete the other sections.
 In the template, instructions for each section are included in
{blue italics} (“CROMS_Instruction” style). Instructional text will
also be enclosed in braces to signify this text for screen-
readers used by the visually impaired. As you complete a
section, delete the instructions.
 Where sample text is included in standard font, you may
include it in your protocol as written or modify as needed for
your study. Sample text is set off by the introductory
instructional text {Begin sample text} and closing instructional
text {End sample text}. Remove this instructional text if you
use the sample text.
Note: Sample text may contain additional embedded
instructional text. As you complete a section, delete the
embedded instructions.
 Required protocol text is set off by the introductory instructional
text {Begin required text} and the closing instructional text {End
required text}. Remove this instructional text while maintaining
the required text in the document.
Note: Required text may contain additional embedded
instructional text. As you complete a section, delete the
embedded instructions.
 Text enclosed with < > is a placeholder for a specific detail
(e.g., <protocol title>); replace as appropriate.

 It is not necessary to include text under a major numbered
heading (e.g., 1, 2) that is immediately followed by numbered
subheadings, (e.g., 2.1, 2.2). That is because certain
numbered headings are used only for organizational purposes.
Text should be entered under all numbered subheadings. See
<Insert text> notations for guidance.
 It is easiest and cleanest to use the styles that are embedded
in the document, rather than to create your own. In MS Word
2007: From the Home menu, select the bottom right arrow key
to bring up the styles box, select “Options”, under “Select
Styles to Show” select “in current document.”
 Protocol version control: Refer to NIDCR Version Control
Guidance. Primary author controls version number and date,
which appear on title page and header/footer of each protocol
page. Use 0.1, 0.2, 0.3, etc., for early drafts of the protocol.
Once all NIDCR and study team comments have been
resolved, re-label last draft version 0.x as final version 1.0 for
IRB submission. When drafting an amendment to an IRB-
approved protocol, use the protocol whole version number with
draft numbers in the decimal. For example, version 2.1 is the
first draft of an amendment to protocol version 2.0. When the
final draft of this amended protocol is ready for IRB review,
change the version number to Version 3.0 before IRB
submission.
 Versioning includes both a version number and version date.
When the version number and date change, be sure to update
them in the header of each section of the protocol.
 Remove this Tool Summary Sheet before use.
Tool Revision History:
Version Version Date Summary of Revisions Made:

Number
3.0 11Feb2013 Original version with Tool Summary Sheet
4.0 03Jan2014 Revised text regarding Safety Oversight method, Final
Statistical Analysis, Data Sharing, and Clinical Site
Monitoring; clarified instructional text and added text
placeholders

<Protocol Title> Version <x.x>
Protocol <#> <DD Month YYYY>
________________________________________________________________________________________________________
<Title>
NIDCR Protocol Number: <number provided by NIDCR>
NIDCR Grant Number:
Principal Investigator:
NIDCR Program Official:
NIDCR Medical Monitor:
IND/IDE Sponsor: <sponsor name, if applicable; do not include

IND/IDE number>
Draft or Version Number: <x.x>
<Day Month Year>
____________________________________________________________________________________________
________________________________________________________________________________________________________
STATEMENT OF COMPLIANCE
{Begin required text}

The study will be conducted in accordance with the International Conference on
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR
Clinical Terms of Award. All personnel involved in the conduct of this study have
completed human subjects protection training.
{End required text}
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SIGNATURE PAGE

The signature below constitutes the approval of this protocol and the attachments, and
provides the necessary assurances that this trial will be conducted according to all
stipulations of the protocol, including all statements regarding confidentiality, and
according to local legal and regulatory requirements and applicable US federal
regulations and ICH guidelines.
Principal Investigator or Clinical Site Investigator:
Signed: Date:
Name:
Title:
{End required text}
{For multi-site studies, the protocol should be signed by the clinical site investigator who
is responsible for the day to day study implementation at his/her specific clinical site.
For a clinical trial involving an Investigational New Drug (IND), this is the individual who
signs the Form FDA 1572 for a drug or the investigator agreement for a device.}
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Based on NIDCR Clinical Trial (Interventional) Protocol Template v4.0 - 20140103 ii
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TABLE OF CONTENTS
{This table uses the Table of Contents function in Microsoft Word that will automatically
update headings and page numbers used in the body of the report. To update the
Table of Contents and all cross-references in the document, press CTRL-A to select the
entire document, then press F9.}
PAGE
STATEMENT OF COMPLIANCE ................................................................................................. I
SIGNATURE PAGE .................................................................................................................... II
TABLE OF CONTENTS ............................................................................................................. III
LIST OF ABBREVIATIONS ....................................................................................................... VI
PROTOCOL SUMMARY ......................................................................................................... VIII
1 KEY ROLES AND CONTACT INFORMATION ................................................................... 1
2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 2
2.1 Background Information .......................................................................................... 2
2.2 Rationale ................................................................................................................ 2
2.3 Potential Risks and Benefits ................................................................................... 2
2.3.1 Potential Risks ............................................................................................ 2
2.3.2 Potential Benefits ........................................................................................ 3
3 OBJECTIVES ..................................................................................................................... 4
3.1 Study Objectives ..................................................................................................... 4
3.2 Study Outcome Measures ...................................................................................... 4
3.2.1 Primary........................................................................................................ 5
3.2.2 Secondary ................................................................................................... 5
4 STUDY DESIGN ................................................................................................................ 6
4.1 Substudies (if applicable) ........................................................................................ 6
5 STUDY ENROLLMENT AND WITHDRAWAL .................................................................... 8
5.1 Subject Inclusion Criteria ........................................................................................ 9
5.2 Subject Exclusion Criteria ....................................................................................... 9
5.3 Strategies for Recruitment and Retention ............................................................. 10
5.4 Treatment Assignment Procedures ....................................................................... 10
5.4.1 Randomization Procedures (if applicable) ................................................. 11
5.4.2 Masking Procedures (if applicable) ............................................................ 11
5.5 Subject Withdrawal ............................................................................................... 11
5.5.1 Reasons for Withdrawal ............................................................................ 11
5.5.2 Handling of Subject Withdrawals or Subject Discontinuation of Study
Intervention ............................................................................................... 12
5.6 Premature Termination or Suspension of Study .................................................... 12
6 STUDY INTERVENTION.................................................................................................. 13
6.1 Study Product Description .................................................................................... 13
6.1.1 Acquisition ................................................................................................. 13
6.1.2 Formulation, Packaging, and Labeling....................................................... 13
6.1.3 Product Storage and Stability .................................................................... 14
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6.2 Dosage, Preparation and Administration of Study Product .................................... 14

6.3 Modification of Study Product Administration for a Subject ................................... 14
6.4 Accountability Procedures for the Study Product .................................................. 14
6.5 Assessment of Subject Compliance with Study Product Administration ................ 14
6.6 Concomitant Medications/Treatments ................................................................... 14
6.7 Study Behavioral or Social Intervention(s) Description .......................................... 15
6.8 Administration of Intervention................................................................................ 15
6.9 Procedures for Training Interventionists and Monitoring Intervention Fidelity ........ 16
6.10 Assessment of Subject Compliance with Study Intervention ................................. 16
6.11 Study Procedural Intervention(s) Description ........................................................ 16
6.12 Administration of Procedural Intervention.............................................................. 16
6.13 Procedures for Training of Clinicians on Procedural Intervention .......................... 17
6.14 Assessment of Clinician and/or Subject Compliance with Study Procedural
Intervention ........................................................................................................... 17
7 STUDY SCHEDULE ......................................................................................................... 18
7.1 Screening ............................................................................................................. 18
7.2 Enrollment/Baseline .............................................................................................. 19
7.3 Intermediate Visits ................................................................................................ 19
7.4 Final Study Visit .................................................................................................... 20
7.5 Withdrawal Visit .................................................................................................... 21
7.6 Unscheduled Visit ................................................................................................. 21
8 STUDY PROCEDURES /EVALUATIONS ........................................................................ 22
8.1 Study Procedures/Evaluations .............................................................................. 22
8.2 Laboratory Procedures/Evaluations ...................................................................... 22
8.2.1 Clinical Laboratory Evaluations ................................................................. 22
8.2.2 Special Assays or Procedures ................................................................... 23
8.2.3 Specimen Preparation, Handling, and Storage .......................................... 23
8.2.4 Specimen Shipment .................................................................................. 23
9 ASSESSMENT OF SAFETY ............................................................................................ 24
9.1 Specification of Safety Parameters ....................................................................... 24
9.1.1 Unanticipated Problems ............................................................................ 24
9.1.2 Adverse Events ......................................................................................... 25
9.1.3 Serious Adverse Events ............................................................................ 25
9.2 Time Period and Frequency for Event Assessment and Follow-Up ....................... 26
9.3 Characteristics of an Adverse Event ..................................................................... 26
9.3.1 Relationship to Study Intervention ............................................................. 26
9.3.2 Expectedness of SAEs .............................................................................. 27
9.3.3 Severity of Event ....................................................................................... 27
9.4 Reporting Procedures ........................................................................................... 28
9.4.1 Unanticipated Problem Reporting to IRB and NIDCR ................................ 28
9.4.2 Serious Adverse Event Reporting to NIDCR.............................................. 29
9.4.3 Reporting of SAEs and AEs to FDA .......................................................... 30
9.4.4 Events of Special Interest (if applicable) .................................................... 31
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9.4.5 Reporting of Pregnancy ............................................................................. 31

9.5 Halting Rules ........................................................................................................ 31
10 STUDY OVERSIGHT ....................................................................................................... 32
11 CLINICAL SITE MONITORING ........................................................................................ 34
12 STATISTICAL CONSIDERATIONS .................................................................................. 36
12.1 Study Hypotheses ................................................................................................. 36
12.2 Sample Size Considerations ................................................................................. 36
12.3 Planned Interim Analyses (if applicable) ............................................................... 37
12.3.1 Safety Review ........................................................................................... 37
12.3.2 Efficacy Review ......................................................................................... 37
12.4 Final Analysis Plan ............................................................................................... 37
13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 39
14 QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 40
15 ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................. 41
15.1 Ethical Standard ................................................................................................... 41
15.2 Institutional Review Board .................................................................................... 41
15.3 Informed Consent Process ................................................................................... 41
15.4 Exclusion of Women, Minorities, and Children (Special Populations) .................... 42
15.5 Subject Confidentiality .......................................................................................... 43
15.6 Future Use of Stored Specimens and Other Identifiable Data ............................... 44
16 DATA HANDLING AND RECORD KEEPING ................................................................... 45
16.1 Data Management Responsibilities ....................................................................... 45
16.2 Data Capture Methods .......................................................................................... 45
16.3 Types of Data ....................................................................................................... 46
16.4 Schedule and Content of Reports ......................................................................... 46
16.5 Study Records Retention ...................................................................................... 46
16.6 Protocol Deviations ............................................................................................... 47
17 PUBLICATION/DATA SHARING POLICY ........................................................................ 48
18 LITERATURE REFERENCES .......................................................................................... 50
SUPPLEMENTAL MATERIALS ................................................................................................ 51
APPENDICES ........................................................................................................................... 52
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 53
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LIST OF ABBREVIATIONS
{Please add all disease or study-specific abbreviations/acronyms in this section. Modify

this list as needed for your particular study and remove abbreviations that are not used
in the document.}
AE Adverse Event/Adverse Experience

CFR Code of Federal Regulations
CIOMS Council for International Organizations of Medical Sciences
CONSORT Consolidated Standards of Reporting Trials
CRF Case Report Form
CRO Contract Research Organization
CSOC Clinical Study Oversight Committee
DCC Data Coordinating Center
DHHS Department of Health and Human Services
DMFS Decayed, missing, and filled tooth surfaces
DSMB Data and Safety Monitoring Board
eCRF Electronic Case Report Form
FDA Food and Drug Administration
FFR Federal Financial Report
FWA Federalwide Assurance
GCP Good Clinical Practice
HIPAA Health Insurance Portability and Accountability Act
IB Investigator’s Brochure
ICF Informed Consent Form
ICH International Conference on Harmonisation
ICMJE International Committee of Medical Journal Editors
IDE Investigational Device Exemption
IND Investigational New Drug Application
IRB Institutional Review Board
ISM Independent Safety Monitor

MedDRA Medical Dictionary for Regulatory Activities
MOP Manual of Procedures
N Number (typically refers to subjects)
NDA New Drug Application
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NIDCR National Institute of Dental and Craniofacial Research, NIH, DHHS

NIH National Institutes of Health
OCTOM Office of Clinical Trials Operations and Management, NIDCR, NIH
OHRP Office for Human Research Protections
PHI Protected Health Information
PI Principal Investigator
QA Quality Assurance
QC Quality Control
SAE Serious Adverse Event/Serious Adverse Experience
SOP Standard Operating Procedure
UP Unanticipated Problem
US United States
WHO World Health Organization
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PROTOCOL SUMMARY
{Limit to 1-2 pages; put key words in boldface in Protocol Summary.}

Title:
Précis: <A brief overview of the study design, including study groups,
schedule of interventions, schedule for specimen or data
collection, and analyses to be performed.>
{The précis should be only a few sentences in length. A
detailed schematic describing all visits and assessments
(schedule of events) should be included as Appendix A.}
Objectives: <Insert objectives copied from the body of the protocol. Include
the primary objective and secondary objectives and specify
outcome measures.>
Primary:
Secondary:
Population: <Population information, including sample size, gender, age,
demographic group, general health status, geographic
location.>
Phase: <I, II, III, or IV (if applicable)>
Number of Sites: <Insert a list of sites if 3 or fewer sites; for more than 3 sites,
insert the number of sites only, and list the sites in Section 1.>
Description of <Describe the intervention. If intervention is a drug, include
Intervention: dose and route of administration. For a non-pharmaceutical
study (device, procedure or behavioral intervention), provide
brief description.>
Study Duration: <Estimated time (in months) from when the study opens to
enrollment until completion of data analyses.>
Subject <Time it will take to conduct the study for each individual
Participation subject.>
Duration:
Estimated Time to <Estimated time from enrollment into study of the first subject
Complete to enrollment into study of the last subject.>
Enrollment:
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Based on NIDCR Clinical Trial (Interventional) Protocol Template v4.0 - 20140103 viii
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Schematic of Study Design:

{The diagram below shows the preferred format and the level of detail needed to convey
an overview of study design. Complete each text box with study-specific information
and adapt the diagram to illustrate your study design (e.g., changing method of
assignment to study group, adding study arms, visits, etc.). The time point(s) indicated
in the schematic should correspond to the time point(s) in Section 7 of the protocol,
Study Schedule, e.g., Visit 1, Day 0; Visit 2, Day 30 ± 7; etc.}
Prior to Total N: Obtain informed consent. Screen potential subjects by inclusion and
Enrollment exclusion criteria; obtain history, document.
Randomize
Arm 1 Arm 2
N subjects N subjects
Perform baseline assessments.

Visit 1 (list specimens to be collected, examinations or imaging or laboratory assays to
Time Point be performed, questionnaires to be completed)
Administer initial study intervention.
Visit 2 Repeat study intervention (if applicable).

Time Point
Visit 3 Follow-up assessments of outcome measures and safety

Time Point (list specimens to be collected, examinations or imaging or laboratory assays to
be performed, questionnaires to be completed)
Visit 4 Follow-up assessments of outcome measures and safety

Time Point (list specimens to be collected, examinations or imaging or laboratory assays to
be performed, questionnaires to be completed)
Visit X Final Assessments

Time Point List analyses to be performed
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Based on NIDCR Clinical Trial (Interventional) Protocol Template v4.0 - 20140103 ix
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1 KEY ROLES AND CONTACT INFORMATION
{Provide the following information for each individual:

Name, degree, title
Institution Name
Address
Phone Number
Fax Number
Email}
Principal <Site investigator responsible for conducting the study>
Investigator:
Medical Monitor: {if applicable}
NIDCR Program
Official:
Clinical Site <if applicable, investigator name, institution>
Investigators:
Institutions: {List study sites, clinical laboratory(ies), data coordinating
centers, and other medical or technical departments and/or
institutions, as applicable.
Provide the following information for each organization or
institution:
Institution Name
Address
Contact Person/Local Investigator
Phone Number
Fax Number
Email}
Other Key {Consider listing, for example:
Personnel:
 Collaborating Program Officials from other National
Institutes of Health Institutes or Centers
 Major international collaborators, if not included as site
investigators
 Protocol data manager
 Epidemiologist
 Statistician}
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Based on NIDCR Clinical Trial (Interventional) Protocol Template v4.0 - 20140103 1
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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE
2.1 Background Information

<Insert text>
{This section should include brief background information for this trial. It should not be a
copy of the background information from a grant application.
Include:
 A brief description of the health problem that the study will address
 The name and description of the study intervention/study product(s)
 Discussion of important research relevant to the study that provides background
and scientific justification for the study (include findings from in vitro studies,
preclinical in vivo studies, and relevant clinical trials)
 A brief description of the study’s overall goal
 Applicable clinical, epidemiological, or public health background or context of the
study
 Importance of the study and any relevant treatment issues or controversies}
2.2 Rationale
<Insert text>
{Include a description of, and justification for, the route of administration, dosage, dosing
regimen, intervention periods, or behavioral intervention methods and selection of study
population. Include a statement of the hypothesis.}
2.3 Potential Risks and Benefits

<Insert text>
{Include in Sections 2.3.1 and 2.3.2 a discussion of known risks and benefits, if any, to
human subjects. Be sure that information in these sections is consistent with your
consent document.
NOTE: This information will be used to determine whether an event is “Expected” and
therefore not an unanticipated problem requiring expedited reporting.}
2.3.1 Potential Risks

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{Describe in detail any physical, psychological, social, legal, economic, or any other
anticipated risks to study subjects. Include risks of study intervention and other study
procedures.
One or more of the following may serve as the source of risk information:
 Package insert for a licensed product
 Investigator’s Brochure (IB) for an investigational product
 Preclinical data reports
 Literature search and review (include references)}
2.3.2 Potential Benefits

<Insert text>
{If the research is beneficial, describe any physical, psychological, social, legal, or any
other anticipated benefits to subjects. While it may not provide direct benefit to subjects,
the importance of the knowledge that may result from the study may be mentioned.
Note: Compensation to subjects is not considered a “benefit.” See Strategies for
Recruitment and Retention, Section 5.3.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
3 OBJECTIVES
3.1 Study Objectives

<Insert text>
{Provide a detailed description of the one primary objective and any secondary
objectives of the study. An objective is the reason for performing the study in terms of
the scientific question to be answered. The primary objective is the main question. This
objective generally drives statistical planning for the trial (e.g., calculation of the sample
size to provide the appropriate power for statistical testing). Secondary objectives are
goals that will provide further information on the use of the intervention.
For behavioral and social intervention studies, common primary objectives are to
determine the efficacy or effectiveness of an intervention, or to test a proposed
mechanism of action of an intervention. Common secondary objectives are to identify
mediators or moderators of an intervention effect.
Express each objective as a statement of purpose (e.g., to assess, to determine, to

compare, to evaluate) and include:
 General purpose (e.g., feasibility, acceptability, efficacy, safety, tolerability,
pharmacokinetics) and/or specific purpose (e.g., dose-response, superiority to
placebo, mechanisms of action, effect of an intervention on disease incidence,
disease severity, or health behavior)
 Name(s) of intervention (e.g., procedure, drug, biologic, behavioral intervention)
being evaluated, specification of doses or dose ranges to be studied, dose
regimens, intervention frequency}
3.2 Study Outcome Measures

<Insert text>
{This section should include the methods for assessing how the objectives are met, i.e.,
the study outcome measures.
An outcome measure is a specific measurement or observation used to assess the
effect of the study intervention. Outcome measures should be prioritized and should
correspond to the study objectives and hypotheses being tested. Give succinct but
precise definitions of the outcome measures used to address the study’s primary
objective and key secondary objectives (e.g., specific laboratory tests that define safety
or efficacy, clinical assessments of disease status, assessments of psychological
characteristics, assessments of individual or group oral health behaviors, assessments
of healthcare visit attendance, etc.). Include the study visits or time points at which data
will be recorded or samples will be obtained.}
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3.2.1 Primary
<Insert text>
{Generally, there should be just one primary outcome measure that will provide a
clinically relevant, valid, and reliable measure of the primary objective. Additional
measures may require an adjustment to the sample size calculations and p-value
threshold.
For behavioral or social intervention studies testing for efficacy or effectiveness, there
may be several indicators of a primary outcome of interest, e.g., pain, parenting, oral
hygiene, etc. In such cases, describe the primary outcome and the measures meant to
capture it. For behavioral or social intervention studies testing something other than
efficacy or effectiveness, describe the measures to be included in the analysis that are
most central to the primary study objective. Identify the hypothesized role that each
measure plays in the study hypotheses, e.g., moderator, mediator, co-variate, etc.}
3.2.2 Secondary
<Insert text>
{Describe secondary outcome measures, whether they add information about the
primary objective or address secondary objectives. Discuss their importance and role in
the analysis and interpretation of study results.}
____________________________________________________________________________________________
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4 STUDY DESIGN
<Insert text>
{The scientific integrity of the trial and the credibility of the data from the trial depend
substantially on the trial design. Include a brief paragraph or bulleted text describing the
trial design. This section should include:
 A brief description of the type/design of trial to be conducted (e.g., randomized,
placebo-controlled, double-mask, parallel group, cross-over, open-label, dose-
escalation, dose-ranging)
 A description of the study population (e.g., healthy/sick, inpatient/outpatient,
demographic groups). Do not list inclusion/exclusion criteria here, as these will
be listed in Sections 5.1 and 5.2.
 A brief discussion of the rationale for design features
 Phase of trial, if applicable
 Single or multicenter
 The number of study groups/arms
 Description of study groups/arms including sample size (including a table, if
appropriate); stratifications that will affect enrollment
 Approximate time to complete study enrollment
 The expected duration of subject participation
 Identification and specifics of administration of the study intervention and its
control or comparison (e.g., placebo, current standard of care treatment, etc.)
 A brief description of the sequence and duration of all trial periods, including
follow-up (specify individual subjects vs. entire trial). Details of study visit
schedules will be included in Section 7, Study Schedule.
 Planned variation in intervention dose or schedule (e.g., dose escalation)
 A brief summary of methods for collecting data for assessment of study
objectives (detailed methods will be included in Section 8)
 Other protocol-specific details, such as centralization of evaluations (e.g., central
laboratory or central reading center for clinical scans)}
4.1 Substudies (if applicable)

<Insert text>
{A substudy asks a separate research question from that of the parent protocol. It may
or may not contribute to the parent protocol’s objectives but uses all or a subset of study
subjects or specimens from the main protocol.
____________________________________________________________________________________________
________________________________________________________________________________________________________
A concept for a proposed substudy must be approved by the NIDCR Program Official. A
substudy may be included in the main protocol or in a stand-alone protocol. If a
substudy is added to the protocol for an ongoing study, a protocol amendment is
required. List with brief description:
 Description of the substudy and its objectives
 Impact on main study
 Potential participating sites}
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5 STUDY ENROLLMENT AND WITHDRAWAL
{In subsections 5.1 to 5.6, define the study population, describe subject recruitment, and
discuss issues related to subject withdrawal. The study population should be
appropriate for the stage of the study and the development stage of the study product or
other intervention. Address the following in these subsections as applicable:
 Provide the target sample size; identify anticipated number to be screened in
order to reach the target enrollment.
 Specify approach(es) for conforming with NIH policy on inclusion of women and
minorities. Include numbers of women and minorities expected to be recruited,
or provide justification if women and/or minorities will not be recruited.
 Indicate from where the study population will be drawn (e.g., inpatient hospital
setting, outpatient clinics, student health service, or general public). Where
appropriate (single center studies), include names of hospitals, clinics, etc.
 If the study intends to enroll children, pregnant women, prisoners, or other
vulnerable populations, refer to applicable section of 45 CFR Part 46 Subpart B –
Additional Protections for Pregnant Women, Human Fetuses and Neonates
Involved in Research (45 CFR Part 46.201-46.207); Subpart C – Additional
Protections Pertaining to Biomedical and Behavioral Research Involving
Prisoners as Subjects (45 CFR Part 46.301-46.306); Subpart D – Additional
Protections for Children Involved as Subjects in Research (45 CFR Part 46.401-
46.409). Please refer to these regulations and Office for Human Research
Protections (OHRP) guidelines when choosing the study population. Note that
these regulations apply if any subjects are members of the designated population
even if it is not the target population (for example, if a subject becomes a
prisoner during the study). Refer to:
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html and
http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm
Use the following guidelines when developing subject eligibility criteria to be listed in
subsections 5.1 and 5.2:
 The eligibility criteria should provide a definition of subject characteristics
required for study entry.
 The risks of the intervention should be considered in the development of the
inclusion/exclusion criteria so that risk is minimized.
 The same criterion should not be listed as both an inclusion and exclusion
criterion (e.g., do not state age >32 years old as an inclusion criterion and age
≤32 years old as an exclusion criterion).
 Identify specific laboratory tests or clinical characteristics that will be used as
criteria for enrollment.
____________________________________________________________________________________________
________________________________________________________________________________________________________
 If reproductive status (i.e., pregnancy, lactation, reproductive potential) is an

eligibility criterion, provide specific contraception requirements (e.g., licensed
hormonal methods).}
5.1 Subject Inclusion Criteria

<Insert text>
{Provide a statement that individuals must meet all of the inclusion criteria in order to be
eligible to participate in the study and then list each criterion.}
{Begin sample text}
In order to be eligible to participate in this study, an individual must meet all of the
following criteria:
 Provide signed and dated informed consent form

 Willing to comply with all study procedures and be available for the duration of
the study
 Male or female, aged XX to XX
 In good general health as evidenced by medical history or Diagnosed with
specific condition/disease or Exhibits specific clinical signs or symptoms or
physical/oral examination findings
 Laboratory results within a specific range
 Women of reproductive potential must use highly effective contraception {specify
methods of contraception acceptable for the study, e.g., licensed hormonal
methods. See ICH M3 Guidance for information on highly effective
contraception.}
 Men of reproductive potential must use condoms {if appropriate for study}.
{End sample text}
5.2 Subject Exclusion Criteria

<Insert text>
{Provide a statement that all individuals meeting any of the exclusion criteria at baseline
will be excluded from study participation and then list each criterion.}
{Begin sample text}
An individual who meets any of the following criteria will be excluded from participation
in this study:
____________________________________________________________________________________________
________________________________________________________________________________________________________
 Medical condition, laboratory finding, or physical exam finding {specify, e.g., vital
signs outside of specific range} that precludes participation
 Use of disallowed concomitant medications {specify}
 Presence of <specific devices (e.g., orthodontic appliances, dentures)>
 Recent febrile illness that precludes or delays participation {specify time frame}
 Pregnancy or lactation
 Known allergic reactions to components of the study product(s)
 Treatment with another investigational drug or other intervention {within a
specified time frame}
 History of or current tobacco, drug or alcohol use {define parameters for
exclusion}
 Characteristics of household or close contacts {e.g., household contacts who are
immunocompromised, residence in same household as a subject already
participating in study, if blinding or compliance could potentially be compromised}
 Anything that would place the individual at increased risk or preclude the
individual’s full compliance with or completion of the study.
{End sample text}
5.3 Strategies for Recruitment and Retention

<Insert text>
{Identify strategies for subject recruitment and retention. If subjects will be

compensated for study participation, describe amount and schedule of payments. If the
study requires long-term subject participation, describe procedures that will be used to
enhance subject retention (e.g., multiple methods for contacting subjects, visit
reminders, incentives for visit attendance, etc.)}
5.4 Treatment Assignment Procedures

<Insert text>
{This section should describe the methods of assigning subjects to study group
including randomization procedures (if applicable to the study design). It should include
a description or a table that describes how study subjects will be assigned to study
groups, without being so specific that masking or randomization might be compromised
(e.g., the ratio between intervention and placebo groups may be stated but the
randomization block sizes should not.)}
____________________________________________________________________________________________
________________________________________________________________________________________________________
5.4.1 Randomization Procedures (if applicable)

<Insert text>
{Include plans for the maintenance of trial randomization codes. The timing and
procedures for planned and unplanned breaking of randomization codes should be
included.}
5.4.2 Masking Procedures (if applicable)

<Insert text>
{State whether the intervention arms will be masked if the study includes more than one
intervention. Plans for maintaining appropriate masking for the study should be
discussed. Refer to unmasking procedures described in the Manual of Procedures
(MOP).}
5.5 Subject Withdrawal

<Insert text>
{Subjects may withdraw voluntarily from the study or the investigator may terminate a
subject's participation.}
5.5.1 Reasons for Withdrawal

<Insert text>
{Provide a list of reasons subjects may be withdrawn from the study. It may be
appropriate to provide distinct discontinuation criteria for subjects and cohorts. If so,
both sets of criteria should be listed separately and the distinction between the two must
be stated clearly. Also note that subjects may withdraw voluntarily from participation in
the study at any time.}
{Begin sample text}
Subjects are free to withdraw from participation in the study at any time upon request.
An investigator may terminate a study subject’s participation in the study if:
 Any clinical adverse event (AE), laboratory abnormality, or other medical

condition or situation occurs such that continued participation in the study would
not be in the best interest of the subject.
 The subject meets an exclusion criterion (either newly developed or not
previously recognized) that precludes further study participation.
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
5.5.2 Handling of Subject Withdrawals or Subject Discontinuation of Study

Intervention
<Insert text>
{Describe efforts that will be made to continue follow-up of withdrawn subjects or

subjects who discontinue study intervention, especially for safety and efficacy outcome
measures (if applicable). Every effort must be made to undertake protocol-specified
safety follow-up procedures to capture adverse events (AEs), serious adverse events
(SAEs), and unanticipated problems (UPs).
This section should include a discussion of replacement of subjects who withdraw or
discontinue early, if replacement is allowed.}
5.6 Premature Termination or Suspension of Study

<Insert text>
{List possible reasons for termination or suspension of the study, e.g., study closure
based on principal investigator (PI) decision, or NIDCR decision. For any study that is
prematurely terminated or suspended, the PI will promptly inform the IRB and NIDCR
and provide the reason(s) for the termination or suspension.}
{Begin sample text}
This study may be suspended or prematurely terminated if there is sufficient reasonable
cause. Written notification, documenting the reason for study suspension or
termination, will be provided by the suspending or terminating party to <investigator,
funding agency, the Investigational New Drug (IND) /Investigational Device Exemption
(IDE) sponsor and regulatory authorities>. If the study is prematurely terminated or
suspended, the principal investigator will promptly inform the IRB and will provide the
reason(s) for the termination or suspension.
Circumstances that may warrant termination include, but are not limited to:
 Determination of unexpected, significant, or unacceptable risk to subjects.

 Insufficient adherence to protocol requirements.
 Data that are not sufficiently complete and/or evaluable.
 Determination of futility.
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
6 STUDY INTERVENTION
{An interventional study may involve an investigational drug or device or an approved

drug or device (Section 6.1), and/or a behavioral intervention (Section 6.7), and/or a
surgical or other intervention (Section 6.11). Depending on the type of intervention(s) in
your study, some of the sections below may not apply. Complete applicable sections
and delete sections and subsections that do not apply (including headings). For
example, if your study involves only a behavioral intervention, delete Sections 6.1 to 6.6
and 6.11 to 6.14; numbering of behavioral section headers will then automatically
update, so that the first behavioral section becomes Section 6.1, etc. Include additional
subsections, if necessary.}
6.1 Study Product Description

<Insert text>
{If the study does not use a study product, delete this section, including the
heading and associated subheadings.
Product information can usually be obtained from:
 Investigator’s Brochure, if available, for investigational drug or biologic
 package insert, for licensed drug or biologic
 proposed labeling and material safety data sheet (MSDS) for investigational
device
 final labeling for a marketed device.
Provide this study product information to all investigators and NIDCR.
If multiple products are to be evaluated, this section and the following sections should
be repeated for each product and the sections should be renumbered accordingly.
Include sections to describe placebo or control product.}
6.1.1 Acquisition
<Insert text>
{Describe how the study product will be acquired (e.g., an investigational product may
be supplied by the manufacturer or IND/IDE sponsor, an approved product may be
acquired from the hospital pharmacy, etc.)}
6.1.2 Formulation, Packaging, and Labeling

<Insert text>
{Describe the formulation, packaging, and labeling of the study product as supplied.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
6.1.3 Product Storage and Stability

<Insert text>
{Describe product’s storage needs. Include storage requirements and stability

(temperature, humidity, security, and container).
Provide additional information regarding stability and expiration time for studies in which
multidose vials are entered (i.e., the seal is broken).}
6.2 Dosage, Preparation and Administration of Study Product

<Insert text>
{List study product(s), route, doses, and frequency of administration. Include thawing,
diluting, mixing, and reconstitution or other preparation instructions, as appropriate.
Include any specific instructions or safety precautions for administration of study
products or masking of the product or the study staff administering it. Include maximum
hold time and conditions of product once thawed, mixed, diluted, reconstituted, etc.}
6.3 Modification of Study Product Administration for a Subject

<Insert text>
{Clearly explain instructions for modification of dose due to toxicity or any other reason.
Address dose modifications for specific abnormal laboratory values of concern or other
AEs that are known to be associated with the planned intervention regimen. Do not
restate reasons for withdrawal of subjects. Cross-reference relevant sections, as
appropriate.}
6.4 Accountability Procedures for the Study Product

<Insert text>
{Provide plans for how the study product will be distributed, including participation of a
drug repository, frequency of product distribution, amount of product shipped, device
tracking procedures, and plans for return of unused product.}
6.5 Assessment of Subject Compliance with Study Product Administration

<Insert text>
{If applicable, include in this section plans for compliance assessment (e.g.,
questionnaires, direct observation, pill counts).}
6.6 Concomitant Medications/Treatments

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{This section should be consistent with the medications restrictions in the

inclusion/exclusion criteria.
Describe the data that will be recorded related to permitted concomitant medications
and/or treatments. Include details about when the information will be collected (at
screening, at all study visits, etc.). Discuss any rescue treatments or medications that
are included in the study design.}
________________________________________________________________
6.7 Study Behavioral or Social Intervention(s) Description

<Insert text>
{If the study does not use a behavioral or social intervention, delete this section,
including the heading and associated subheadings.
Provide a general description of the behavioral and social intervention(s) included in this
study. If one or more intervention(s) will be compared to a control intervention or to
treatment as usual, include a general description of these. Detailed descriptions of
behavioral or social intervention(s), including any intervention manuals, scripts,
participant hand-outs, etc., can be provided in a separate Manual of Procedures
(MOP).}
{Begin sample text}
This study will compare 3 behavioral interventions, each using a different approach to
behavior change. The study intervention called “Coping Moments” teaches problem-
solving skills, including anticipating challenging situations and developing strategies for
coping with these. Coping Moments is a cognitive-behavioral intervention. The study
intervention called “Motivating Moments” makes salient the participant’s ambivalence
about behavior change, and empowers the participant to make behavior-change
decisions. Motivating Moments is a motivation-based intervention. The control
intervention called “Teaching Moments” provides participants information about the
connection between daily tooth brushing and oral health. Teaching Moments is a
psycho-educational intervention.
{End sample text}
6.8 Administration of Intervention

<Insert text>
{Describe whether the intervention will be delivered in-person or in some other modality.
If in-person, describe who will administer the intervention. If not in-person, describe how
subjects will access the intervention. Describe the number of sessions to be delivered,
the frequency of session delivery, and the approximate duration of each session.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
6.9 Procedures for Training Interventionists and Monitoring Intervention

Fidelity
<Insert text>
{Describe the training and supervision of staff who will administer the intervention, or of
staff who will facilitate subjects’ accessing the intervention. Describe the procedures for
monitoring intervention fidelity, including how interventionists’ fidelity to the intervention
manual will be documented and assessed, what criteria will signal inadequate fidelity,
and how re-training or replacement of interventionists will be managed. If audio or video
recordings of sessions will be used to monitor intervention fidelity, describe the coding
system to be used to extract fidelity data from these recordings, and how fidelity coders
will be selected and trained.}
6.10 Assessment of Subject Compliance with Study Intervention

<Insert text>
questionnaires, telephone follow-up contacts, direct observation, pill counts).}
________________________________________________________________
6.11 Study Procedural Intervention(s) Description

<Insert text>
{If the study does not use a procedural intervention, delete this section, including
the heading and associated subheadings.
Describe the dental, surgical or other medical procedural intervention(s) that will be
tested in the study. If one or more intervention(s) will be compared to a control
intervention or to treatment as usual, include a general description of these. Detailed
descriptions of the intervention(s), including any intervention manuals, detailed
procedures, subject handouts, etc., can be provided in a separate Manual of
Procedures.}
6.12 Administration of Procedural Intervention

<Insert text>
{Include information about who will administer the intervention and how the intervention
will be administered. In addition, describe the schedule of the intervention procedure(s),
including the number of interventions, frequency of the intervention delivery, and the
approximate duration of each intervention.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
6.13 Procedures for Training of Clinicians on Procedural Intervention

<Insert text>
{Describe any means used to standardize the surgical or procedural intervention (e.g.,
single operator, calibration, images, minimal time of therapy required, specialized
required instruments and/or materials, required measurements). Describe any re-
standardization or re-evaluation procedures and time intervals between
reassessments.}
6.14 Assessment of Clinician and/or Subject Compliance with Study

Procedural Intervention
<Insert text>
questionnaires, research record review, medical record review, laboratory result review,
telephone follow-up contacts, direct observation).}
____________________________________________________________________________________________
________________________________________________________________________________________________________
7 STUDY SCHEDULE
{Information outlined in this section should refer to and be consistent with the
information in the Schedule of Events in Appendix A and in Section 8.
Provide a schedule of initial, intermediate, and final study visits, and include all contacts
with subjects, e.g., telephone contacts. State permissible time windows for study visits,
e.g., Day 7 ± 1 day (weekly visits will have a small window, whereas a 6-month follow-
up visit might have a window of several weeks). When establishing visit intervals and
windows, consider feasibility and relevance to study outcome measures, and take into
account how weekends and holidays will affect the windows.
For each visit, identify the purpose and describe what will occur at the visit. If any of the
procedures occurring at a visit are completed as part of standard clinical care rather
than as study procedures, identify them as such.}
7.1 Screening
<Insert text>
{Include any evaluations necessary to assess whether an individual meets eligibility

criteria. Discuss the sequence of events that should occur during screening and the
decision points regarding eligibility. List the time frame prior to enrollment within which
screening tests and evaluations must be done (e.g., within 28 days prior to enrollment).
This section must include instructions for obtaining signed informed consent. If
screening procedures are required for eligibility (e.g., review of medical records,
clinical examination, or laboratory tests), they may be performed under a
separate screening consent form. State if a separate screening consent will be
used. If a separate screening consent form will not be used, the study consent
form must be signed prior to screening.
Confirm that the procedures listed are consistent with those included in the Schedule of
Events (Appendix A).}
{Begin sample text}
Screening Visit (Day -28 to -1) {include a window that is appropriate for the study}
 Obtain and document consent from potential subject on screening consent form.
 Review medical/dental history to determine eligibility based on
inclusion/exclusion criteria.
 Review medications history to determine eligibility based on inclusion/exclusion
criteria.
 Perform medical/dental examinations needed to determine eligibility.
 Collect blood/urine/saliva.
____________________________________________________________________________________________
________________________________________________________________________________________________________
 Schedule study visits for individuals who are eligible and available for the
duration of the study.
 Provide potential subjects with instructions needed to prepare for first study visit
{specify instructions to be provided}.
{End sample text}
7.2 Enrollment/Baseline
<Insert text>
{Discuss evaluations/procedures necessary to assess or confirm whether an individual

still meets the eligibility criteria and may be enrolled, and specify what will be recorded
at baseline for later outcome measure comparison after study intervention (e.g.,
baseline signs and symptoms prior to treatment). Discuss the sequence of events that
should occur during enrollment and/or initial administration of study product or
intervention. List any special conditions (e.g., results of the pregnancy test must be
negative and available prior to administration of study product or intervention). List the
procedures for administering the study product or intervention and follow-up procedures
after administration.
{Begin sample text}
Enrollment/Baseline Visit (Visit 1, Day 0)
 Obtain and document consent from subject on study consent form.

 Verify inclusion/exclusion criteria.
 Obtain demographic information, medical/dental history, medication history,
alcohol, and tobacco use history.
 Record results of physical and dental examinations.
 Collect blood/urine/saliva/other specimen.
 Administer the intervention. Following administration of <intervention>
o Assess pain on visual analog scale
o Administer Symptoms Questionnaire
{End sample text}
7.3 Intermediate Visits

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{List each intervention or evaluation visit, including visit number and visit window. For
each visit, list the procedures to be completed (in chronological order, if applicable).
{Begin sample text}
Visit 2, Day X ± Y
{Repeat for each visit, providing a study-appropriate window for the visit.}
 Record adverse events as reported by subject or observed by investigator.
 Administer the <intervention>.
 Record subject’s compliance with <intervention>.
 Following administration of <intervention>
o Assess vital signs
o Administer Symptoms Questionnaire
{End sample text}
7.4 Final Study Visit

<Insert text>
{Define when the final study visit should occur and any special procedures/evaluations
or instructions to the subject. Describe provisions for follow-up of ongoing AEs/SAEs. If
study results will be shared with subjects, discuss when and how subjects will receive
this information.
{Begin sample text}
Final Study Visit (Final Visit, Day X ± Y)
 Record adverse events as reported by subject or observed by investigator.

 Record subject’s compliance with <intervention>.
____________________________________________________________________________________________
________________________________________________________________________________________________________
 Provide final instructions to subject {e.g., follow-up of ongoing adverse events,

oral hygiene instructions}.
{End sample text}
7.5 Withdrawal Visit

<Insert text>
{If subject withdraws early or investigator terminates subject participation, specify which
of the evaluations required for the final study visit should be offered to the subject.}
7.6 Unscheduled Visit

<Insert text>
{Specify how unscheduled visits will be handled and documented.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
8 STUDY PROCEDURES /EVALUATIONS
{Information outlined in the Procedures/Evaluations section should refer to and be

consistent with the information in the Schedule of Events in Appendix A.
In the following subsections, describe procedures for collection of all study data
including clinical observations, laboratory results, biospecimens, images, questionnaire
responses.
All procedures listed here should be specific to the study and not part of standard
clinical care. Procedures completed during the study as part of normal standard of
clinical care should be identified as such and summarized in a separate section.}
8.1 Study Procedures/Evaluations

<Insert text>
{List and describe all study procedures and evaluations to be done as part of the study.
Possible content includes:
 Medical history (describe what is included for history, e.g., time-frame
considerations, whether history will be obtained by interview or from medical
records).
 Medications history (e.g., describe if a complete medications history is needed,
or if only currently taken medications should be included; prescription
medications only or also over-the-counter). Assessment of eligibility should
include a review of permitted and prohibited medications.
 Physical examination (list the vital signs [including height and weight] and organ
systems to be assessed. Address details in the MOP.); if appropriate, discuss
what constitutes a targeted physical examination and at what visits it may occur.
 Oral exams, including caries assessments or periodontal measurements.
 Radiographic or other imaging assessments.
 Biological specimen collection.
 Administration of questionnaires or other instruments for subject-reported
outcomes, daily diary.
 Observation and coding of subject behaviors.}
8.2 Laboratory Procedures/Evaluations
8.2.1 Clinical Laboratory Evaluations

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{List all laboratory evaluations to be done as part of the study (e.g., hematology, clinical
chemistry, urinalysis, pregnancy testing). Differentiate screening laboratories from
those taken after treatment. Include specific test components and estimated volume
and type of specimens needed for each test (or refer to the study’s MOP). Specify
laboratory methods to provide for appropriate longitudinal and cross-sectional
comparison (e.g., use of consistent laboratory method throughout study, use of single
laboratory for multi-site studies). If more than one laboratory will be used, specify which
evaluations will be done by each laboratory.}
8.2.2 Special Assays or Procedures

<Insert text>
{List special assays or procedures required to assess the effect of the intervention (e.g.,
immunology assays, pharmacokinetic studies, images, flow cytometry assays,
microarray, DNA sequencing). For research laboratory assays, include specific assays,
estimated volume and type of specimen needed for each test. For procedures, provide
special instructions or precautions or refer to the study’s MOP. If more than one
laboratory will be used, specify which assays will be done by each laboratory.}
8.2.3 Specimen Preparation, Handling, and Storage

<Insert text>
{Special instructions for the preparation, handling, and storage of specimens should be
explained clearly in this section (or refer to the study’s MOP), including specific time
requirements for processing, required temperatures, aliquots of specimens, where they
will be stored, and how they will be labeled.}
8.2.4 Specimen Shipment

<Insert text>
{State the frequency with which specimens are to be shipped and to what address.
Include contact information for laboratory personnel. Include days and times shipments
are allowed, and any labeling requirements for specimen shipping. Also, include any
special instructions such as dry ice or wet ice or the completion of a specimen-tracking
log (or refer to the study’s MOP).}
____________________________________________________________________________________________
________________________________________________________________________________________________________
9 ASSESSMENT OF SAFETY
{Develop this section in consultation with the NIDCR Program Official and Medical
Monitor. To establish a meaningful safety system for the study, consider the risks of the
study intervention and other study procedures as well as the characteristics of the study
population (healthy individuals, individuals with disease, vulnerable populations such as
children). This section should be tailored for specific study characteristics, including but
not limited to the following:
 the study involves an investigational new drug or investigational device;
 the study requires selection of an appropriate toxicity grading scale;
 the study involves risks to individuals other than research subjects (e.g., study
interventionists, other study staff, family members or associates of study
subjects, communities, etc.);
 reporting of certain events (e.g., suspected child abuse or substance abuse) is
mandatory because of the study population or study design characteristics;
 the study is conducted at multiple sites, and will require centralized safety
oversight.}
9.1 Specification of Safety Parameters

<Insert text>
{Describe safety parameters that will be recorded in the safety reporting system.
“Recording” refers to documenting data in the study database. Define what data will
require reporting for protection of human subjects.}
9.1.1 Unanticipated Problems

<Insert text>
{Begin sample text}

The Office for Human Research Protections (OHRP) considers unanticipated problems
involving risks to subjects or others to include, in general, any incident, experience, or
outcome that meets all of the following criteria:
 unexpected in terms of nature, severity, or frequency given (a) the research

procedures that are described in the protocol-related documents, such as the
IRB-approved research protocol and informed consent document; and (b) the
characteristics of the subject population being studied;
 related or possibly related to participation in the research (“possibly related”
means there is a reasonable possibility that the incident, experience, or outcome
may have been caused by the procedures involved in the research); and
____________________________________________________________________________________________
________________________________________________________________________________________________________
 suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously
known or recognized.
{End sample text}
{Per the definition, only a subset of adverse events would be characterized as
unanticipated problems. There are other types of incidents, experiences, and outcomes
that are not considered adverse events, but are characterized as unanticipated
problems (e.g., breach of confidentiality or other incidents involving social or economic
harm).}
9.1.2 Adverse Events

<Insert text>
{Consult Program Official/NIDCR Medical Monitor about this section. The definition of
adverse event here is drawn from the OHRP guidance; for some studies, the ICH E6
definition may be more appropriate.}
{Begin sample text}
An adverse event is any untoward or unfavorable medical occurrence in a human
subject, including any abnormal sign (for example, abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with the subject’s
participation in the research, whether or not considered related to the subject’s
participation in the research.
{End sample text}
9.1.3 Serious Adverse Events

<Insert text>
{SAEs are a subset of all AEs.}

{Begin sample text}
A serious adverse event (SAE) is one that meets one or more of the following criteria:
 Results in death
 Is life-threatening (places the subject at immediate risk of death from the event
as it occurred)
 Results in inpatient hospitalization or prolongation of existing hospitalization
 Results in a persistent or significant disability or incapacity
 Results in a congenital anomaly or birth defect
____________________________________________________________________________________________
________________________________________________________________________________________________________
 An important medical event that may not result in death, be life threatening, or
require hospitalization may be considered an SAE when, based upon appropriate
medical judgment, the event may jeopardize the subject and may require medical
or surgical intervention to prevent one of the outcomes listed in this definition.
{End sample text}
{Some protocols may list events specific to the protocol that should be reported as
serious. Examples might be post-extraction bleeding in anticoagulated subjects and
anaphylactic reaction after lidocaine or analgesic administration.}
9.2 Time Period and Frequency for Event Assessment and Follow-Up
<Insert text>
{Describe how UPs will be recorded and how AEs and SAEs will be followed until
resolved or considered stable. Specify procedures for recording and follow-up of UPs,
SAEs, and AEs that are consistent with the Schedule of Events. Include duration of
follow-up after appearance of events (e.g., 1 week, 2 months).}
{Begin sample text}
Unanticipated problems will be recorded in the data collection system throughout the
study.
The PI will record all reportable events with start dates occurring any time after informed
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day
of study participation. At each study visit, the investigator will inquire about the
occurrence of AE/SAEs since the last visit. Events will be followed for outcome
information until resolution or stabilization.
{End sample text}
9.3 Characteristics of an Adverse Event
9.3.1 Relationship to Study Intervention

<Insert text>
{All adverse events must have their relationship to study intervention or study
participation assessed as either related or not related. Evaluation of relatedness must
consider etiologies such as natural history of the underlying disease, concurrent illness,
concomitant therapy, study-related procedures, accidents, and other external factors.
In a clinical trial, the study intervention must always be suspect.}
{Begin sample text}
To assess relationship of an event to study intervention, the following guidelines are
used:
____________________________________________________________________________________________
________________________________________________________________________________________________________
1. Related (Possible, Probable, Definite)
a. The event is known to occur with the study intervention.
b. There is a temporal relationship between the intervention and event onset.
c. The event abates when the intervention is discontinued.
d. The event reappears upon a re-challenge with the intervention.
2. Not Related (Unlikely, Not Related)
a. There is no temporal relationship between the intervention and event

onset.
b. An alternate etiology has been established.
{End sample text}
9.3.2 Expectedness of SAEs

<Insert text>
{The risk information to assess expectedness can be obtained from preclinical studies,
the investigator’s brochure, published medical literature, the protocol, or the informed
consent document.}
{Begin sample text}
The NIDCR Medical Monitor and the Study PI will be responsible for determining
whether an SAE is expected or unexpected. An adverse event will be considered
unexpected if the nature, severity, or frequency of the event is not consistent with the
risk information previously described for the intervention.
{End sample text}
9.3.3 Severity of Event

<Insert text>
{Describe the method of grading an adverse event for severity. Many toxicity tables are
available for use and are adaptable to various study designs. Selection of a toxicity
table should be made in consultation with the NIDCR Medical Monitor.}
{Begin sample text}
The following scale will be used to grade adverse events:
1. Mild: no intervention required; no impact on activities of daily living (ADL)
____________________________________________________________________________________________
________________________________________________________________________________________________________
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact

on ADL
3. Severe: significant symptoms requiring invasive intervention; subject seeks

medical attention, needs major assistance with ADL
{End sample text}
9.4 Reporting Procedures

<Insert text>
{Institutions engaged in human subjects research conducted or supported by the

Department of Health and Human Services (DHHS) must have written procedures for
ensuring prompt reporting to the IRB, appropriate institutional officials, and any
supporting department or agency head of any unanticipated problem involving risks to
subjects or others [45 CFR 46.103(b)(5)]. In a federally-funded study, institutions are
required to promptly report unanticipated problems to OHRP.
Describe the protocol-specific reporting procedures, including the individual responsible
for each step (e.g., the investigator, the Data Coordinating Center, the Medical Monitor),
which forms should be completed, timeframes for reporting, how reports will be
distributed, and what follow-up is required.
Include specific details of reporting procedures for:
 Deaths and life-threatening events
 Other SAEs
 Other adverse events
The sample text in the following sections may be customized by including IRB-specified
reporting time frames or protocol-specific parameters (safety issues) that need to be
reported in an expedited fashion, either to the IRB, sponsor, or other regulatory body.
For multi-site studies, be cognizant of different IRB reporting requirements.}
9.4.1 Unanticipated Problem Reporting to IRB and NIDCR

<Insert text>
{Begin sample text}

Incidents or events that meet the OHRP criteria for unanticipated problems require the
creation and completion of an unanticipated problem report form. OHRP recommends
that investigators include the following information when reporting an adverse event, or
any other incident, experience, or outcome as an unanticipated problem to the IRB:
 appropriate identifying information for the research protocol, such as the title,
investigator’s name, and the IRB project number;
____________________________________________________________________________________________
________________________________________________________________________________________________________
 a detailed description of the adverse event, incident, experience, or outcome;

 an explanation of the basis for determining that the adverse event, incident,
experience, or outcome represents an unanticipated problem;
 a description of any changes to the protocol or other corrective actions that have
been taken or are proposed in response to the unanticipated problem.
To satisfy the requirement for prompt reporting, unanticipated problems will be reported
using the following timeline:
 Unanticipated problems that are serious adverse events will be reported to the
IRB and to NIDCR within 1 week of the investigator becoming aware of the
event.
 Any other unanticipated problem will be reported to the IRB and to NIDCR within
2 weeks of the investigator becoming aware of the problem.
 All unanticipated problems should be reported to appropriate institutional officials
(as required by an institution’s written reporting procedures), the supporting
agency head (or designee), and OHRP within one month of the IRB’s receipt of
the report of the problem from the investigator.
All unanticipated problems will be reported to NIDCR’s centralized reporting system via
Rho Product Safety:
 Product Safety Fax Line (US): 1-888-746-3293

 Product Safety Fax Line (International): 919-287-3998
 Product Safety Email: [email protected]
General questions about SAE reporting can be directed to the Rho Product Safety Help
Line (available 8:00AM – 5:00PM Eastern Time):
 US: 1-888-746-7231
 International: 919-595-6486
{End sample text}
9.4.2 Serious Adverse Event Reporting to NIDCR

<Insert text>
{Describe the SAE reporting procedures. Include description of when events are
reported to various oversight and regulatory groups.}
{Begin sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
Any AE meeting the specified Serious Adverse Event criteria will be submitted on an
SAE form to NIDCR’s centralized safety system via Rho Product Safety. This report
may be sent by fax or email. Once submitted, Rho Product Safety will send a
confirmation email to the investigator within 1 business day. The investigator should
contact Rho Product Safety if this confirmation is not received. This process applies to
both initial and follow-up SAE reports.
SAE Reporting Contact Information:
 Product Safety Fax Line (US): 1-888-746-3293

 Product Safety Fax Line (International): 919-287-3998
 Product Safety Email: [email protected]
General questions about SAE reporting can be directed to the Rho Product Safety Help
Line (available 8:00AM – 5:00PM Eastern Time):
 US: 1-888-746-7231
 International: 919-595-6486
The study clinician will complete a Serious Adverse Event Form and submit via fax or
email within the following timelines:
 All deaths and immediately life-threatening events, whether related or unrelated,

will be recorded on the Serious Adverse Event Form and submitted to Product
Safety within 24 hours of site awareness.
 Serious adverse events other than death and immediately life-threatening events,
regardless of relationship, will be reported by fax within 72 hours of site
awareness.
All SAEs will be followed until resolution or stabilization.
{End sample text}

{Other supporting documentation of the event may be requested and should be
provided as soon as possible.}
9.4.3 Reporting of SAEs and AEs to FDA

<Insert text>
{If the study is conducted under an IND or IDE, describe the process for complying with
mandatory reporting of safety events to the Food and Drug Administration (FDA).
Regulations for drugs and biologics are found in 21 CFR 312.32 and regulations for
medical devices are found in 21 CFR 812.150. Consult the NIDCR Program Official
____________________________________________________________________________________________
________________________________________________________________________________________________________
and Medical Monitor for assistance. State in the protocol that NIDCR will be copied on
any reports.
If the study intervention includes a regulated product but the study is not conducted
under an IND or IDE, it may be appropriate to name alternative means for voluntary
reporting of events (e.g., MedWatch). State in the protocol that NIDCR will be copied on
any reports.}
9.4.4 Events of Special Interest (if applicable)

<Insert text>
{Describe any other events that merit reporting to the sponsor, study leadership, IRB,
and regulatory agencies.}
9.4.5 Reporting of Pregnancy

<Insert text>
{State the study’s pregnancy-related policy and procedure. Include appropriate

mechanisms for reporting to NIDCR, an IND or IDE sponsor, study leadership, IRB, and
regulatory agencies. Provide appropriate modifications to study procedures (e.g.,
discontinuation of treatment while continuing safety follow-up, requesting permission to
follow pregnant women to pregnancy outcome).}
9.5 Halting Rules

<Insert text>
{Describe safety findings that would prompt temporary suspension of enrollment and/or
study interventions until a safety review is convened (either routine or ad hoc). The
objective of the safety review is to decide whether the study (or intervention for an
individual or study cohort) should continue per protocol, proceed with caution, be further
investigated, be discontinued, or be modified and then proceed. Suspension of
enrollment (for a particular group, a particular study site or for the entire study) is a
potential outcome of a safety review.
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor,
DSMB, IRB, the sponsor(s), or the FDA or relevant local regulatory authorities may also
result in suspension of further trial interventions/administration of study product at a site.
The FDA and study sponsor(s) retain the authority to suspend additional enrollment and
study interventions/administration of study product for the entire study, as applicable.
Examples of findings that might trigger a safety review are the number of SAEs overall,
the number of occurrences of a particular type of SAE, severe AEs/reactions, or
increased frequency of events.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
10 STUDY OVERSIGHT
<Insert text>
{NIDCR clinical research studies must be monitored for subject safety, protocol
compliance, and data integrity. The method and degree of monitoring required varies,
depending on the potential risk for subjects and the complexity of the clinical study. For
clinical research deemed to be more than minimal risk or for clinical research where the
nature, size, complexity or importance of the study merits additional oversight,
independent data and safety monitoring will usually be required. Such clinical research
may include clinical trials of investigational drugs, devices, or biologics; clinical trials of
licensed products; clinical trials of surgical interventions including dental restorative and
periodontal procedures; clinical trials of behavioral interventions. Based on both study
risk and complexity, the NIDCR Medical Monitor will determine the appropriate level of
data and safety monitoring, which may include oversight by one or more of the
following: Data and Safety Monitoring Board (DSMB), Clinical Study Oversight
Committee (CSOC), Independent Safety Monitor (ISM), or NIDCR Medical Monitor.
After consulting with the NIDCR Program Official and Medical Monitor, describe in this
section the type of oversight for the study. Identify who is responsible (e.g., DSMB,
CSOC, ISM, NIDCR MM), and note the expertise represented. State what outcomes
will be monitored and the frequency of data and safety monitoring.}
{Begin sample text for DSMB}
In addition to the PI’s responsibility for oversight, study oversight will be under the
direction of a Data and Safety Monitoring Board (DSMB) composed of members with
expertise in <in consultation with NIDCR, appropriate clinical, statistical, scientific,
ethical disciplines will be inserted>. The DSMB will meet <insert time interval> to
assess safety and efficacy data (if applicable), study progress, and data integrity for the
study. If safety concerns arise, more frequent meetings may be held. The DSMB will
operate under the rules of an NIDCR-approved charter that will be approved at the
organizational meeting of the DSMB. At this time, most data elements that the DSMB
needs to assess will be clearly defined. The DSMB will provide recommendations to the
NIDCR.
{End sample text for DSMB}
{Begin sample text for CSOC}

direction of a Clinical Study Oversight Committee (CSOC) composed of members with
expertise in <in consultation with NIDCR, appropriate clinical, statistical, scientific,
ethical disciplines will be inserted>. The CSOC will meet <insert time interval> to
assess unanticipated problems, study conduct, and progress. If major concerns arise,
more frequent meetings may be held. The CSOC will operate under the rules of an
____________________________________________________________________________________________
________________________________________________________________________________________________________
NIDCR-approved charter that will be approved at the organizational meeting of the

CSOC. At this time, most data elements that the CSOC needs to assess will be clearly
defined. The CSOC will provide recommendations to the NIDCR.
{End sample text for CSOC}
{Begin sample text for ISM}

direction of an Independent Safety Monitor (ISM), <in consultation with NIDCR, name
the individual, and describe his/her expertise>. The ISM is independent of the study
and will be available in real time to review and recommend appropriate action regarding
adverse events and other safety issues.
{End sample text for ISM}
{Begin sample text for NIDCR Medical Monitor}
direction of the NIDCR Medical Monitor. The PI will submit a report every 6 months to
the NIDCR Medical Monitor for review. This report will include data regarding enrollment
and retention, unanticipated problems and protocol deviations, disposition of
biospecimens, outcome measures, quality management findings and other relevant
parameters. If necessary, additional steps may be taken to ensure data integrity and
protocol compliance.
{End sample text for NIDCR Medical Monitor}
____________________________________________________________________________________________
________________________________________________________________________________________________________
11 CLINICAL SITE MONITORING
<Insert text>
{Consult Program Official and the NIDCR Office of Clinical Trials Operations and
Management (OCTOM) about this section. Based on a determination of study oversight
requirements, clinical site monitoring may be required. Site monitoring is conducted to
ensure that the rights of human subjects are protected, that the study is implemented in
accordance with the protocol and/or other operating procedures, and that the study
uses high quality data collection processes. The monitor will evaluate study processes
based on NIDCR or other study sponsor standards, ICH E6 and, when appropriate,
regulatory guidelines.
Include in this section a general description of the site monitoring planned for the study.
State who will conduct the monitoring. Indicate the frequency of monitoring visits. This
section may refer to a separate detailed monitoring plan document developed by or
provided to OCTOM. The separate monitoring plan will describe in detail who will
conduct the monitoring, the frequency of monitoring, the level of detail of monitoring
(e.g., the number of subject data forms to be reviewed, the percentage of particular data
fields to be monitored) and who is responsible for addressing findings in the monitoring
report.
State that NIDCR will receive monitoring reports from the organization that conducts
monitoring. NIDCR reserves the right to conduct independent audits as necessary.
Begin sample text for Clinical Monitoring; adapt as needed for a specific study.}
Clinical site monitoring is conducted to ensure that the rights of human subjects are
protected, that the study is implemented in accordance with the protocol and/or other
operating procedures, and that the quality and integrity of study data and data collection
methods are maintained. Monitoring for this study will be performed by NIDCR’s
Clinical Research Operations and Management Support (CROMS) contractor. The
monitor will evaluate study processes and documentation based on NIDCR standards
and the International Conference on Harmonisation (ICH), E6: Good Clinical Practice
guidelines (GCP).
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP)
developed by the CROMS contractor, in collaboration with the NIDCR Office of Clinical
Trials and Operations Management (OCTOM) and the NIDCR Program Official. The
CMP will specify the frequency of monitoring, monitoring procedures, the level of clinical
site monitoring activities (e.g., the percentage of subject data to be reviewed), and the
distribution of monitoring reports. Some monitoring activities may be performed
remotely, while others will take place at the study site(s). Staff from the CROMS
contractor will conduct monitoring activities and provide reports of the findings and
associated action items in accordance with the details described in the CMP.
Documentation of monitoring activities and findings will be provided to the site study
team, the study PIs, OCTOM, and the NIDCR. The NIDCR reserves the right to conduct
independent audits as necessary.
____________________________________________________________________________________________
________________________________________________________________________________________________________
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
12 STATISTICAL CONSIDERATIONS
{The following subsections describing statistical considerations should be “self-

contained” for coherence and ready reference. The statistical plan should show how
the study will answer the most important questions with precision and a minimum of
bias, while remaining feasible. Many elements below can be found in ICH guidance
document E9 (Statistical Principles for Clinical Trials) and the CONSORT statement
(http://www.consort-statement.org/), which describes standards for improving the quality
of reporting randomized controlled trials.}
12.1 Study Hypotheses

<Insert text>
{State the formal, testable, null, and alternate hypotheses for the primary objective and
key secondary objectives.}
12.2 Sample Size Considerations

<Insert text>
{Provide all information needed to validate your calculations, and also to judge the
feasibility of enrolling and following the necessary numbers of subjects.
Consider applicable items from the following list when describing sample size
determination:
 Statistical method used to calculate the sample size
 Outcome measure used for calculations (almost always the primary variable)
 Test statistic
 Type I error rate
 Type II error rate
 Method for adjusting calculations for planned interim analyses, if any
 Assumptions used in calculations:
o Assumed event rate for dichotomous outcome (or mean or variance of
continuous outcome) for each study arm, justified and referenced by historical
data as much as possible
o Assumed dropout rates, withdrawal, cross-over to other study arms, missing
data, etc., also justified
o Approach to handling withdrawals and protocol violations, i.e., to what extent
data from withdrawn subjects will be evaluable (e.g., whether subjects will be
included in the “intent-to-treat” population), whether withdrawn subjects will be
replaced
____________________________________________________________________________________________
________________________________________________________________________________________________________
Present calculations from a suitable range of assumptions to gauge the robustness of

the proposed sample size. Most assumptions are not accurate as point estimates.
Discuss whether the sample size also provides sufficient power for addressing
secondary objectives or for secondary analyses in key subgroup populations.}
12.3 Planned Interim Analyses (if applicable)

<Insert text>
{Describe the types of statistical interim analyses and stopping guidelines (if any) that
are proposed, including their timing.}
12.3.1 Safety Review

<Insert text>
{If statistical rules will be used to halt enrollment into all or a portion of the study (see
Section 9.5), describe the statistical techniques and their operating characteristics, e.g.,
the probability of stopping under different safety event rates and the associated number
of subjects that would be enrolled.}
12.3.2 Efficacy Review

<Insert text>
{Provide the same information as in Section 12.3.1, but for efficacy outcome measures.
Also discuss the impact of the interim analysis (if being done) on the final efficacy
analyses, particularly on Type I error.
If formal interim analyses will be performed, provide unambiguous and complete
instructions so that an independent statistician could perform the analyses.}
12.4 Final Analysis Plan

<Insert text>
{Describe analyses for assessing the primary and secondary objectives.

Plans must clearly identify the analyses cohorts (e.g., “Per Protocol” or “Intent to Treat,”
as well as subsets of interest) and methods to account for missing, unused or spurious
data.
Discuss how outcome measures will be assessed and transformed, if relevant, before
analysis. (Examples: Is the primary variable binary, categorical, or continuous? Will a
series of measurements within a subject be summarized, such as by calculating the
area under the curve? For survival outcome measures, what are the competing risks
and censoring variables?)
____________________________________________________________________________________________
________________________________________________________________________________________________________
For complex data analyses (e.g., multiple secondary objectives), an overview of the
statistical analyses may be provided here, with more details in a separate statistical
analysis plan written prior to performing any analyses.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS
<Insert text>
{Source data are all information, original records of clinical findings, observations, or
other activities in a clinical trial necessary for the reconstruction and evaluation of the
trial. Examples of these original documents and data records include, but are not
limited to, hospital records, clinical and office charts, laboratory notes, memoranda,
subjects’ memory aid or evaluation checklists, pharmacy dispensing records, recorded
data from automated instruments, audio recordings of counseling sessions or other data
collection events, copies or transcriptions certified after verification as being accurate
and complete, photographs or digital photo files, x-rays, and subject files and records
kept at the pharmacy, at the laboratories, and medico-technical departments involved in
the clinical trial. It may be acceptable to use case report forms (CRFs) as source
documents, but plans should be discussed with OCTOM before this process is finalized
to ensure that source documentation is adequate. If CRFs are used as source
documents, it should be stated in this section what data will be collected on CRFs and
what data will be collected from other sources.
Describe how source documents will be managed in the study. Specify what will be
considered source documents, how they will be maintained, and who will have access
to records.}
{Begin required text; adapt as needed to specify what will be source documents for your
study}
Study staff will maintain appropriate medical and research records for this study, in
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for
the protection of confidentiality of subjects. Study staff will permit authorized
representatives of NIDCR and regulatory agencies to examine (and when required by
applicable law, to copy) research records for the purposes of quality assurance reviews,
audits, and evaluation of the study safety, progress and data validity.
{End required text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
14 QUALITY CONTROL AND QUALITY ASSURANCE
<Insert text>
{This section will address the plans for local quality assurance and quality control.
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073122.pdf).
Quality Management is the overall process of establishing and ensuring the quality of
processes, data, and documentation associated with clinical research activities. It
encompasses both quality control (QC), and quality assurance (QA) activities. All sites
conducting research under the sponsorship of the NIDCR are required to have a plan in
place for assuring the quality of the research being conducted.
Each site should have standard operating procedures (SOPs) and/or a quality
management plan that describe:
 How data will be evaluated for compliance with the protocol and for accuracy in
relation to source documents.
 The documents to be reviewed (e.g., CRFs, clinic notes, product accountability
records, specimen tracking logs, questionnaires, audio or video recordings), who
is responsible, and the frequency for reviews.
 Who will be responsible for addressing quality assurance issues (correcting
procedures that are not in compliance with protocol) and quality control issues
(correcting errors in data entry).
 Staff training methods and how such training will be tracked.
 If applicable, calibration exercises conducted prior to and during the study to train
examiners and maintain acceptable intra- and inter-examiner agreement.
Quality management tools designed for clinical site use are available on the NIDCR
Toolkit for Clinical Researchers at http://www.nidcr.nih.gov/Research/toolkit/.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
15 ETHICS/PROTECTION OF HUMAN SUBJECTS
15.1 Ethical Standard

<Insert text>
{Include in this section the guiding ethical principles being followed by the study.}
The investigator will ensure that this study is conducted in full conformity with the
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the
Protection of Human Subjects of Research, as drafted by the US National Commission
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18,
1979) and codified in 45 CFR Part 46 and/or the ICH E6.
{End required text}

{If the study is conducted at international sites, the statement could be as above and/or
could reference compliance with the Declaration of Helsinki, CIOMS, International
Ethical Guidelines for Biomedical Research Involving Human Subjects (2002), or
another country’s ethical policy statement, whichever provides the most protection to
human subjects.}
15.2 Institutional Review Board

<Insert text>
{Each participating institution must provide for the review and approval of this protocol
and the associated informed consent documents and recruitment materials by an
appropriate IRB registered with the OHRP. Any amendments to the protocol or consent
materials must also be approved before they are placed into use. In the United States
and in other countries, only institutions holding a current US Federalwide Assurance
issued by OHRP may participate. Refer to: http://www.hhs.gov/ohrp/assurances/.}
{Begin required text; modify as appropriate for a multi-site study}
The protocol, informed consent form(s), recruitment materials, and all subject materials
will be submitted to the IRB for review and approval. Approval of both the protocol and
the consent form must be obtained before any subject is enrolled. Any amendment to
the protocol will require review and approval by the IRB before the changes are
implemented in the study.
{End required text}
15.3 Informed Consent Process

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{Identify different consent forms that are needed for the study (e.g., screening, study
participation, future use of specimens, assent form for minors).
When a study includes subjects who may be enrolled in the trial only with the consent of
the subject’s legally authorized representative (e.g., minors or subjects whose cognitive
impairment is such that they are unable to give informed consent), the subject should be
informed about the trial to the extent compatible with the subject’s understanding. If
capable, the subject should assent and sign and personally date the written consent
form. A separate IRB-approved assent form, describing (in simplified terms) the details
of the study intervention, study procedures, and risks may be used. Assent forms do
not substitute for the consent form signed by the subject’s legally authorized
representative.
If non-English speakers will be enrolled, state that a translated consent document will
be available and an appropriate person will conduct the consent process. Consider
other special circumstances such as low literacy, braille, or web-based consenting.
For a multi-site study, each participating institution will be provided with a model
informed consent form. Each institution may revise or add information to comply with
institution consent templates, but may not remove procedural or risk content from the
model consent form.}
{Begin required text; adapt as needed for a specific study}
Informed consent is a process that is initiated prior to the individual agreeing to
participate in the study and continues throughout study participation. Extensive
discussion of risks and possible benefits of study participation will be provided to
subjects and their families, if applicable. A consent form describing in detail the study
procedures and risks will be given to the subject. Consent forms will be IRB-approved,
and the subject is required to read and review the document or have the document read
to him or her. The investigator or designee will explain the research study to the subject
and answer any questions that may arise. The subject will sign the informed consent
document prior to any study-related assessments or procedures. Subjects will be given
the opportunity to discuss the study with their surrogates or think about it prior to
agreeing to participate. They may withdraw consent at any time throughout the course
of the study. A copy of the signed informed consent document will be given to subjects
for their records. The rights and welfare of the subjects will be protected by
emphasizing to them that the quality of their clinical care will not be adversely affected if
they decline to participate in this study.
The consent process will be documented in the clinical or research record.
{End required text}
15.4 Exclusion of Women, Minorities, and Children (Special Populations)

<Insert text>
____________________________________________________________________________________________
________________________________________________________________________________________________________
{Explain why any of these populations are excluded from study participation, or state
that individuals of any age, gender or racial/ethnic group may participate.}
15.5 Subject Confidentiality

<Insert text>
{Include procedures for maintaining subject confidentiality and any special data security
requirements. Describe who would have access to records, including the investigator
and other study staff, the clinical monitor, representatives of NIDCR or other funding
institutions, IRB representatives and regulatory representatives. For some studies, it
may be necessary to obtain a Certificate of Confidentiality. A Certificate of
Confidentiality protects researchers and research institutions from being forced to
provide identifying information on study subjects to any federal, state, or local authority.
Authorization comes from NIH through section 301 (d) of the Public Health Service Act
[42 U.S.C. 241 (d)] which provides the Secretary of Health and Human Services the
authority to protect the privacy of study subjects. For additional information, see
http://grants.nih.gov/grants/policy/coc/appl_extramural.htm.}
{Begin sample text; include Certificate of Confidentiality and Data Sharing Policy text,
only if applicable}
Subject confidentiality is strictly held in trust by the investigators, study staff, and the
sponsor(s) and their agents. This confidentiality is extended to cover testing of
biological samples and genetic tests in addition to any study information relating to
subjects.
The study protocol, documentation, data, and all other information generated will be
held in strict confidence. No information concerning the study or the data will be
released to any unauthorized third party without prior written approval of the sponsor.
The study monitor or other authorized representatives of the sponsor may inspect all
study documents and records required to be maintained by the investigator, including
but not limited to, medical records (office, clinic, or hospital) for the study subjects. The
clinical study site will permit access to such records.
Certificate of Confidentiality (if applicable)
To further protect the privacy of study subjects, a Certificate of Confidentiality will be

obtained from the NIH. This certificate protects identifiable research information from
forced disclosure. It allows the investigator and others who have access to research
records to refuse to disclose identifying information on research participation in any civil,
civil, criminal, administrative, legislative, or other proceeding, whether at the federal,
state, or local level. By protecting researchers and institutions from being compelled to
disclose information that would identify research subjects, Certificates of Confidentiality
help achieve the research objectives and promote participation in studies by helping
assure confidentiality and privacy to subjects.
____________________________________________________________________________________________
________________________________________________________________________________________________________
NIH Data Sharing Policy for Genome-Wide Association Studies (GWAS) (if applicable)
This study is a genome-wide association study and will comply with the NIH Policy for
Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association
Studies, which calls for investigators funded by the NIH for GWAS to 1) share de-
identified genetic (genotypic and phenotypic) data through a centralized NIH data
repository; and 2) submit documentation that describes how the institutions have
considered the interests of the research participants, such as privacy and confidentiality.
Submission of data to the NIH GWAS repository will be consistent with the permissions
and limitations delineated on the study consent signed by study participants.
{End sample text}
15.6 Future Use of Stored Specimens and Other Identifiable Data

<Insert text>
{Refer to Human Subject Regulations Decision Charts 2 and 5:

http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html#c2.
If residual specimens or other identifiable data will be maintained after the study is
complete, include the provisions for consent and the options that are available for the
subject to agree to the future use of his/her specimens, images, audio or video
recordings. Specify the location(s), if other than the clinical site, where specimens or
other data will be maintained, how long specimens or other data will be stored, if the
site's IRB will review future studies, and protections of confidentiality for any future
studies with the stored specimens or data (e.g., specimens will be coded, bar-coded,
de-identified, identifying information will be redacted from audio recording transcripts,
etc.). Include a statement that genetic testing will or will not be performed. A Certificate
of Confidentiality may be obtained if genomic testing is planned.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
16 DATA HANDLING AND RECORD KEEPING
<Insert text>
{Include instructions for data handling or record-keeping procedures required for

maintaining subject confidentiality, any special data security or data transfer
requirements, and record retention.
Briefly describe steps to be taken to ensure that the data collected are accurate,
consistent, complete, reliable, and in accordance with ICH E6. The description should
include reference to source documentation, CRFs, instructions for completing forms,
data handling procedures, and procedures for data monitoring. Details may be provided
in a MOP, a data management plan or other citable reference document. Data
management tools are available on the NIDCR Toolkit for Clinical Researchers at
http://www.nidcr.nih.gov/Research/toolkit/.}
{Begin sample text}
The investigators are responsible for ensuring the accuracy, completeness, legibility,
and timeliness of the data reported. All source documents should be completed in a
neat, legible manner to ensure accurate interpretation of data. The investigators will
maintain adequate case histories of study subjects, including accurate case report
forms (CRFs), and source documentation.
{End sample text}
16.1 Data Management Responsibilities

<Insert text>
{Include a general description as in the sample text below and add study-specific details
and information about the role of a data coordinating center, if applicable.}
{Begin sample text}
Data collection and accurate documentation are the responsibility of the study staff
under the supervision of the investigator. All source documents and laboratory reports
must be reviewed by the study team and data entry staff, who will ensure that they are
accurate and complete. Unanticipated problems and adverse events must be reviewed
by the investigator or designee.
{End sample text}
16.2 Data Capture Methods

<Insert text>
{Provide details regarding the type of data capture that will be used for the study.
Specify whether it will be paper or electronic, distributed or central, batched or ongoing
____________________________________________________________________________________________
________________________________________________________________________________________________________
processing, and specify any related requirements (e.g., password protection and data
quality checks for an electronic data system). Indicate expectations for time for
submission of CRFs to a data coordinating center, if applicable.}
16.3 Types of Data

<Insert text>
{Indicate the types of data that will be collected, such as safety, laboratory (clinical,
immunology, pharmacokinetic, other study specific), and outcome measure data (e.g.,
periodontal measurements, caries assessments, physical measurements, questionnaire
responses). Specify if safety data are collected in a separate database.}
16.4 Schedule and Content of Reports

<Insert text>
{Indicate, as applicable, the schedule and content for data review and reports.
Examples include reports to monitor enrollment, reports to study oversight committee,
reports of study conduct, and reports for interim data analysis and study progress.
Identify plans for data analysis and interim and final study reports, steps for locking the
database prior to analysis, and precautions related to masked data. Indicate whether
and when coding is to occur.}
16.5 Study Records Retention

<Insert text>
{Specify the length of time for the investigator to maintain all records pertaining to this
study. Consideration should be given to NIH grant and ICH guidance, federal and state
and local regulations.}
{Begin sample text}
Study records will be maintained for at least three years from the date that the grant
federal financial report (FFR) is submitted to the NIH.
Study documents should be retained for a minimum of 2 years after the last approval of
a marketing application in an ICH region and until there are no pending or contemplated
marketing applications in an ICH region or until at least 2 years have elapsed since the
formal discontinuation of clinical development of the investigational product. These
documents should be retained for a longer period, however, if required by local
regulations. No records will be destroyed without the written consent of the sponsor, if
applicable. It is the responsibility of the sponsor to inform the investigator when these
documents no longer need to be retained.
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
16.6 Protocol Deviations

<Insert text>
{Begin sample text}

A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical
Practice, or Manual of Procedures requirements. The noncompliance may be on the
part of the subject, the investigator, or study staff. As a result of deviations, corrective
actions are to be developed by the study staff and implemented promptly.
These practices are consistent with investigator and sponsor obligations in ICH E6:
 Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4.

 Quality Assurance and Quality Control, Section 5.1.1
 Noncompliance, Sections 5.20.1 and 5.20.2.
All deviations from the protocol must be addressed in study subject source documents
and promptly reported to NIDCR and the local IRB, according to their requirements.
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
17 PUBLICATION/DATA SHARING POLICY
<Insert text>
{The publication and authorship policies should be established and briefly outlined in
this section. For example, for a study with multiple investigators, this section might
state that an Executive Committee will be responsible for developing publication
procedures and resolving authorship issues. If details of the publication policy will be
described in the study’s MOP, refer to it here.}
{Begin sample text; include applicable text and add study-specific information on
publication and authorship policies, and compliance with NIH Data Sharing Policy, if
applicable.}
This study will comply with the NIH Public Access Policy, which ensures that the public
has access to the published results of NIH funded research. It requires scientists to
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital
archive PubMed Central upon acceptance for publication.
The International Committee of Medical Journal Editors (ICMJE) member journals have
adopted a clinical trials registration policy as a condition for publication. The ICMJE
defines a clinical trial as any research project that prospectively assigns human subjects
to intervention or concurrent comparison or control groups to study the cause-and-effect
relationship between a medical intervention and a health outcome. Medical
interventions include drugs, surgical procedures, devices, behavioral treatments,
process-of-care changes, and the like. Health outcomes include any biomedical or
health-related measures obtained in patients or participants, including pharmacokinetic
measures and adverse events. The ICMJE policy requires that all clinical trials be
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the
National Library of Medicine. Other biomedical journals are considering adopting similar
policies. For interventional clinical trials performed under NIDCR grants and cooperative
agreements, it is the grantee’s responsibility to register the trial in an acceptable
registry, so the research results may be considered for publication in ICMJE member
journals. The ICMJE does not review specific studies to determine whether registration
is necessary; instead, the committee recommends that researchers who have questions
about the need to register err on the side of registration or consult the editorial office of
the journal in which they wish to publish.
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or
FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or
designated principal investigator) register and report results of certain "applicable
clinical trials:"
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I
investigations, of a product subject to FDA regulation;
____________________________________________________________________________________________
________________________________________________________________________________________________________
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA
regulation (other than small feasibility studies) and pediatric postmarket surveillance
studies.
NIH grantees must take specific steps to ensure compliance with NIH implementation of
FDAAA.
{End sample text}
{Begin sample text for GWAS data sharing}

This study will comply with the NIH Policy for Sharing of Data Obtained in NIH
Supported or Conducted Genome-Wide Association Studies (GWAS). Genotype and
phenotype data will be submitted to the Database of Genotypes and Phenotypes
(dbGaP), with a certification that the IRB has verified that
 the submission of data to the NIH GWAS data repository and subsequent sharing
for research purposes are consistent with the informed consent of study
participants from whom the data were obtained;
 the investigator's plan for de-identifying data is consistent with the Policy
standards;
 it has considered the risks to individuals, their families, and groups or populations
associated with data submitted to the NIH GWAS data repository; and
 the genotype and phenotype data to be submitted were collected in a manner
consistent with 45 CFR Part 46.
{End sample text}
____________________________________________________________________________________________
________________________________________________________________________________________________________
18 LITERATURE REFERENCES
<Insert text>
{Include a list of relevant literature references in this section. Use a consistent,

standard, modern format, which might be dependent upon the required format for the
anticipated journal for publication (e.g., N Engl J Med, JAMA, etc). The preferred format
is ICMJE.}
{Begin examples}
“Journal citation:
Davis JT, Allen HD, Powers JD, Cohen DM. Population requirements for
capitation planning in pediatric cardiac surgery. Arch Pediatr Adolesc Med.
1996;150(1):257-9.
Whole book citation:

Sherlock S, Dooley J. Diseases of the liver and biliary system. 9th ed. Oxford
(England): Blackwell Scientific Publications; 1993.
Chapter in a book citation:

Cole BR. Cystinosis and cystinuria. In: Jacobson HR, Striker GE, Klarh S,
editors. The principles and practice of nephrology. Philadelphia (PA): BC Decker
Inc.; 1991. p.396-403.”
{End examples}
{A full listing of ICMJE style guidelines can be found at:
International Committee of Medical Journal Editors. Uniform requirements for
manuscripts submitted to biomedical journals. JAMA. 1997;277:927-34.
You may also refer to:
http://www.nlm.nih.gov/bsd/uniform_requirements.html.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
SUPPLEMENTAL MATERIALS
These documents are relevant to the protocol, but they are not considered part of the
protocol. They are stored and modified separately. As such, modifications to these
documents do not require protocol amendments.
{These are examples of documents that you may want to include as Supplemental
Materials. If there are no supplemental materials to be referenced, this section should
be deleted.
 Site Roster
 Manual of Procedures
 Behavioral Intervention Manual (if applicable)
 Calibration protocol (if applicable)
 Repository Instructions (if applicable)
 Biosafety Precautions (if applicable)
 Ionizing Radiation safety (if applicable)
 Laboratory Handling (if applicable)
 Case report forms
 Quality Management Plan
 Data Management Plan
 Clinical Monitoring Plan
 Statistical Analysis Plan
 DSMB or Oversight Committee Charter}
____________________________________________________________________________________________
________________________________________________________________________________________________________
APPENDICES
{In this section, include the list of documents that are officially affiliated with the protocol
and will be submitted to the IRB as a part of the protocol. As such, changes to these
items require a protocol amendment. When including items in this section, it is useful to
number them (e.g., “Appendix 1: Schedule of Events”).
These are examples of documents you may want to include as Appendices:
 Schedule of Events diagram or table (must match with Section 7)
 Key Study Questionnaires (validated and/or are not likely to change during the
course of the study)
 Observational Coding Schemes (if applicable)
 Consent Form(s) sample/template (if applicable)
Include a cover page for each listed Appendix. The following page includes an
example.}
____________________________________________________________________________________________
________________________________________________________________________________________________________
APPENDIX A: SCHEDULE OF EVENTS
{Create a detailed schematic describing all visits and assessments, consistent with
those listed in Sections 7 and 8.}
{Begin sample text}
Study Completion
Discontinuation
(Day –X to –Y)
Study Visit 1
Study Visit 2
Study Visit 3
Study Visit 4
(Day X ± Y)
(Day X ± Y)
(Day X ± Y)
(Day X ± Y)
(Day X ± Y)
Premature
Screening
Baseline
(Day 0)
Procedures
Signed Consent Form X X
Assessment of Eligibility Criteria X X
Review of Medical/Dental History X X
Review of Concomitant
X X X X X X X X
Medications
Study Intervention X X X X X
Complete
X X X
Examination
Symptom-
Physical
X (X) (X) (X) (X)

Directed
Vital Signs (X) (X) (X) (X) (X)
Behavioral Assessment X X X
Assessment of Adverse Events (X) (X) (X) (X) X X
Pregnancy test
Research Laboratory Clinical Laboratory
X X
Chemistry X X (X) (X) (X) (X) X X
Hematology X X (X) (X) (X) (X) X X
Urinalysis X X (X) (X) (X) (X) X X
Immunology
__mL whole X (X) (X) X X
blood
Biomarkers
X X
__mL saliva
Sample for
Genetic Analysis X X
Periodontal
Procedures
Measurements X X
Other
Pain Assessment
(X) (X) (X) (X) (X)
____________________________________________________________________________________________
________________________________________________________________________________________________________
{End sample text}

{Specify time points for intervention or intermediate visits in days, weeks, or months, as
appropriate for protocol. For each visit, provide a window during which the visit can
occur. The window should be appropriate for the parameters to be assessed at the
visit.
(X) – As indicated/appropriate.
Note: List the tests applicable to your specific protocol.
Provide a list of Clinical Laboratory tests, e.g.:
 Pregnancy Test – urine or serum test to establish eligibility
 Hematology – Hemoglobin, hematocrit, WBC and differential count, platelet
count.
 Biochemistry – Sodium, potassium, chloride, urea, creatinine, glucose, uric
acid, bicarbonate, amylase, lipase, albumin, total bilirubin, cholesterol,
triglycerides, and creatine phosphokinase, as appropriate for the study.
 Urinalysis (protein and glucose), as appropriate for the study.
Provide a list of Research Laboratory tests and the required specimen types, e.g.:
 Gene sequencing, Immunology – X mL blood
 Biomarkers – X mL saliva or blood
Provide a list of other procedures done to evaluate outcome measures (e.g., caries
assessments, periodontal measurements, photographs, x-rays, questionnaires, pain
assessments).
Study intervention – Modify as appropriate if intervention is administered more than
once throughout the study.}
____________________________________________________________________________________________

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Tool Summary Sheet

Tool: NIDCR Clinical Trial (Interventional) Protocol Template

The National Institutes of Health (NIH) defines a clinical trial as a

The Grantee Institution may have an IRB-specified protocol format.

Tool Summary Sheet Page 1 of 3

Terminology has been consistently applied throughout this template.

Tool Summary Sheet Page 2 of 3

Tool Revision History:

Version Version Date Summary of Revisions Made:

Tool Summary Sheet Page 3 of 3

NIDCR Grant Number:

NIDCR Program Official:

NIDCR Medical Monitor:

IND/IDE Sponsor: <sponsor name, if applicable; do not include

Draft or Version Number: <x.x>

<Day Month Year>

{Begin required text}

{End required text}

{Begin required text}

Principal Investigator or Clinical Site Investigator:

{End required text}

6.2 Dosage, Preparation and Administration of Study Product .................................... 14

9.4.5 Reporting of Pregnancy ............................................................................. 31

{Please add all disease or study-specific abbreviations/acronyms in this section. Modify

AE Adverse Event/Adverse Experience

NIDCR National Institute of Dental and Craniofacial Research, NIH, DHHS

{Limit to 1-2 pages; put key words in boldface in Protocol Summary.}

Schematic of Study Design:

Perform baseline assessments.

Visit 2 Repeat study intervention (if applicable).

Visit 3 Follow-up assessments of outcome measures and safety

Visit 4 Follow-up assessments of outcome measures and safety

Visit X Final Assessments

1 KEY ROLES AND CONTACT INFORMATION

{Provide the following information for each individual:

2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE

2.1 Background Information

2.3 Potential Risks and Benefits

2.3.1 Potential Risks

2.3.2 Potential Benefits

3.1 Study Objectives

Express each objective as a statement of purpose (e.g., to assess, to determine, to

3.2 Study Outcome Measures

4.1 Substudies (if applicable)

5 STUDY ENROLLMENT AND WITHDRAWAL

 If reproductive status (i.e., pregnancy, lactation, reproductive potential) is an

5.1 Subject Inclusion Criteria

 Provide signed and dated informed consent form

5.2 Subject Exclusion Criteria

5.3 Strategies for Recruitment and Retention

{Identify strategies for subject recruitment and retention. If subjects will be

5.4 Treatment Assignment Procedures

5.4.1 Randomization Procedures (if applicable)

5.4.2 Masking Procedures (if applicable)

5.5 Subject Withdrawal

5.5.1 Reasons for Withdrawal

An investigator may terminate a study subject’s participation in the study if:

 Any clinical adverse event (AE), laboratory abnormality, or other medical

5.5.2 Handling of Subject Withdrawals or Subject Discontinuation of Study