Tool Summary Sheet

Tool:	NIDCR Clinical Study (Observational) Protocol Template
Purpose:	To provide an instructional template for use in development of a protocol for observational studies
Audience/User:	Principal Investigators and Study Staff
Details:	This document is the National Institute of Dental and Craniofacial Research (NIDCR) protocol template for an observational study. In an observational study, the investigator does not alter the care that people receive, but simply records observations and analyzes data. These studies may focus on risk factors, natural history, variations in disease progression or in disease treatment. They often assess specific health characteristics of the enrolled human subjects by collecting biospecimens (e.g., for biomarker or genomic analyses), obtaining photographic, radiographic or other images, and/or collecting medical history or exposure data from research subjects. Observational studies that collect biospecimens, images, or other data involve human subjects, and require Institutional Review Board (IRB) approval. 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 study protocol that meets NIDCR standards and includes all elements required for an 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 study, 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. Changes to the protocol via an amendment cannot be implemented until IRB approval is received. Terminology has been consistently applied throughout this template. The template uses “subject” and “participant” interchangeably, and a protocol author may use either or both terms. For definitions and synonyms (e.g., case report form = data collection form), please refer to the NIDCR Glossary of Clinical Terms available on the NIDCR Toolkit for Clinical Researchers website.
Best Practice Recommendations:	Refer questions regarding use of this protocol template to the appropriate NIDCR Program Official or the NIDCR Office of Clinical Trials Operations and Management (OCTOM). 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 Number	Version Date	Summary of Revisions Made:
2.0	11Feb2013	Original version with Tool Summary Sheet
3.0	06Jan2014	Revised text regarding Safety Oversight method, Final Statistical Analysis, Data Sharing, and Clinical Site Monitoring; clarified instructional text and added text placeholders

<Title>

NIDCR Protocol Number: <number provided by NIDCR>

NIDCR Grant Number:

Principal Investigator:

NIDCR Program Official:

NIDCR Medical Monitor:

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}

SIGNATURE PAGE

{Begin required text}

The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that this study 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.}

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	i

TABLE OF CONTENTS	i

LIST OF ABBREVIATIONS	i

PROTOCOL SUMMARY	i

1	KEY ROLES AND CONTACT INFORMATION	1

2	INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE	1

2.1	Background Information	1

2.2	Rationale	1

2.3	Potential Risks and Benefits	1

2.3.1	Potential Risks	1

2.3.2	Potential Benefits	1

3	OBJECTIVES	1

3.1	Study Objectives	1

3.2	Study Outcome Measures	1

4	STUDY DESIGN	1

5	STUDY ENROLLMENT AND WITHDRAWAL	1

5.1	Subject Inclusion Criteria	1

5.2	Subject Exclusion Criteria	1

5.3	Strategies for Recruitment and Retention	1

5.4	Subject Withdrawal	1

5.4.1	Reasons for Withdrawal	1

5.4.2	Handling of Subject Withdrawals	1

5.5	Premature Termination or Suspension of Study	1

6	STUDY SCHEDULE	1

6.1	Screening	1

6.2	Enrollment/Baseline	1

6.3	Intermediate Visits	1

6.4	Final Study Visit	1

6.5	Withdrawal Visit	1

6.6	Unscheduled Visit	1

7	STUDY PROCEDURES/EVALUATIONS	1

7.1	Study Procedures/Evaluations	1

7.2	Laboratory Procedures/Evaluations	1

7.3	Study Specific Biospecimens	1

7.3.1	Specimen Collection Procedures	1

7.3.2	Specimen Preparation, Handling, and Storage	1

7.3.3	Specimen Shipment	1

7.4	Questionnaire Administration	1

8	ASSESSMENT OF SAFETY	1

8.1	Specification of Safety Parameters	1

8.1.1	Unanticipated Problems	1

8.1.2	Serious Adverse Events	1

8.2	Reporting Procedures	1

9	STUDY OVERSIGHT	1

10	CLINICAL SITE MONITORING	1

11	STATISTICAL CONSIDERATIONS	1

11.1	Study Hypotheses	1

11.2	Sample Size Considerations	1

11.3	Final Analysis Plan	1

12	SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS	1

13	QUALITY CONTROL AND QUALITY ASSURANCE	1

14	ETHICS/PROTECTION OF HUMAN SUBJECTS	1

14.1	Ethical Standard	1

14.2	Institutional Review Board	1

14.3	Informed Consent Process	1

14.4	Exclusion of Women, Minorities, and Children (Special Populations)	1

14.5	Participant Confidentiality	1

14.6	Future Use of Stored Specimens and Other Identifiable Data	1

15	DATA HANDLING AND RECORD KEEPING	1

15.1	Data Management Responsibilities	1

15.2	Data Capture Methods	1

15.3	Types of Data	1

15.4	Schedule and Content of Reports	1

15.5	Study Records Retention	1

15.6	Protocol Deviations	1

16	PUBLICATION/DATA SHARING POLICY	1

17	LITERATURE REFERENCES	1

SUPPLEMENTAL MATERIALS	1

APPENDICES	1

APPENDIX A: Schedule of Events	1

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
CRF	Case Report Form
CSOC	Clinical Study Oversight Committee
DCC	Data Coordinating Center
DHHS	Department of Health and Human Services
DSMB	Data and Safety Monitoring Board
FFR	Federal Financial Report
FWA	Federalwide Assurance
GCP	Good Clinical Practice
HIPAA	Health Insurance Portability and Accountability Act
ICF	Informed Consent Form
ICH	International Conference on Harmonisation
IRB	Institutional Review Board
ISM	Independent Safety Monitor
MOP	Manual of Procedures
N	Number (typically refers to participants)
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
OHSR	Office of Human Subjects Research
PI	Principal Investigator
QA	Quality Assurance
QC	Quality Control
SAE	Serious Adverse Event/Serious Adverse Experience
SOP	Standard Operating Procedure
US	United States

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 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.>
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.>
Study Duration:	<Estimated time (in months) from when the study opens to enrollment until completion of data analyses.>
Subject Participation Duration:	<Time it will take to conduct the study for each individual subject.>
Estimated Time to Complete Enrollment:	<Estimated time from enrollment into study of the first subject to enrollment into study of the last subject.>

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. The time point(s) indicated in the schematic should correspond to the time point(s) in Section 6 of the protocol, Study Schedule, e.g., Visit 1, Day 0; Visit 2, Day 30 ± 7; etc.}

Total N: Obtain informed consent. Screen potential participants by inclusion and exclusion criteria; obtain history, document.

Prior to

Enrollment

Initial assessments (list specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed)

Visit 1

Time Point

Follow-up assessments (list specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed)

Visit 2

Time Point

Follow-up assessments (list specimens to be collected, examinations or imaging or laboratory assays to be performed, questionnaires to be completed)

Visit 3

Time Point

Final Assessments List analyses to be performed

Visit X

Time Point…

KEY ROLES AND CONTACT INFORMATION

{Provide the following information for each individual:
Name, degree, title
Institution Name
Address
Phone Number
Fax Number
Email}

Principal Investigator:	<Site investigator responsible for conducting the study>
Medical Monitor:	{if applicable}
NIDCR Program Official:
Clinical Site Investigators:	<if applicable, investigator name, institution>
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 Personnel:	{Consider listing, for example: 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}

INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE

Background Information

<Insert text>

{This section should include brief background information for this study. 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

Discussion of important research relevant to the study that provides background and scientific justification for the study

A brief description of the study’s overall goal}

Rationale

<Insert text>

{Include a description of, and justification for, the need to collect biospecimens, images or other data, the means of collection, collection time frame and selection of study population. Include a statement of the hypothesis.}

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 the participant. 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.}

Potential Risks

<Insert text>

{Describe in detail any physical, psychological, social, legal, economic, or any other anticipated risks to study participants. Consider describing inconveniences to the participant, if relevant. Briefly describe measures taken to mitigate risks.}

Potential Benefits

<Insert text>

{If the research is beneficial, describe any physical, psychological, social, legal, or any other anticipated benefits to participants. While it may not provide direct benefit to participants, the importance of the knowledge that may result from the study may be mentioned.

Note: Compensation to participants is not considered a “benefit.” See Strategies for Recruitment and Retention, Section 5.3.}

OBJECTIVES

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 study (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 health condition that is the focus of the study.

Express each objective as a statement of purpose (e.g., to assess, to determine, to compare, to evaluate) and include the general or specific purpose, e.g., to evaluate biomarkers as physiologic correlates of disease, to determine genomic factors affecting oral health conditions, to determine risk factors for disease or condition, etc.}

Study Outcome Measures

<Insert text>

{Specify the primary and any secondary outcome measures, i.e., the measurements or observations used to describe the patterns of diseases or traits or associations with exposures, risk factors, or treatment. Include the study visits at which the biospecimens, images or other data will be obtained and the specific laboratory tests or other analytical measures to be used.

Outcome measures should be prioritized and should correspond to the study objectives and hypotheses being tested.}

STUDY DESIGN

<Insert text>

{Include a brief paragraph or bulleted text describing the study design. This section should include:

A brief description of the type/design of study to be conducted [e.g., cross-sectional, cohort, case-control, case-only, case-crossover, ecological or community study, family-based or other (explain)]; state if it is a multicenter study

A brief description of the study population (e.g., healthy/sick, inpatient/outpatient, demographic groups), sample size and characteristics of different study groups, if applicable. 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

A brief description of the study timeline, including approximate time to complete enrollment and expected duration of subject participation (details of study visit schedule will be included in Section 6, Study Schedule)

A brief summary of methods for collecting data for assessment of study objectives (detailed methods will be included in Section 7, Study Procedures)

Other protocol-specific details, such as centralization of evaluations (e.g., central laboratory or central reading center for clinical images)

If the study requires that study staff (investigator, examiner, laboratory personnel, etc.) be masked with respect to the study group of a research participant, specimen, or image, state how masking will be maintained.}

STUDY ENROLLMENT AND WITHDRAWAL

{In subsections 5.1 to 5.5, define the study population, describe subject recruitment and discuss issues related to subject withdrawal. 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#46 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 being in the study 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 also 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).}

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}

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

Participation in a clinical study that may interfere with participation in this study {within a specified time frame}

History of or current tobacco, drug and alcohol use {define parameters for exclusion}

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}

Strategies for Recruitment and Retention

<Insert text>

{Identify strategies for participant recruitment and retention. If participants 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 retention (e.g., multiple methods for contacting participants, visit reminders, incentives for visit attendance, etc.}

Subject Withdrawal

<Insert text>

{Subjects may withdraw voluntarily from the study or the investigator may terminate a subject's participation.}

Reasons for Withdrawal

<Insert text>

{Provide a list of reasons subjects may be withdrawn from the study.}

{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 medical condition, event 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}

Handling of Subject Withdrawals

<Insert text>

{Describe the efforts to follow subjects who are withdrawn from the study. It may be appropriate to collect safety data on a subject discontinued because of an unanticipated problem (UP) or serious adverse event (SAE).

This section should include a discussion of replacement of subjects who withdraw or discontinue early, if replacement is allowed.}

Premature Termination or Suspension of Study

<Insert text>

{List possible reasons for termination or suspension of the study in this section, e.g., study closure based on principal investigator (PI) decision, or NIDCR decision, which may be informed by the clinical study oversight committee recommendation.}

{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. If the study is prematurely terminated or suspended, the principal investigator will promptly inform the IRB and will provide the reason(s) for suspension or termination.

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}

STUDY SCHEDULE

<Insert text>

{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 7.

Provide a schedule of initial, intermediate, and final study visits, and include all contacts with participants, e.g., telephone contacts. State permissible time windows for study visits, e.g., Day 7 1 day. 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 briefly describe what will occur at the visit.}

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 participant 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 participants with instructions needed to prepare for first study visit {specify instructions to be provided}.

{End sample text}

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 comparison with later assessments. Discuss the sequence of events that should occur during the enrollment visit. List any special conditions (e.g., negative pregnancy test must be available prior to initiating study procedures).

Confirm that the procedures listed are consistent with those included in the Schedule of Events (Appendix A).}

{Begin sample text}

Enrollment/Baseline Visit (Visit 1, Day 0)

Obtain and document consent from participant 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.

{End sample text}

Intermediate Visits

<Insert text>

{List each visit, including visit number and visit window. For each visit, list the evaluations/procedures/specimen collections to be completed (in chronological order, if applicable).

Confirm that the procedures listed are consistent with those included in the Schedule of Events (Appendix A).}

{Begin sample text}

Visit 2, Day X ± Y

{Repeat for each visit, providing a study-appropriate window for the visit}

Record results of physical and dental examinations.

Collect blood/urine/saliva/other specimen.

{End sample text}

Final Study Visit

<Insert text>

{Define when the final study visit should occur and any special procedures/evaluations or instructions to the participant. Describe provisions for follow-up of ongoing AEs/SAEs. If study results will be shared with participants, discuss when and how they will receive this information.

Confirm that the procedures listed are consistent with those included in the Schedule of Events (Appendix A).}

{Begin sample text}

Final Study Visit (Final Visit, Day X ± Y)

Record results of physical and dental examinations.

Collect blood/urine/saliva/other specimen.

Provide final instructions to participant {e.g., follow-up of ongoing adverse events, oral hygiene instructions}.

{End sample text}

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.}

Unscheduled Visit

<Insert text>

{Specify how unscheduled visits will be handled and documented.}

STUDY PROCEDURES/EVALUATIONS

{In the following subsections, describe procedures for collection of all study data including clinical observations, laboratory results, biospecimens, images, questionnaire responses. 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 6.

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.}

Study Procedures/Evaluations

<Insert text>

{Describe assessments to be done, such as baseline medical or dental history, medications history, oral exam (e.g., periodontal assessment, caries assessment), radiographs or photographs, other health status evaluations.}

Laboratory Procedures/Evaluations

<Insert text>

{List all laboratory evaluations. Differentiate screening laboratories from evaluations required for study outcomes. Include specific test components and estimated volume and type of specimens needed for each test [or refer to the study’s Manual of Procedures (MOP)]. Specify laboratory methods to provide for appropriate longitudinal and cross-comparison (e.g., use of consistent laboratory method throughout study). If more than one laboratory will be used, specify which evaluations will be done by each laboratory.}

Study Specific Biospecimens

Specimen Collection Procedures

<Insert text>

{Specify what specimens will be collected specifically for the study and the general procedures for the collection. If specimen collection procedures are complex, the protocol should include only a general description and details should be provided in a study MOP.

Specimen source – Describe how the biospecimens will be obtained, e.g., from enrolled subjects or a biorepository.

Pre-collection preparation – Provide information on how the subject will be prepared for collection of the biospecimen (e.g., pre-collection restrictions, collection site cleansing).

Mode of collection – Describe how and when the biospecimen will be collected from the subject. Identify whether control specimens will also be collected, from where and how.

Amount, frequency, and quality of specimen collection - Provide the maximum amount of biospecimen that could be obtained at each collection point and the total amount of specimen that could be obtained from each subject. Provide details of additional procedures to be done if the specimen is of poor quality or insufficient quantity.

Specimen collection duration – Describe how much time the subject will spend in providing a biospecimen.}

Specimen Preparation, Handling, and Storage

<Insert text>

{Describe where and how the specimens are processed after collection. Explain any special instructions for the preparation, handling, and storage of specimens (or refer to the study’s MOP). Include required temperatures for immediate and long-term storage, procedures for aliquoting specimens, where specimens will be stored, how they will be labeled and tracked for inventory, and measures taken to ensure sample integrity during storage. Include a discussion of long-term access and consent for future use of specimens.}

Specimen Shipment

<Insert text>

{If specimens will be shipped to another location for analysis or storage, identify the receiver and provide destination and shipment information, including shipping frequency. Refer to the study MOP for details, or include here the contact information for laboratory personnel, 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. Indicate how specimens will be labeled for tracking purposes and whether labels include subject identifying information. Provide information on the general mode of shipment and measures taken to protect specimen integrity.}

Questionnaire Administration

<Insert text>

{If questionnaire completion is required in conjunction with biospecimen collection or other study procedures, describe the purpose and content of the questionnaire. Specify by whom and how the questionnaire will be administered and who will be the respondents. State whether the questionnaire has been previously validated. Attach the questionnaire as a protocol appendix.}

ASSESSMENT OF SAFETY

{Develop this section in consultation with the NIDCR Program Official and Medical Monitor. This section should be tailored for specific study characteristics.}

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.}

{Begin sample text}

Safety monitoring for this study will focus on unanticipated problems involving risks to participants, including unanticipated problems that meet the definition of a serious adverse event.

{End sample text}

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).}

Serious Adverse Events

<Insert text>

{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}

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.}

{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: {IRB reporting timeframes may be modified according to local IRB rules.}

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: rho_productsafety@rhoworld.com

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}

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. Monitoring activities may range from data and safety monitoring implemented by the principal investigator to independent data and safety monitoring boards established by the NIDCR. 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), NIDCR Medical Monitor or Principal Investigator (PI).

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, PI), 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, 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}

In addition to the PI’s responsibility for oversight, study oversight will be under the 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}

In addition to the PI’s responsibility for oversight, study oversight will be under the 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}

In addition to the PI’s responsibility for oversight, study oversight will be under the 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}

{Begin sample text for PI oversight}

The investigator will be responsible for study oversight, including monitoring safety, ensuring that the study is conducted according to the protocol and ensuring data integrity. The PI will review the data for safety concerns and data trends at regular intervals, and will promptly report to the IRB and NIDCR any Unanticipated Problem (UP), protocol deviation, or any other significant event that arises during the conduct of the study.

{End sample text for PI oversight}

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 standards and ICH E6.

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}

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.

Some studies may be conducted to obtain preliminary qualitative data. The statistical section should describe this approach, including frequency reporting of variables, confidence intervals, etc.}

Study Hypotheses

<Insert text>

{State the formal, testable, null, and alternate hypotheses for the primary objective and key secondary objectives.}

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 number 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:

Assumed event rate for dichotomous outcome (or mean or variance of continuous outcome), justified and referenced by historical data as much as possible

Assumed dropout rates, withdrawal, missing data, etc., also justified

Approach to handling withdrawals and protocol violations, i.e., to what extent data from withdrawn subjects will be evaluable, 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.}

Final Analysis Plan

<Insert text>

{Describe analyses for assessing the primary and secondary objectives. Plans must clearly identify the analyses, data stratifications, and methods to account for missing, unused or spurious data. Discuss how outcome measures will be assessed and transformed, if relevant, before analysis (e.g., Is the primary variable binary, categorical, or continuous?).

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.}

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 research study necessary for the reconstruction and evaluation of the study. 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, recorded data from automated instruments, audio recordings of 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 study. 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}

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/Guidances/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/.}

ETHICS/PROTECTION OF HUMAN SUBJECTS

Ethical Standard

<Insert text>

{Include in this section the guiding ethical principles being followed by the study.}

{Begin required text}

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.}

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 material 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 participant 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 participant 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}

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 participants who may be enrolled in the study only with the consent of the participant’s legally authorized representative (e.g., minors or participants whose cognitive impairment is such that they are unable to give informed consent), the participant should be informed about the study to the extent compatible with the participant’s understanding. If capable, the participant 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 participant’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 participants and their families, if applicable. A consent form describing in detail the study procedures and risks will be given to the participant. Consent forms will be IRB-approved, and the participant 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 participant and answer any questions that may arise. The participant will sign the informed consent document prior to any study-related assessments or procedures. Participants 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 participants for their records. The rights and welfare of the participants 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}

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.}

Participant Confidentiality

<Insert text>

{Include procedures for maintaining participant 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, and IRB 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 participants 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 participants. 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}

Participant 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 participants.

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 participants. The clinical study site will permit access to such records.

Certificate of Confidentiality (if applicable)

To further protect the privacy of study participants, 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 participants.

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}

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 participant 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.}

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 participants, including accurate case report forms (CRFs), and source documentation.

{End sample text}

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 must be reviewed by the investigator or designee.

{End sample text}

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.}

Types of Data

<Insert text>

{Indicate the types of data that will be collected, such as safety (unanticipated problems), laboratory results (e.g., genetic sequences, biomarker levels, etc.), and outcome measure data (e.g., periodontal measurements, caries assessments, physical measurements, questionnaire responses). Specify if safety data are collected in a separate database.}

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.}

Study Records Retention

<Insert text>

{Specify the length of time for the investigator to maintain all records pertaining to this study. Note that other laws or local IRB policies may mandate a longer period for record retention than NIH requires. Indicate whether permission is required (and from whom) prior to destruction of records.}

{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.

{End sample text}

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}

PUBLICATION/DATA SHARING POLICY

<Insert text>

{Include the required text below, and provide study-specific policies on publication and data sharing, if applicable (e.g., authorship rules, registering the study on ClinicalTrials.gov, compliance with NIH GWAS data sharing policy, etc.).}

{Begin required text}

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.

{End required 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}

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

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 A: 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 6)

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 6 and 7.}

{Begin sample text}

Procedures	Screening (Day –X to –Y)	Study Visit 1 (Day 0)	Study Visit 2 (Day X ± Y)	Study Visit 3 (Day X ± Y)	Study Completion (Day X ± Y)	Premature Discontinuation
Signed Consent Form	X	X
Assessment of Eligibility Criteria	X	X
Review of Medical/Dental History	X	X
Physical Examination	Complete	X	X	X
Symptom-Directed	X	(X)	(X)
Vital Signs	(X)	(X)	(X)
Oral Exam	X	X	(X)	(X)	X	X
Clinical Lab	Urine Pregnancy Test	X
Research Laboratory	Immunology __mL whole blood	X	(X)	X	X
Biomarkers __mL saliva (or blood)	X	X
Sample for Genetic Analysis	X	X
Other Procedures	Caries Assessment or Periodontal Measurements	X	X
Pain Assessment or Other Questionnaire	X	(X)	X	(X)
Photograph or Other Imaging	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

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).}