**PREFACE**

*This document is the DMID protocol template, which is required for
developing DMID-sponsored clinical research protocols. Note that
instructions and explanatory text are indicated by italics and should be
replaced in your protocol document with appropriate protocol-specific
text. Section headings and template text formatted in regular type
should be included in your protocol document as provided in the
template. Text should be formatted using Body Text style. Bulleted lists
should be formatted using Bullet (listing) style.*

*This template attempts to provide a general format applicable to all
clinical trials evaluating an investigational product. Where specific
examples are provided, they are often from the vaccine area.*

*Throughout this protocol template, there may be subject headings that
do not apply to your particular study. In such instances, please write
"not applicable."*

*In places where the information is duplicative, it is acceptable to
reference another section rather that repeating the information.*

*Refer questions regarding use of this protocol template to the
appropriate DMID Protocol Champion or Clinical Affairs Specialist.*

**TITLE**

**DMID Protocol Number:**

**DMID Funding Mechanism:** *(eg, grant #, contract #)*

**Pharmaceutical Support Provided by:** *(if applicable)*

**Other Identifying Numbers:**

**IND Sponsor:** *(if applicable. Do not include IND number)*

**Principal Investigator:**

**DMID Protocol Champion:**

**DMID Medical Monitor:**

**DMID Clinical Affairs Specialist:**

**DMID Regulatory Affairs Specialist:** *(if applicable)*

**Draft or Version Number:** *(Refer to DMID SOP for assigning version
numbers)*

**Day Month Year**\
*(Write out the month and use international date format, eg, 23 January
2004)*

*[This template is adapted from the ICH guidance document E6 (Good
Clinical Practice), Section 6.]{.mark}*

[]{#__RefHeading___Toc105911945 .anchor}Statement of Compliance

*Refer to:*

*<http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46>\
<http://www.fda.gov/cder/guidance/959fnl.pdf>\
<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html>\
<http://www.cancer.gov/clinicaltrials/learning/page3>.*

*Provide a statement that the trial will be conducted in compliance with
the protocol, International Conference on Harmonisation E6: Good
Clinical Practice: Consolidated Guideline (ICH E6) and the applicable
regulatory requirements.*

*Example text:*

The study will be carried out in accordance with Good Clinical Practice
(GCP) as required by the following *(use applicable regulations
depending on study location and sponsor requirements; samples follow)*:

-   United States (US) Code of Federal Regulations (CFR) applicable to
    clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56,
    and 21 CFR Part 312)

-   ICH E6; 62 Federal Register 25691 (1997)

-   NIH Clinical Terms of Award

    All key personnel (all individuals responsible for the design and
    conduct of this study) have completed Human Subjects Protection
    Training.

[]{#__RefHeading___Toc105911946 .anchor}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.

+------+-----------------------------------------+-----+--------------+
| Site |                                         |     |              |
| Inv  |                                         |     |              |
| esti |                                         |     |              |
| gato |                                         |     |              |
| r:\* |                                         |     |              |
+------+-----------------------------------------+-----+--------------+
| Sig  |                                         | Da  |              |
| ned: |                                         | te: |              |
+------+-----------------------------------------+-----+--------------+
|      | *Name*                                  |     |              |
|      |                                         |     |              |
|      | *Title*                                 |     |              |
+------+-----------------------------------------+-----+--------------+

*\* The protocol should be signed by the local investigator who is
responsible for the study implementation at his/her specific site; ie,
if Investigational New Drug study, the individual who signs the Form FDA
1572.*

[]{#__RefHeading___Toc105911947 .anchor}Table of Contents

Page

[Statement of Compliance ii](#__RefHeading___Toc105911945)

[Signature Page iii](#__RefHeading___Toc105911946)

[Table of Contents iv](#__RefHeading___Toc105911947)

[List of Abbreviations vii](#__RefHeading___Toc105911948)

[Protocol Summary ix](#__RefHeading___Toc105911949)

[1 Key Roles 1](#key-roles)

[2 Background Information and Scientific Rationale
3](#background-information-and-scientific-rationale)

[2.1 Background Information 3](#background-information)

[2.2 Rationale 3](#rationale)

[2.3 Potential Risks and Benefits 3](#potential-risks-and-benefits)

[2.3.1 Potential Risks 3](#potential-risks)

[2.3.2 Known Potential Benefits 4](#known-potential-benefits)

[3 Objectives 5](#objectives)

[3.1 Study Objectives 5](#study-objectives)

[3.2 Study Outcome Measures 5](#study-outcome-measures)

[3.2.1 Primary Outcome Measures 5](#primary-outcome-measures)

[3.2.2 Secondary Outcome Measures 6](#secondary-outcome-measures)

[4 Study Design 7](#study-design)

[4.1 Substudies (if applicable) 8](#substudies-if-applicable)

[5 Study Enrollment](#__RefHeading___Toc105911964) 9

[5.1 Subject Inclusion Criteria 10](#subject-inclusion-criteria)

[5.2 Subject Exclusion Criteria 10](#subject-exclusion-criteria)

[5.3 Treatment Assignment Procedures](#__RefHeading___Toc105911967) 11

[5.3.1 Randomization Procedures](#__RefHeading___Toc105911967) 11

[5.3.2 Masking Procedures](#__RefHeading___Toc105911968) 11

[5.3.3 Reasons for Withdrawal](#__RefHeading___Toc105911969) 11

[5.3.4 Handling of Withdrawals 12](#handling-of-withdrawals)

[5.3.5 Termination of Study 12](#termination-of-study)

[6 Study Intervention/Investigational Product
13](#study-interventioninvestigational-product)

[6.1 Study Product Description 13](#study-product-description)

[6.1.1 Acquisition 13](#acquisition)

[6.1.2 Formulation, Packaging, and Labeling
13](#formulation-packaging-and-labeling)

[6.1.3 Product Storage and Stability 13](#product-storage-and-stability)

[6.2 Dosage, Preparation, and Administration of Study
Intervention/Investigational Product
13](#dosage-preparation-and-administration-of-study-interventioninvestigational-product)

[6.3 Modification of Study Intervention/Investigational Product for a
Participant
13](#modification-of-study-interventioninvestigational-product-for-a-participant)

[6.4 Accountability Procedures for the Study
Intervention/Investigational Product(s)
14](#accountability-procedures-for-the-study-interventioninvestigational-products)

[6.5 Assessment of Subject Compliance with Study
Intervention/Investigational Product
14](#assessment-of-subject-compliance-with-study-interventioninvestigational-product)

[6.6 Concomitant Medications/Treatments
14](#concomitant-medicationstreatments)

[7 Study Schedule 15](#study-schedule)

[7.1 Screening 15](#screening)

[7.2 Enrollment/Baseline 15](#enrollmentbaseline)

[7.3 Follow-up 16](#follow-up)

[7.4 Final Study Visit 16](#final-study-visit)

[7.5 Early Termination Visit 16](#early-termination-visit)

[8 Study Procedures/Evaluations 17](#study-proceduresevaluations)

[8.1 Clinical Evaluations 17](#clinical-evaluations)

[8.2 Laboratory Evaluations 17](#laboratory-evaluations)

[8.2.1 Clinical Laboratory Evaluations
17](#clinical-laboratory-evaluations)

[8.2.2 Special Assays or Procedures 18](#special-assays-or-procedures)

[8.2.3 Specimen Preparation, Handling, and Shipping
18](#specimen-preparation-handling-and-shipping)

[9 Assessment of Safety 19](#assessment-of-safety)

[9.1 Specification of Safety Parameters
19](#specification-of-safety-parameters)

[9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety
Parameters
19](#methods-and-timing-for-assessing-recording-and-analyzing-safety-parameters)

[9.2.1 Adverse Events 19](#adverse-events)

[9.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials)
21](#reactogenicity-for-vaccine-studies-and-some-therapeutic-trials)

[9.2.3 Serious Adverse Events 21](#serious-adverse-events)

[9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory
Test Values or Abnormal Clinical Findings
22](#procedures-to-be-followed-in-the-event-of-abnormal-laboratory-test-values-or-abnormal-clinical-findings)

[9.3 Reporting Procedures 23](#reporting-procedures)

[9.3.1 Serious Adverse Events 24](#serious-adverse-events-1)

[9.3.2 Regulatory Reporting for Studies Conducted Under DMID‑Sponsored
IND
24](#regulatory-reporting-for-studies-conducted-under-dmidsponsored-ind)

[9.3.3 Regulatory Reporting for Studies Not Conducted Under
DMID‑Sponsored IND
25](#regulatory-reporting-for-studies-not-conducted-under-dmidsponsored-ind)

[9.3.4 Other Adverse Events (if applicable)
25](#other-adverse-events-if-applicable)

[9.3.5 Reporting of Pregnancy 25](#reporting-of-pregnancy)

[9.4 Type and Duration of Follow-up of Subjects after Adverse Events
25](#type-and-duration-of-follow-up-of-subjects-after-adverse-events)

[9.5 Halting Rules 25](#halting-rules)

[9.6 Safety Oversight 26](#safety-oversight-ism-plus-smc-or-dsmb)

[10 Clinical Monitoring 27](#clinical-monitoring)

[10.1 Site Monitoring Plan 27](#site-monitoring-plan)

[11 Statistical Considerations 28](#statistical-considerations)

[11.1 Study Hypotheses 28](#study-hypotheses)

[11.2 Sample Size Considerations 28](#sample-size-considerations)

[11.3 Planned Interim Analyses (if applicable)
29](#planned-interim-analyses-if-applicable)

[11.3.1 Safety Review (ISM plus SMC or DSMB) 29](#safety-review)

[11.3.2 Immunogenicity or Efficacy Review
29](#immunogenicity-or-efficacy-review)

[11.4 Final Analysis Plan 29](#final-analysis-plan)

[12 Source Documents and Access to Source Data/Documents
31](#source-documents-and-access-to-source-datadocuments)

[13 Quality Control and Quality Assurance
32](#quality-control-and-quality-assurance)

[14 Ethics/Protection of Human Subjects
33](#ethicsprotection-of-human-subjects)

[14.1 Ethical Standard](#__RefHeading___Toc105912023) 33

[14.2 Institutional Review Board 33](#institutional-review-board)

[14.3 Informed Consent Process 33](#informed-consent-process)

[14.3.1 Informed Consent/Assent Process (in Case of a Minor)
35](#informed-consentassent-process-in-case-of-a-minor)

[14.4 Exclusion of Women, Minorities, and Children (Special Populations)
35](#exclusion-of-women-minorities-and-children-special-populations)

[14.5 Subject Confidentiality 35](#subject-confidentiality)

[14.6 Study Discontinuation 36](#study-discontinuation)

[14.7 Future Use of Stored Specimens
36](#future-use-of-stored-specimens)

[15 Data Handling and Record Keeping
37](#data-handling-and-record-keeping)

[15.1 Data Management Responsibilities
37](#data-management-responsibilities)

[15.2 Data Capture Methods 38](#data-capture-methods)

[15.3 Types of Data 38](#types-of-data)

[15.4 Timing/Reports 39](#timingreports)

[15.5 Study Records Retention 39](#study-records-retention)

[15.6 Protocol Deviations 39](#protocol-deviations)

[16 Publication Policy 41](#publication-policy)

[17 Literature References 41](#literature-references)

[Supplements/Appendices 43](#__RefHeading___Toc105912040)

[Appendix A: Schedule of Events 44](#__RefHeading___Toc105912041)

[]{#__RefHeading___Toc105911948 .anchor}List of Abbreviations

  ---------------------- ------------------------------------------------
  AE                     Adverse Event/Adverse Experience

  CFR                    Code of Federal Regulations

  CIOMS                  Council for International Organizations of
                         Medical Sciences

  CONSORT                Consolidated Standards of Reporting Trials

  CFR                    Code of Federal Regulations

  CRF                    Case Report Form

  CRO                    Contract Research Organization

  DCC                    Data Coordinating Center

  DHHS                   Department of Health and Human Services

  DMID                   Division of Microbiology and Infectious
                         Diseases, NIAID, NIH, DHHS

  DSMB                   Data and Safety Monitoring Board

  eCRF                   Electronic Case Report Form

  FDA                    Food and Drug Administration

  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

  IEC                    Independent or Institutional Ethics Committee

  IND                    Investigational New Drug Application

  IRB                    Institutional Review Board

  ISM                    Independent Safety Monitor

  JAMA                   Journal of the American Medical Association

  MedDRA ^^             Medical Dictionary for Regulatory Activities

  MOP                    Manual of Procedures

  N                      Number (typically refers to subjects)

  NCI                    National Cancer Institute, NIH, DHHS

  NDA                    New Drug Application

  NEJM                   New England Journal of Medicine

  NIAID                  National Institute of Allergy and Infectious
                         Diseases, NIH, DHHS

  NIH                    National Institutes of Health

  OCRA                   Office of Clinical Research Affairs, DMID,
                         NIAID, NIH, DHHS

  OHRP                   Office for Human Research Protections

  OHSR                   Office for Human Subjects Research

  ORA                    Office of Regulatory Affairs, DMID, NIAID, NIH,
                         DHHS

  PHI                    Protected Health Information

  PI                     Principal Investigator

  PK                     Pharmacokinetics

  QA                     Quality Assurance

  QC                     Quality Control

  SAE                    Serious Adverse Event/Serious Adverse Experience

  SMC                    Safety Monitoring Committee

  SOP                    Standard Operating Procedure

  US                     United States

  WHO                    World Health Organization
  ---------------------- ------------------------------------------------

*Please modify list to include your protocol-specific terms.*

[]{#__RefHeading___Toc105911949 .anchor}Protocol Summary

***Limit to 1-2 pages\
Put key words in boldface in Protocol Summary.***

+----------------------+-----------------------------------------------+
| **Title:**           | *Include type of trial (eg, dose-ranging,     |
|                      | observational, double‑blind)*                 |
+----------------------+-----------------------------------------------+
| **Phase:**           | *I, II, III, IV*                              |
+----------------------+-----------------------------------------------+
| **Population:**      | *Include sample size, gender, age, general    |
|                      | health status, geographic location*           |
+----------------------+-----------------------------------------------+
| **Number of Sites:** | *3 or fewer, list here; otherwise, list only  |
|                      | in Section 1*                                 |
+----------------------+-----------------------------------------------+
| **Study Duration:**  | *Provide time from when the study opens until |
|                      | the monitor completes the close out visit.*   |
+----------------------+-----------------------------------------------+
| **Subject            | *Provide time it will take to conduct the     |
| Participation        | study for each individual participant.*       |
| Duration:**          |                                               |
+----------------------+-----------------------------------------------+
| **Description of     | *Include dose and route of administration*    |
| Agent or             |                                               |
| Intervention:**      |                                               |
+----------------------+-----------------------------------------------+
| **Objectives:**      | *Copy objectives and clinical/laboratory      |
|                      | outcome measures from the appropriate         |
|                      | sections of the protocol. Include             |
|                      | primary/secondary outcome measures and method |
|                      | by which outcome will be determined.*         |
|                      |                                               |
|                      | Primary:                                      |
|                      |                                               |
|                      | Secondary:                                    |
+----------------------+-----------------------------------------------+
| **Description of     | *This schematic should provide an overview of |
| Study Design:**      | the study design, including study arms,       |
|                      | sample size and schedule of interventions     |
|                      | (eg, vaccine administration), if applicable;  |
|                      | a detailed schematic describing all visits    |
|                      | and assessments (schedule of events*) *will   |
|                      | be included in Appendix A.*                   |
+----------------------+-----------------------------------------------+
| **Estimated Time to  |                                               |
| Complete             |                                               |
| Enrollment:**        |                                               |
+----------------------+-----------------------------------------------+

**\*Schematic of Study Design**:

Example #1: Table format (eg, dose escalation)

  --------------- ----------------- ------------------- -------------------
  Cohort A        ARM 1             Sample Size         Intervention 1

                  ARM 2             Sample Size         Intervention 2
  --------------- ----------------- ------------------- -------------------

Instructions for progressing to next phase (if applicable):

  --------------- ----------------- ------------------- -------------------
  Cohort B        ARM 1             Sample Size         Intervention 1

                  ARM 2             Sample Size         Intervention 2
  --------------- ----------------- ------------------- -------------------

*Example #2: Flow diagram*

Prior to

Enrollment

Time Point or

Study Visit 1

Time Point or

Study Visit 2

Time Point or

Study Visit 3

Time Point

or Study Visit ...

*\*This schematic study design may be modified to include 3 arms or your
protocol-specific design.*

# Key Roles

*Refer to ICH E6, Section 6.1\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

For questions regarding this protocol, contact \<\<*insert name of
appropriate DMID staff\>\>* at \<\<*NIAID/DMID (insert contact
information)\>\>.*

+----------------------+-----------------------------------------------+
| **Individuals:**     | **Protocol Champion:** *Division of           |
|                      | Microbiology and Infectious Diseases (DMID)   |
|                      | official authorized to sign the protocol and  |
|                      | protocol amendments on behalf of the Protocol |
|                      | Team:*                                        |
|                      |                                               |
|                      | *Provide the following information for each   |
|                      | individual:\                                  |
|                      | Name, degree, title\                          |
|                      | Institution Name\                             |
|                      | Address\                                      |
|                      | Phone Number\                                 |
|                      | Fax Number\                                   |
|                      | E-mail*                                       |
+----------------------+-----------------------------------------------+
|                      | **Principal Investigator:** *Site             |
|                      | investigator responsible for conducting the   |
|                      | study*                                        |
+----------------------+-----------------------------------------------+
|                      | **Medical Monitor:** *(if applicable)*        |
+----------------------+-----------------------------------------------+
| **Institutions:**    | *Study sites, clinical laboratory(ies), 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\                                   |
|                      | E-mail*                                       |
+----------------------+-----------------------------------------------+
| **Optional:**        | *Consider listing, for example:*              |
|                      |                                               |
|                      | -   *Major international collaborators, if    |
|                      |     not included as site investigators*       |
|                      |                                               |
|                      | -   *Protocol data manager, epidemiologist,   |
|                      |     statistician*                             |
|                      |                                               |
|                      | -   *DMID clinical affairs specialist*        |
|                      |                                               |
|                      | -   *Industry representative(s)*              |
|                      |                                               |
|                      | -   *Other individuals should be listed in a  |
|                      |     separate document (eg, the Manual of      |
|                      |     Procedures \[MOP\]) as appropriate*       |
|                      |                                               |
|                      | -   *Institutional Review Board (IRB) contact |
|                      |     information*                              |
+----------------------+-----------------------------------------------+

# Background Information and Scientific Rationale

## Background Information

*Refer to ICH E6, Section 6.2\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*Include:*

-   *The name and description of the study intervention/investigational
    products(s)*

-   *A summary of findings from nonclinical in vitro or in vivo studies
    that have potential clinical significance*

-   *A summary from relevant clinical trials*

-   *Discussion of important literature and data that are relevant to
    the trial and that provide background for the trial (reference
    citations are listed in Section 17)*

-   *Applicable clinical, epidemiological, or public health background
    or context of the study*

-   *Importance of the study and any relevant treatment issues or
    controversies*

## Rationale

*Include a description of and justification for the route of
administration, dosage, dosing regimen, intervention periods, and
selection of study population. Include a statement of the hypothesis.*

## Potential Risks and Benefits

*Refer to 45 CFR Part 46.116 (a) (2) and (3)\
(<http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116>).*

*Include a discussion of known risks and benefits, if any, to human
subjects.*

### Potential Risks

*Include a review of relevant literature, which should be referenced.
Add relevant websites, etc from which the information could be drawn.*

*If a package insert is available, it should be used as the primary
source of risk information. If the product is investigational, the
Investigator's Brochure (IB) should be the primary source of the risk
information. In addition, literature searches can also provide relevant
risk information. If the risk profile cannot be described from any of
the above sources, the risk information discussion will result from the
literature search and review.*

*Describe in detail any physical, psychological, social, legal,
economic, or any other risks to subjects that the Principal Investigator
(PI) foresees, as to each of the following:*

-   *Immediate risks*

-   *Long-range risks*

-   *Rationale for the necessity of such risks*

-   *Alternative data gathering procedures that have been considered or
    will be considered*

-   *Why alternative procedures may not be feasible*

-   *Why the value of the information to be gained outweighs the risks
    involved.*

### Known Potential Benefits

*If the research is beneficial, describe in detail any physical,
psychological, social, legal, economic, or any other benefits to
subjects that the PI foresees.*

*Note: Payment to subjects, whether as an inducement to participate or
as compensation for pain and inconvenience, is not considered a
"benefit."*

# Objectives

## Study Objectives

*A detailed description of the primary and secondary objectives of the
study is included in this section. These typically include:*

-   *Statement of purpose, eg, to assess, to determine, to compare, to
    evaluate*

-   *General purpose, eg, efficacy, safety, immunogenicity,
    pharmacokinetics*

-   *Specific purpose, eg, dose-response, superiority to placebo*

-   *Name(s) of intervention (eg, vaccine, drug, biologic) being
    evaluated, specification of doses or dose ranges to be studied, dose
    regimens*

## Study Outcome Measures

*Refer to ICH E6, Sections 6.7-6.8\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*This section should include the methods for assessing how the
objectives are met, ie, the study outcome measures.*

*An outcome measure is "an observation variable recorded for
\[subjects\] in the trial at 1 or more time points after enrollment for
the purpose of assessing the effects of the study treatments" (Meinert
CL. Clinical trials: design, conduct, and analysis. Oxford: Oxford
University;1986). Give succinct but precise definitions of the outcome
measures used to measure the primary and key secondary outcomes stated
in the study objectives, including the study visits at which the samples
will be obtained and the specific laboratory tests to be used.*

### Primary Outcome Measures

*Outcome measures should be prioritized. Generally, there should be just
1 primary variable, with evidence that it will provide a clinically
relevant, valid, and reliable measure of the primary objective (eg,
laboratory procedures, safety assays).*

### Secondary Outcome Measures

*Secondary outcome measures should be included, whether or not they add
information about the primary objective or address secondary objectives.
Discuss their importance and role in the analysis and interpretation of
study results.*

# Study Design

*Refer to ICH E6, Section 6.4\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*The scientific integrity of the trial and the credibility of the data
from the trial depend substantially on the trial design. A description
of the trial design should include:*

-   *A description of the type/design of trial to be conducted (eg,
    placebo-controlled, double-mask, parallel design, open-label,
    dose-escalation, dose-ranging)*

-   *A description of the study population (eg, healthy/sick,
    inpatient/outpatient)*

-   *The rationale for design features should be discussed*

-   *Phase of trial*

-   *Single or multicenter*

-   *The number of study groups/arms*

-   *Description of study groups/arms including sample size (including a
    table, if appropriate)*

-   *Approximate time to complete study enrollment*

-   *The expected duration of subject participation*

-   *Identification of the test agent and specifics of administration of
    other agents (eg, placebo)*

-   *A description of the sequence and duration of all trial periods,
    including follow-up (specify individual subjects vs entire trial)*

-   *Changes in scheduling, such as dose escalation*

-   *Any stratifications*

-   *A specific statement of the primary and secondary outcomes to be
    measured during the trial (must be consistent with Study Objectives,
    as stated in Section 3)*

-   *Methods for collecting data for assessment of study objectives*

-   *Other protocol-specific details, such as centralization of
    evaluations (eg, central laboratory or central reading center for
    clinical scans)*

-   *Interim analysis plans*

-   *Identify structure for safety oversight per DMID guidelines (eg,
    Data and Safety Monitoring Board (DSMB), Safety Monitoring Committee
    (SMC), and/or Independent Safety Monitor (ISM), and DMID medical
    monitor). Ensure consistency with Section 9.6. For DMID guidelines
    refer to: <http://www.niaid.nih.gov/dmid/clinresearch/>.*

## Substudies (if applicable)

*Definition: A substudy asks a separate research question from the
parent protocol and may or may not contribute to the parent protocol's
objectives but uses all or a subset of study participants or specimens.*

*Note that substudies do not have full protocols but rather are
incorporated into the main protocol*.

*A concept sheet for a proposed substudy must be approved by the DMID
Project Officer/Program Officer. Once the concept for a substudy is
approved by the Program Officer, a decision must be made by DMID, in
conjunction with the investigator, whether the concept is appropriate as
a substudy or should be a stand-alone study.*

*List with brief description:*

-   *Description of the substudy and its objectives*

-   *Impact on main study*

-   *Potential participating sites*

-   *Behavioral issues*

*If substudy is added to an ongoing study, a protocol amendment is
required.*

# Study Enrollment and Withdrawal

*The study population and inclusion/exclusion criteria should be clearly
defined in this section of the protocol.*

*The study population should be commensurate with the stage of the study
and the development stage for the study product. This section should
include a discussion of recruitment strategies, specifically for
achieving NIH gender/minority guidelines.*

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 Pertaining to Research,
Development and Related Activities Involving Fetuses, Pregnant Women,
and Human In Vitro Fertilization (45 CFR Part 46.201-46.211); 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 46.401-409). 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.htm#4](http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46)6*;
and
[*http://www.hhs.gov/ohrp/irb/irb_guidebook.htm.*](http://www.hhs.gov/ohrp/irb/irb_guidebook.htm.)

-   *Provide the target sample size, including actual numbers to be
    enrolled.*

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-   *Include numbers of women, minorities, and children expected to be
    recruited. If women, minorities, or children will not be recruited,
    explain why not. Provide justification for Exclusion in
    Ethics/Protection of Human Subjects, Section 14.4.\
    Refer to:*
    *<http://grants2.nih.gov/grants/funding/women_min/women_min.htm>.*

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-   *Indicate from where the study population will be drawn (eg,
    inpatient hospital setting, outpatient clinics, student health
    service, or general public). Where appropriate (single‑center
    studies), include names of hospitals, clinics, etc.*

-   *Identify strategies for subject recruitment and retention.*

-   *If subjects require screening: distinguish between screening
    subjects (eg, discussing the study with them) vs enrolling subjects
    (eg, obtaining informed consent and obtaining samples).*

    *Note: if screening procedures are required for eligibility (eg,
    review of medical records or laboratory tests), they must be
    performed under a separate screening consent form in addition to the
    consent form for study participation.*

*[Eligibility Criteria]{.underline}:*

-   *The eligibility criteria should provide a definition of subject
    characteristics required for study entry.*

-   *The risks of the test agent/product should structure the
    development of the inclusion/exclusion criteria.*

-   *The same criterion should not be listed as both an inclusion and
    exclusion criterion (eg, do not state age \>32 years old as an
    inclusion criterion and also age ≤32 years old as an exclusion
    criterion).*

-   *Select screening laboratory tests carefully, if they will be used
    (laboratory parameters selected should be related to evaluation of
    safety, with ranges based on toxicity criteria).*

-   *If males and females of reproductive potential will be enrolled,
    provide specific contraception requirements (eg, licensed hormonal
    methods).*

## Subject Inclusion Criteria

*Provide a statement that subjects must meet all of the inclusion
criteria in order to be eligible to participate in the study and then
list each criterion.*

*Examples include the following: informed consent obtained and signed,
age, presence or absence of a medical condition/disease, required
laboratory result, understanding of study procedures, ability to comply
with study procedures for the entire length of the study, requirements
for agreement to avoid conception, etc. If men and women of reproductive
capability will be enrolled, include details of allowable contraception
methods for trial (eg, licensed hormonal methods).*

*The ICH M3 footnote on highly effective contraception:*

*A highly effective method of birth control is defined as one that
results in a low failure rate (ie, less than 1 percent per year) when
used consistently and correctly, such as implants, injectables, combined
oral contraceptives, some intrauterine devices (IUDs), sexual
abstinence, or a vasectomized partner. For subjects using a hormonal
contraceptive method, information regarding the product under evaluation
and its potential effect on the contraceptive should be addressed.*

*ICH Guidance for Industry M3 Nonclinical Safety Studies for the Conduct
of Human Clinical Trials for Pharmaceuticals (April 1997)*

## Subject Exclusion Criteria

*Provide a statement that all subjects meeting any of the exclusion
criteria at baseline will be excluded from study participation and then
list each criterion.*

*Examples include the following: medical condition or laboratory finding
that precludes participation, recent (with time frame) febrile illness
that precludes or delays participation, pregnancy or lactation,
characteristics of household or close contacts (eg, household contacts
who are immunocompromised), known allergic reactions to components of
the study product(s), treatment with another investigational drug (with
time frame), history of drug/alcohol abuse, disallowed concomitant
medications, etc.*

## Treatment Assignment Procedures

*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 (eg, the
ratio between intervention and placebo groups may be stated but the
randomization block sizes should not).*

### Randomization Procedures

*State if the trial will be randomized or not. Include plans for the
maintenance of trial randomization codes. The timing and procedures for
planned and unplanned breaking of randomization codes should be
included.*

### Masking Procedures

*State whether the treatment arms will be masked if more than 1
treatment. Plans for maintaining appropriate masking for the study
should be discussed. Refer to unmasking procedures described in the
Manual of Procedures.*

### Reasons for Withdrawal

*Provide a list of reasons subjects may be discontinued 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. Subjects may also withdraw voluntarily from
receiving the study intervention for any reason.*

*Example text:*

A study subject will be discontinued from participation in the study if:

-   Any clinical adverse event (AE), laboratory abnormality,
    intercurrent illness, or other medical condition or situation occurs
    such that continued participation in the study would not be in the
    best interest of the subject.

-   Development of any exclusion criteria may be cause for
    discontinuation.

Subjects are free to withdraw from participating in the study at any
time upon request.

### Handling of Withdrawals

*Describe the efforts to follow subjects who withdrawal from the study.
It is vital to collect safety data on any subject discontinued because
of an AE or SAE. In any case, every effort must be made to undertake
protocol-specified safety follow-up procedures. If voluntary withdrawal
occurs, the subject should be asked to continue scheduled evaluations,
complete an end-of-study evaluation, and be given appropriate care under
medical supervision until the symptoms of any AE resolve or the
subject's condition becomes stable. Describe efforts to continue
follow-up, especially for safety and efficacy (if applicable) outcome
measures.*

*A discussion of replacement of participants who discontinue early, if
allowed, should be included in this section.*

### Termination of Study 

*List possible reasons for discontinuation of the study in this section,
eg, development of laboratory toxicities, study closure due to DSMB
review, discretion of DMID/or IND holder.*

# Study Intervention/Investigational Product

*Note: If multiple products are to be evaluated in the study, the
following sections should be repeated for each product and the sections
should be renumbered accordingly. Describe placebo or control product.*

## Study Product Description

*Information in this section can usually be obtained from the IB or the
package insert. Make IB or package insert available to all investigators
as part of the study's MOP or distributed separately, as appropriate.*

### Acquisition

### Formulation, Packaging, and Labeling

### Product Storage and Stability

*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 (ie, the seal is
broken).*

## Dosage, Preparation and Administration of Study Intervention/Investigational Product

*List investigational agents, route, doses, and frequency of
administration in this section. Include thawing, diluting, mixing, and
reconstitution/preparation instructions, as appropriate. Include any
specific instructions or safety precautions for administration of study
products or masking of the product or the administrator. Include maximum
hold time and conditions of product once thawed, mixed, diluted,
reconstituted, etc.*

## Modification of Study Intervention/Investigational Product for a Participant

*Clearly explain instructions for modification of dose due to toxicity
or any other potential 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.*

## Accountability Procedures for the Study Intervention/Investigational Product(s)

*Provide plans for how the study intervention/investigational product(s)
will be distributed including participation of a drug repository,
frequency of product distribution, amount of product shipped, and plans
for return of unused product.*

## Assessment of Subject Compliance with Study Intervention/Investigational Product 

*Include this section, if applicable.*

*Include plans for compliance assessment (eg, questionnaires, direct
observation, pill counts) in this section.*

## Concomitant Medications/Treatments

*Note: This section should be consistent with the medications
restrictions in the inclusion/exclusion criteria.*

*List all drugs and/or treatments that are permitted, including rescue
medications, while on study.*

# 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.*

*Allowable windows should be stated for all visits. The schedule must
include clinic visits and all contacts, eg, telephone contacts. To
determine the appropriate windows, consider feasibility and relevance of
the time point to study outcome measures (eg, pharmacokinetic (PK)
studies may allow little or no variation, with required time points
measured in minutes or hours, whereas a 6-month follow-up visit might
have a window of several weeks).*

## Screening 

*Include only those evaluations necessary to assess whether a subject
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 (eg, within 28 days prior to enrollment).*

***This section must include instructions for obtaining signed informed
consent. State if a separate screening consent will be used. If a
separate screening consent will not be used, the study consent must be
signed prior to screening.***

***If an individual's medical chart or results diagnostic tests
performed as part of an individual's medical care are going to be used
for screening, written informed consent must be obtained prior to review
of that information.***

*The evaluations to be done may be listed individually in this section,
or alternatively, refer to the Schedule of Events (Appendix A).*

## Enrollment/Baseline

*Discuss evaluations/procedures necessary to assess or confirm whether a
subject still meets the eligibility criteria and may be enrolled, and
discuss those assessments that are required at baseline for later
outcome measure comparison after study intervention (eg, baseline signs
and symptoms prior to vaccination). Discuss the sequence of events that
should occur during enrollment and/or initial administration of study
product. List any special conditions (eg, results of the pregnancy test
must be negative and available prior to administration of study
product). List the procedures for administering the study product or
intervention and follow-up procedures after administration (eg,
assessment of vital signs, reactogenicity).*

*The evaluations to be done may be listed individually in this section
or, alternatively, refer to the Schedule of Events (Appendix A).*

## Follow-up 

*Include discussion of evaluations/procedures required to assess or
confirm study outcome measures and study evaluations. Discuss the
sequence of events that should occur during the visit, if applicable.
Include, as applicable, counseling, review of reactogenicity,
medications, assessment of AEs, etc.*

*The evaluations to be done may be listed individually in this section
or, alternatively, refer to the Schedule of Events (Appendix A).*

## Final Study Visit

*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/serious adverse events (SAEs).*

*The evaluations to be done may be listed individually in this section
or, alternatively, refer to the Schedule of Events (Appendix A).*

## Early Termination Visit

*Specify which of the evaluations required for the final study visit
should be done at a termination visit if early termination occurs and if
the participant is willing. Clearly differentiate between what
evaluations are to be done in each of these circumstances.*

## Unscheduled Visit 

*Specify how unscheduled visits(s) will be handled and documented.*

# 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.*

## Clinical Evaluations

*List all clinical evaluations to be done during the protocol, and
provide details of what are included and special instructions, if any.*

*Examples:*

-   *Medical history (describe what is included for history, eg,
    time-frame considerations, whether history will be obtained by
    interview or from medical records).*

-   *Medications history (eg, 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 in the MOP
    whether it is an actual measurement or subject\'s self report); if
    appropriate, discuss what constitutes a targeted physical
    examination and at what visits it may occur. If an adverse event
    occurs, describe if a full physical examination should be done.*

-   *Reactogenicity assessments (eg, pain, tenderness; describe rating
    scale).*

-   *Review of memory cards.*

-   *Counseling procedures.*

-   *Criteria for dose adjustment.*

-   *Rescue therapy.*

## Laboratory Evaluations

### Clinical Laboratory Evaluations

*List all laboratory evaluations. Differentiate screening laboratories
from those taken after vaccination, as appropriate. Include specific
test components and estimated volume and type of specimens needed for
each test. Specify laboratory methods (eg, use consistent laboratory
method throughout study) to provide for appropriate longitudinal and
cross-comparison. If more than one laboratory will be used, specify
which evaluations will be done by each laboratory.*

*Examples:*

-   *[Hematology]{.underline}: hemoglobin, hematocrit, white blood cells
    (WBC) with differential count, platelet count.*

-   *[Biochemistry]{.underline}: creatinine, total bilirubin, alanine
    aminotransferase (ALT), aspartate aminotransferase (AST).*

-   *[Urinalysis]{.underline}: dipstick urinalysis, including protein,
    hemoglobin and glucose; if dipstick is abnormal, complete urinalysis
    with microscopic is required.*

-   *Pregnancy test, usually to be done within 24 hours prior to study
    intervention and results must be available prior to administration
    of study product.*

### Special Assays or Procedures

*List special assays or procedures required to assess the study product
(eg, immunology assays, PK studies, photographs). For laboratory assays,
include specific assays, estimated volume and type of specimen needed
for each test. For procedures, provide special instructions or
precautions. If more than 1 laboratory will be used, specify which
assays will be done by each laboratory.*

### Specimen Preparation, Handling, and Shipping

#### Instructions for Specimen Preparation, Handling, and Storage

*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 required temperatures, aliquots of specimens, if
samples are frozen, where they will be stored, and how they will be
labeled. Include a discussion of long-term access and consent for future
use of specimens (Section 14.7).*

#### Specimen Shipment

*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).*

# Assessment of Safety

## Specification of Safety Parameters

*Reference safety parameters that are outcome measures (Section 3.2).
Include other parameters if not primary study outcome measures.*

## Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters

### Adverse Events

*Refer to ICH E6, Section 1.2\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*An AE is any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and that
does not necessarily have a causal relationship with this treatment. An
AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporally associated
with the use of a medicinal (investigational) product, whether or not
related to the medicinal (investigational) product.*

-   *Describe which AEs will be collected as solicited events (in
    vaccine trials, note that each solicited event will be captured in
    only 1 format \[eg, in a reactogenicity case report form {CRF} or as
    an AE\]). Plan the reporting and data collection system to avoid
    double capture.*

-   *Describe how decisions will be made regarding determining
    relatedness and grading severity.*

-   *Describe how unsolicited events will be captured.*

-   *Include time period of collection (eg, Days 0 -28)* *and note how
    long SAEs are collected -- usually collected through entire study.*

*Example text:*

**Adverse Event:** ICH E6 defines an AE as any untoward medical
occurrence in a patient or clinical investigation subject administered a
pharmaceutical product regardless of its causal relationship to the
study treatment. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease
temporally associated with the use of medicinal (investigational)
product. The occurrence of an AE may come to the attention of study
personnel during study visits and interviews of a study recipient
presenting for medical care, or upon review by a study monitor.

All AEs including local and systemic reactions not meeting the criteria
for "serious adverse events" should be captured on the appropriate CRF.
Information to be collected includes event description, time of onset,
clinician's assessment of severity, relationship to study product
(assessed only by those with the training and authority to make a
diagnosis, which would include MD, PA, Nurse Practitioner, DO, or DDS),
and time of resolution/stabilization of the event. All AEs occurring
while on study must be documented appropriately regardless of
relationship. All AEs will be followed to adequate resolution.

Any medical condition that is present at the time that the patient is
screened should be considered as baseline and not reported as an AE.
However, if it deteriorates at any time during the study, it should be
recorded as an AE.

All AEs must be graded for severity and relationship to study product.

**Severity of Event:** All AEs will be assessed by the clinician using a
protocol defined grading system. For events not included in the protocol
defined grading system, than the following guidelines will be used to
quantify intensity.

-   [Mild]{.underline}: events require minimal or no treatment and do
    not interfere with the patient's daily activities.

-   [Moderate]{.underline}: events result in a low level of
    inconvenience or concern with the therapeutic measures. Moderate
    events may cause some interference with functioning.

-   [Severe]{.underline}: events interrupt a patient's usual daily
    activity and may require systemic drug therapy or other treatment.
    Severe events are usually incapacitating.

-   [Life threatening]{.underline}: any adverse drug experience that
    places the patient or subject, in the view of the investigator, at
    immediate risk of death from the reaction as it occurred, ie, it
    does not include a reaction that had it occurred in a more severe
    form, might have caused death.

Changes in the severity of an AE should be documented to allow an
assessment of the duration of the event at each level of intensity to be
performed. Adverse events characterized as intermittent require
documentation of onset and duration of each episode.

**Relationship to Study Products:** The clinician's assessment of an
AE\'s relationship to test article (vaccine or study drug) is part of
the documentation process, but it is not a factor in determining what is
or is not reported in the study. If there is any doubt as to whether a
clinical observation is an AE, the event should be reported. All AEs
must have their relationship to study product assessed using the terms:
associated or not associated. In a clinical trial, the study product
must always be suspect. To help assess, the following guidelines are
used.

-   [Associated]{.underline} -- The event is temporally related to the
    administration of the study product and no other etiology explains
    the event.

-   [Not Associated]{.underline} -- The event is temporally independent
    of study product and/or the event appears to be explained by another
    etiology.

### Reactogenicity (for Vaccine Studies and Some Therapeutic Trials)

*Reactogenicity events are AEs that are common and known to occur for
the intervention/investigational product being studied and should be
collected in a standard, systematic format using a grading scale based
on functional assessment or magnitude of reaction. Provide a definition
of expected vs unexpected AEs and local vs systemic events, based on the
risk profile of the intervention/investigational product. This
information is found on the IB or package insert. Typically,
reactogenicity AEs are solicited and collected on memory cards and
documented on a reactogenicity CRF. This information comes from the
participant who may also have a memory aid to help recollect their
symptoms.*

*The following is an example of a functional scale for assessing
reactogenicity or other parameters not specifically listed in the
toxicity table:*

*0 = Absence of the indicated symptom*

*1 = Mild (awareness of a symptom but the symptom is easily tolerated)*

*2 = Moderate (discomfort enough to cause interference with usual
activity)*

*3 = Severe (incapacitating; unable to perform usual activities;
requires absenteeism or bed rest)*

*4 = Life threatening*

### Serious Adverse Events

*Refer to ICH E6, Section 1.50\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*An SAE is any adverse event/experience occurring at any study drug dose
that results in any of the following outcomes:*

-   *Death*

-   *Life threatening (subject at immediate risk of death)*

-   *Requires inpatient hospitalization or prolongation of existing
    hospitalization*

-   *Results in congenital anomaly/birth defect*

-   *Results in a persistent or significant disability or incapacity*

-   *Important medical events that may not result in death, be life
    threatening, or require hospitalization may be considered SAEs when,
    based upon appropriate medical judgment, may jeopardize the subject
    and may require medical or surgical intervention to prevent one of
    the outcomes listed in this definition.*

    *Some protocols may list events specific to the protocol that they
    want reported as serious with expedited reporting. An example might
    be for a maternal immunization protocol before eclampsia or preterm
    delivery.*

*Example text:*

**Serious Adverse Event (SAE)**: An SAE is defined as an AE that meets
one of the following conditions:

-   Death during the period of protocol defined surveillance

-   Life-threatening event (defined as a subject at immediate risk of
    death at the time of the event)

-   An event requiring inpatient hospitalization or prolongation of
    existing hospitalization during the period of protocol defined
    surveillance

-   Results in congenital anomaly or birth defect

-   Results in a persistent or significant disability/incapacity

-   Any other important medical event that may not result in death, be
    life threatening, or require hospitalization, may be considered a
    serious adverse experience 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 above. Examples of such medical events include allergic
    bronchospasm requiring intensive treatment in an emergency room or
    at home, blood dyscrasias or convulsions that do not result in
    inpatient hospitalization, or the development of drug dependency or
    drug abuse.

All SAEs will be:

-   recorded on the appropriate SAE CRF

-   followed through resolution by a study clinician

-   reviewed and evaluated by a study clinician

### Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical Findings

*Collection of laboratory data should be limited to those laboratory
parameters that are relevant to safety, study outcome measures, and/or
clinical outcome.*

*The toxicity tables will define what values or findings are considered
abnormal. Reporting will be dependent on the abnormality, the study
intervention, and the study population and should be stated
specifically. Consider the context of the trial and adjust reporting
procedures appropriately for the study population and agent being
studied. Selection of a toxicity table should be made in conjunction
with DMID.*

*Define the circumstances in which abnormal laboratory values will be
reported as AEs/SAEs. Generally, in healthy people, a grade 3
abnormality is an SAE. In sick populations, define in terms of a change
from baseline and disease progression.*

## Reporting Procedures

***Note: All clinical trials must have an AE reporting system in
place.***

*Include details of the protocol-specific reporting procedures,
including the individual responsible for each step (eg, the
investigator, the Medical Monitor), which forms should be completed, 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*

*(Refer to Report of* *Council for International Organizations of
Medical Sciences \[CIOMS\] Working Group V, Appendix 8 for examples of
narrative information for AE reports.)*

*The example language presented in the following sections may be used in
protocols. These sections may be customized by including
protocol-specific information such as:*

-   *Time frame for collecting and reporting AEs and SAEs.*

-   *Identification of additional protocol-specific parameters (safety
    issues) that need to be reported in an expedited fashion -- either
    to the investigator, sponsor, or regulatory body.*

### Serious Adverse Events

*Example text:*

Any AE considered serious by the PI or Subinvestigator or which meets
the aforementioned criteria must be submitted on an SAE form to PPD,
Inc, NIAID's pharmacovigilance contractor, at the following address:

**Medical Affairs/Pharmacovigilance\
PPD, Inc\
929 North Front Street**

**Wilmington, NC 28401-3331**

**SAE Fax line: 888-488-9697**

Questions about SAE reporting can be referred to the SAE Hotline
(available 24 hours a day/7 days a week) at 800-201-8725.

The study clinician will complete a Serious Adverse Event Form 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
    sent by fax within 24 hours of site awareness.

-   Serious adverse events other than death and immediately
    life-threatening events, regardless of relationship, will be
    reported via fax by the site within 72 hours of becoming aware of
    the event.

Other supporting documentation of the event may be requested by the
pharmacovigilance contractor and should be provided as soon as possible.

All SAEs will be followed until satisfactory resolution or until the PI
or Subinvestigator deems the event to be chronic or the patient to be
stable.

### Regulatory Reporting for Studies Conducted Under DMID‑Sponsored IND

*Example text:*

Following notification from the investigator, DMID, the IND sponsor,
will report events that are both serious and unexpected and that are
associated with study product(s) to the Food and Drug Administration
(FDA) within the required timelines as specified in 21 CFR Part 312.32:
fatal and life-threatening events within 7 calendar days (by phone or
fax) and all other SAEs in writing within 15 calendar days. All serious
events designed as "not associated" to study product(s), will be
reported to the FDA at least annually in a summary format.

### Regulatory Reporting for Studies Not Conducted Under DMID‑Sponsored IND

*If a study is not being conducted under an IND, it may be appropriate
to name alternative ways to report AEs (eg, MEDWATCH, VAERS). DMID
should be copied simultaneously when an alternate method of reporting is
utilized.*

### Other Adverse Events (if applicable)

*Describe any other nonserious AEs that merit reporting to the sponsor,
study leadership, IRB, and regulatory agencies.*

### Reporting of Pregnancy

*State the study's pregnancy-related policy and procedure. Include
appropriate mechanisms for reporting to sponsor, study leadership, IRB,
and regulatory agencies. Provide appropriate modifications to study
procedures (eg, discontinuation of vaccination while continuing safety
follow-up, following pregnant women to pregnancy outcome).*

## Type and Duration of Follow-up of Subjects after Adverse Events

*Refer to ICH E6, Section 6.8\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*Describe how AEs will be followed until resolved or considered stable.
Specify procedures for reporting and follow-up of AEs that are
consistent with the Schedule of Events. Include duration of follow-up
for appearance of AEs (eg, 1 week, 2 months).*

## Halting Rules

*Describe safety findings that would temporarily suspend enrollment
and/or study interventions until a safety review is convened (either
routine or ad hoc), the objective of which is a decision as to 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 or for the entire study) is another potential
outcome of a safety review.*

*Subsequent review of serious, unexpected, and related AEs by the
Medical Monitor, DSMB, IEC/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.*

## Safety Oversight (ISM plus SMC or DSMB)

*DMID requires safety oversight in one of 3 forms: ISM, SMC, or DSMB. In
this section, the type of safety oversight should be clearly identified
along with any known responsibilities for the oversight of safety in the
study. State who is responsible for safety oversight, i.e. ISM, SMC, or
DSMB. Will they meet at prearranged time points (enrollment milestones,
prior to next stage in protocol) in the study? Will meetings be
dependent on the halting rules? State which safety outcome measures will
be monitored, the frequency of monitoring, and the specific definitions
of proposed stopping guidelines.*

*Example text:*

Safety oversight will be under the direction of a DSMB composed of a
pediatrician, an intensivist, a statistician, and a cardiologist. The
DSMB will meet semiannually to assess safety and efficacy data on each
arm of the study. If halting rules are initiated, more frequent meetings
may be held. The DMSB will operate under the rules of a DMID-approved
charter that will be written at the organizational meeting of the DSMB.
At this time, each data element that the DSMB needs to assess will be
clearly defined. The DSMB will advise DMID of its findings.

# Clinical Monitoring

*Refer to ICH E6, Section 5.18\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*Also refer to:
<http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46>.*

*This section will give a general description of how site monitoring
will be conducted. A separate clinical monitoring plan will be developed
to describe who will conduct the monitoring, what frequency of
monitoring will be done, and what level of detail monitoring will be
performed.*

## Site Monitoring Plan

*Site monitoring is conducted to ensure that the human subject
protection, study procedures, laboratory, study intervention
administration, and data collection processes are of high quality and
meet the sponsor, ICH E6 and, when appropriate, regulatory guidelines.
This section will give a general description of how site monitoring will
be conducted. A separate monitoring plan document should be developed to
describe who will conduct the monitoring, at what frequency monitoring
will be done, and what level of detail monitoring will be conducted.
Most DMID-sponsored studies are monitored by PPD, and the clinical
monitoring plan is written jointly by DMID and PPD.*

*Preference is given to a separate monitoring plan to be agreed upon
with the Office of Clinical Research Affairs (OCRA), which will describe
protocol-specific items to be monitored. The monitoring plan must
include the number of subject charts to be reviewed, which/what
proportion of data fields and what will be monitored, who will be
responsible for conducting the monitoring visits, and who will be
responsible for ensuring that monitoring findings are addressed.*

# Statistical Considerations

*This section should be "self-contained" for coherence and ready
reference. It 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.*

## Study Hypotheses

*State the formal, testable, null, and alternate hypotheses for primary
and key secondary objectives, specifying the type of comparison (eg,
superiority, equivalence or noninferiority, dose-response).*

## Sample Size Considerations

*Provide all information needed to validate your calculations, and also
to judge the feasibility of enrolling and following the necessary
numbers of subjects.*

*In particular, specify all of the following:*

-   *Outcome measure used for calculations (almost always the primary
    variable)*

-   *Test statistic*

-   *Null and alternate hypotheses*

-   *Type I error rate*

-   *Type II error rate*

-   *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*

-   *Assumed dropout rates, withdrawal, cross-over to other study arms,
    missing data, etc also justified*

-   *Approach to handling withdrawals and protocol violations, ie,
    whether subjects will be included in the "intent-to-treat"
    population*

-   *Statistical method used to calculate the sample size, with a
    reference for it and for any software utilize, and*

-   *Method for adjusting calculations for planned interim analyses, if
    any (see Section 11.3).*

*Further, present calculations from a suitable range of assumptions to
gauge the robustness of the proposed sample size.*

*Discuss whether the sample size also provides sufficient power for
addressing secondary objectives or for secondary analyses in key
subgroup populations.*

## Planned Interim Analyses (if applicable)

*If interim analyses will be reviewed by a DSMB or similar committee,
describe its composition, how often it will meet, and that it advises
DMID.*

*Describe the types of statistical interim analyses and stopping
guidelines (if any) that are proposed, including their timing.*

*Within the following sections, prespecify, to the extent possible, the
criteria used to determine decisions.*

### Safety Review 

*Provide details of the proposed rules for halting study enrollment or
study intervention/administration of study product for safety, including
whether they pertain to the entire study, specific study arms or subject
subgroups, or other components of the study.*

*State which safety outcome measures will be monitored, the frequency of
monitoring, and the specific definitions of proposed stopping
guidelines.*

*If statistical rules will be used to halt enrollment into all or a
portion of the study, describe the statistical techniques and their
operating characteristics, eg, the probability of stopping under
different safety event rates and the associated number of participants
that would be enrolled.*

### Immunogenicity or Efficacy Review

*Provide the same information as in Section 11.3.1, but for
immunogenicity or 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.*

## Final Analysis Plan

*This section can be used to elaborate on primary analyses that underlie
the sample size calculation in Section 11.2 and to describe secondary
analyses for the primary or secondary objectives. Even more details can
be provided in a separate statistical analysis plan written later but
prior to performing any analyses.*

*Plans must clearly identify the analyses cohorts (eg, "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 measured and transformed, if
relevant, before analysis (eg, 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?).*

# Source Documents and Access to Source Data/Documents

*Each participating site will maintain appropriate medical and research
records for this trial, in compliance with ICH E6, Section 4.9 and
regulatory and institutional requirements for the protection of
confidentiality of subjects. Describe who will have access to records.
As part of participating in a DMID-sponsored, DMID-affiliated, or
manufacturer-sponsored study, each site will permit authorized
representatives of the sponsor(s), DMID, and regulatory agencies to
examine (and when required by applicable law, to copy) clinical records
for the purposes of quality assurance reviews, audits, and evaluation of
the study safety and progress.*

*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, copies or
transcriptions certified after verification as being accurate and
complete, microfiches, photographic negatives, microfilm or magnetic
media, x-rays, and subject files and records kept at the pharmacy, at
the laboratories, and medico-technical departments involved in the
clinical trial. It is acceptable to use CRFs as source documents. If
this is the case, it should be stated in this section what data will be
collected on CRFs and what data will be collected from other sources.*

*Refer to: <http://www.fda.gov/cder/guidance/959fnl.pdf>.*

# Quality Control and Quality Assurance

*This section will address the plans for local quality assurance and
quality control.\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*All sites conducting research under the sponsorship of the DMID 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) for quality
management which describes:*

-   *How data will be evaluated for compliance with the protocol and for
    accuracy in relation to source documents.*

-   *The documents to be reviewed (eg, CRFs, clinic notes, product
    accountability), who is responsible, and the frequency for reviews
    should be identified, either in a formal quality management plan or
    in site SOPs.*

-   *Methods of training for staff should be specified.*

*See Section 10.1 for detail on Site Monitoring.*

*You can access the DMID Quality Management Plan (QMP) documentation
requirements and templates on the PPD-CTM Partners website. Go to the
following link:*

[*http://www.dmidctm.com/partners/home.htm*](http://www.dmidctm.com/partners/home.htm)*/
to access the Quality Management tab.*

*The following DMID QMP documents are available on the PPD-CTM website:*

-   *DMID Quality Management Plan - Standard Operating Procedure*

-   *Quality Management Plan, version-controlled, template*

-   *Chart Review Tool, template*

-   *Regulatory File Review Tool, template*

-   *Quality Management Summary Report, template*

-   *Quality Management Plan Fact Sheet*

# Ethics/Protection of Human Subjects

*This section should include a description of the ethical considerations
and context for the conduct of the trial.*

## Ethical Standard

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

*Example 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 of 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; 62 Federal Regulations
25691 (1997).

*If the study is conducted at international sites, the statement could
be as above and/or 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

*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 independent ethics committee
(IEC) or 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/.](http://www.hhs.gov/ohrp/assurances/)*

## Informed Consent Process

*Refer to ICH GCP E6, Section 4.8\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*Refer to FDA regulations on informed consent 21 CFR Part 50 - Subpart B
(<http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50>).*

*Refer to DHHS Regulation on Informed Consent 45 CFR Part 46 - Subpart
A, 46.116
[(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116](http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116)).*

*Refer also to Tips on Informed Consents
(<http://www.hhs.gov/ohrp/humansubjects/guidance/ictips.htm>).*

*Refer also to Informed Consent Checklist
(<http://www.hhs.gov/ohrp/humansubjects/assurance/consentckls.htm>).*

*Describe the procedures for obtaining and documenting informed consent
of study subjects. Make provisions for special populations, eg,
non-English speakers, children, illiterate or non-writing individuals,
vulnerable populations.\
(Refer to:
<http://www.hhs.gov/ohrp/humansubjects/guidance/ic-non-e.htm>).*

*Informed consent is required for all subjects participating in a
DMID-sponsored study. In obtaining and documenting informed consent, the
investigator should comply with applicable regulatory requirements and
should adhere to 45 CFR Part 46 and/or ICH, GCP. Prior to the beginning
of the trial, the investigator should have the IRB/IEC's written
approval, favorable opinion of the written informed consent form(s), and
any other written information to be provided to the subjects.*

*Identify different consent forms that are needed for the study (eg,
screening, study participation, screening for human immunodeficiency
virus, future use specimens, plasmapheresis, assent form for minors).*

*Example text:*

Informed consent is a process that is initiated prior to the
individual's agreeing to participate in the study and continuing
throughout the individual's study participation. Extensive discussion of
risks and possible benefits of this therapy will be provided to the
subjects and their families. Consent forms describing in detail the
study interventions/products, study procedures, and risks are given to
the subject and written documentation of informed consent is required
prior to starting intervention/administering study product. Consent
forms will be IRB-approved and the subject will be asked to read and
review the document. Upon reviewing the document, the investigator will
explain the research study to the subject and answer any questions that
may arise. The subjects will sign the informed consent document prior to
any procedures being done specifically for the study. The subjects
should have the opportunity to discuss the study with their surrogates
or think about it prior to agreeing to participate. The subjects may
withdraw consent at any time throughout the course of the trial. A copy
of the informed consent document will be given to the subjects for their
records. The rights and welfare of the subjects will be protected by
emphasizing to them that the quality of their medical care will not be
adversely affected if they decline to participate in this study.

*Provide each institution with a model inform consent form for subject
participation. The consent form should be separate from the protocol
document. Each institution should place the informed consent document in
its own template. Each institution may add but not remove anything from
the model consent form.*

### Informed Consent/Assent Process (in Case of a Minor)

*Refer to ICH E6, Section 4.8.12\
(<http://www.fda.gov/cder/guidance/959fnl.pdf>).*

*When a study includes subjects who may be enrolled in the trial only
with the consent of the subject's legally authorized representative (eg,
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/product,
study procedures, and risks may be used. Assent forms do not substitute
for the consent form signed by the subject's legally authorized
representative.*

*Note that additional considerations exist for enrollment of minors.
Refer to 45 CFR Part 46.*

## Exclusion of Women, Minorities, and Children (Special Populations)

*If the study intends to exclude any special populations, justify the
exclusion of women, minorities, or children in the context of the study
design.*

## Subject Confidentiality

*Include procedures for maintaining subject confidentiality, any special
data security requirements, and record retention per the sponsor's
requirements. Possible persons that might have access to records, in
addition to the clinical monitor, would be funding institutions, IND
sponsor, representatives of DMID, representative from the IRB/IEC, and
representatives of the pharmaceutical company supplying product to be
tested.*

*Example text:*

Subject confidentiality is strictly held in trust by the participating
investigators, their staff, and the sponsor(s) and their agents. This
confidentiality is extended to cover testing of biological samples and
genetic tests in addition to the clinical information relating to
participating 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 documents and records required to be maintained by the
investigator, including but not limited to, medical records (office,
clinic, or hospital) and pharmacy records for the subjects in this
study. The clinical study site will permit access to such records.

## Study Discontinuation

*In the event that the study is discontinued, provide a plan for the
following:*

-   *Describe procedures for subjects to continue therapy, if
    appropriate*

-   *Describe crossover to study drug for placebo recipients at the
    completion of the study.*

## Future Use of Stored Specimens

*Refer to Human Research Regulation Chart 2\
<http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm>.*

*If residual specimens will be maintained after the study is complete,
include the provisions for consent and the options that are available
for the volunteer to agree to the future use of his/her specimens.
Specify the location(s), if other than the clinical site, where
specimens will be maintained, if the site\'s IRB will review future
studies, and protections of confidentiality for any future studies with
the stored specimens, eg, specimens will be coded, bar-coded, delinked.
Include a statement that genetic testing will not be performed, if
required by the IRB.*

*Additional guidance can be provided by OCRA or the Office of Regulatory
Affairs (ORA) staff.*

# Data Handling and Record Keeping

*Refer to: <http://www.fda.gov/ora/compliance_ref/part11>/.*

*Include instructions for special data-handling or record-keeping
procedures required for maintaining subject confidentiality, any special
data security requirements, and record retention per the sponsor's
requirements in this section.*

*Briefly describe steps to be taken to assure that the data collected
are accurate, consistent, complete, and 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 an MOP, User's Guide or other citable reference document.*

*Example text:*

The investigator is responsible to ensure 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. Black ink is required to ensure clarity of
reproduced copies. When making changes or corrections, cross out the
original entry with a single line, and initial and date the change. DO
NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL.

Copies of the electronic CRF (eCRF) will be provided for use as source
documents and maintained for recording data for each subject enrolled in
the study. Data reported in the eCRF derived from source documents
should be consistent with the source documents or the discrepancies
should be explained

DMID and/or it designee will provide guidance to investigators on making
corrections to the source documents and eCRF.

## Data Management Responsibilities

*Describe responsibilities for data handling and record keeping as they
specifically relate to the IND sponsor if applicable, the award site,
clinical site, laboratory, and data coordinating center. Information
should include the role in data collection, review of data, trial
materials, and reports, as well as retention of source documents, files,
and records. Describe coding dictionaries to be used and reconciliation
processes (if applicable). At the end of the study, a copy of all
datasets will be provided to DMID.*

*If data are to be generated in one location and transferred to another
group, describe the responsibilities of each party.*

*Indicate the roles of each party with regard to interpretation of data,
plans for analysis, review of tables and listings, and plans for
reporting.*

*Example text:*

All source documents and laboratory reports must be reviewed by the
clinical team and data entry staff, who will ensure that they are
accurate and complete. Adverse events must be graded, assessed for
severity and causality, and reviewed by the site PI or designee.

Data collection is the responsibility of the clinical trial staff at the
site under the supervision of the site PI. During the study, the
investigator must maintain complete and accurate documentation for the
study.

The EMMES Corporation will serve as the Statistical and Data
Coordinating Center for this study and will be responsible for data
management, quality review, analysis, and reporting of the study data.

## Data Capture Methods

*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 any related
requirements. Indicate expectations for time for submission of CRFs.*

*Example text:*

Clinical data (including AEs, concomitant medications, and
reactogenicity data) and clinical laboratory data will be entered into a
21 CFR Part 11-compliant Internet Data Entry System (IDES) provided by
The EMMES Corporation. The data system includes password protection and
internal quality checks, such as automatic range checks, to identify
data that appear inconsistent, incomplete, or inaccurate. Clinical data
will be entered directly from the source documents.

## Types of Data

*Indicate the types of data that will be collected, such as safety,
laboratory (clinical, immunology, pharmacokinetic, other study
specific), and outcome measure data (eg, reactogenicity). Specify if
safety data are collected in a separate database.*

*Example text:*

Data for this study will include safety, laboratory (immunologic and
virologic), and outcome measures (eg, reactogenicity, immunogenicity,
virology).

## Timing/Reports

*Indicate the schedule for data review and reports, how outcome measure
data are collected and monitored, data for stopping rules, and reports
for DSMB. Specify whether reviews or reports are ongoing, interim, or
periodic. Identify plans for data analysis and interim and final study
reports, steps for freezing the data prior to analysis, and precautions
related to masked data. Indicate whether and when coding is to occur.*

## Study Records Retention

*Specify the length of time for the investigator to maintain all records
pertaining to this study (eg, a minimum of 2 years following 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
at least 2 years have elapsed since the formal discontinuation of
clinical development of the investigational product). Indicate whether
permission is required (and from whom) prior to destruction of records.
If under an IND, records should not be destroyed without the IND
sponsor's agreement. Pharmaceutical companies who supply unregulated
products should be consulted.*

*Investigational product records may be addressed here if not addressed
elsewhere in the protocol.*

*Example text:*

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 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.

## Protocol Deviations

*Plans for detecting, reviewing, and reporting deviations from the
protocol should be described. A statement may be included to indicate
that deviations are not allowed, unless a statement is included in
investigator agreement. Provisions for approval of deviations can be
described.*

*Example text:*

A protocol deviation is any noncompliance with the clinical trial
protocol, Good Clinical Practice (GCP), or Manual of Procedures
requirements. The noncompliance may be either on the part of the
subject, the investigator, or the study site staff. As a result of
deviations, corrective actions are to be developed by the site and
implemented promptly.

These practices are consistent with ICH E6:

4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3

5.1 Quality Assurance and Quality Control, section 5.1.1

5.20 Noncompliance, sections 5.20.1, and 5.20.2.

It is the responsibility of the site to use continuous vigilance to
identify and report deviations within 5 working days of identification
of the protocol deviation, or within 5 working days of the scheduled
protocol-required activity. All deviations must be promptly reported to
DMID, via The EMMES Corporation's IDES or via the PPD web- or fax-based
system.

Note: Those sites participating in trials with a designated 'central
unit' will follow the reporting requirements specified in their
protocols and MOPs. The 'central unit' will be responsible for
submission of the protocol deviation information to PPD.

All deviations from the protocol must be addressed in study subject
source documents. A completed copy of the DMID Protocol Deviation Form
(PPD or IDES form) must be maintained in the regulatory file, as well as
in the subject's source document. Protocol deviations must be sent to
the local IRB/IEC per their guidelines. The site PI/study staff is
responsible for knowing and adhering to their IRB/IEC requirements.

# Publication Policy

*If appropriate, the publication policy may be described in the study's
MOP.*

*The publication and authorship policies should be determined and
clearly outlined in this section. Please refer to your specific contract
grant and/or Clinical Trials Agreements. Policies regarding substudies
should be outlined in this section.*

*The following language may be used in the protocol:*

Following completion of the study, the investigator is expected to
publish the results of this research in a scientific journal. The
International Committee of Medical Journal Editors (ICMJE) member
journals have adopted a trials-registration policy as a condition for
publication. This policy requires that all clinical trials be registered
in a public trials registry such as
[ClinicalTrials.gov](http://www.clinicaltrials.gov/)\*, which is
sponsored by the National Library of Medicine. Other biomedical journals
are considering adopting similar policies. It is the responsibility of
DMID to register this trial in an acceptable registry. Any clinical
trial starting enrollment after 01 July 2005 must be registered on or
before patient enrollment. For trials that began enrollment prior to
this date, the ICMJE member journals will require registration by 13
September 2005, before considering the results of the trial for
publication.

The ICMJE defines a clinical trial as any research project that
prospectively assigns human subjects to intervention or comparison
groups to study the cause-and-effect relationship between a medical
intervention and a health outcome. Studies designed for other purposes,
such as to study pharmacokinetics or major toxicity (eg, Phase I
trials), would be exempt from this policy.

\*Journal Citation:

[De Angelis
C](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="De+Angelis+C"%5BAuthor%5D),
[Drazen
JM](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Drazen+JM"%5BAuthor%5D),
[Frizelle
FA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Frizelle+FA"%5BAuthor%5D),
[Haug
C](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Haug+C"%5BAuthor%5D),
[Hoey
J](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Hoey+J"%5BAuthor%5D),
[Horton
R](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Horton+R"%5BAuthor%5D),
et al. Clinical trial registration: a statement from the International
Committee of Medical Journal Editors. N Engl J Med. 2004;351:1250-1.

# Literature References

*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 (eg, N Engl
J Med, JAMA, etc). The preferred format is ICMJE.*

*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.

*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](http://www.nlm.nih.gov/bsd/uniform_requirements.html ).*

[]{#__RefHeading___Toc105912040 .anchor}SupplementS/Appendices

*(NOTE: Since the protocol and the clinical trial/study report are
closely related, further relevant information can be found in the ICH
E3: Structure and Content of Clinical Study Reports. These materials
should not be included as part of the protocol.)*

*Supplements and Protocol Appendices*

-   *Substudies*

-   *Schedule of Events*

-   *Toxicity Grading Scales*

-   *Sample Consent Form(s)*

*Related Documents*

-   *Site Roster*

-   *Manual of Procedures*

-   *Repository instructions*

-   *Biosafety Precautions*

-   *Laboratory Handling*

*Other Documents*

-   *CRF copies*

-   *Quality Management Plan*

-   *Data Management Plan*

-   *Clinical Monitoring Plan*

[]{#__RefHeading___Toc105912041 .anchor}Appendix A: Schedule of Events

  ---------------------------------------------------------------------------------------------------------------------------
                                                           Follow-Up                                        
                                                           Schedule                                         
  -------------- ------------------ ----------- ---------- ----------- ------- ------- ------- ------------ -----------------
  Procedures                        Screening   Baseline   Time Point  Time    Time    Time    Study        Premature
                                                           or Study    Point   Point   Point   Completion   Discontinuation
                                                           Visit 1     or      or      or                   
                                                                       Study   Study   Study                
                                                                       Visit 2 Visit 3 Visit                
                                                                                       4, etc               

  Signed Consent                    X           X                                                           
  Form                                                                                                      

  Assessment of                     X           X                                                           
  Eligibility                                                                                               
  Criteria                                                                                                  

  Review of                         X           X                                                           
  Medical                                                                                                   
  History                                                                                                   

  Review of                         X           X          X           X       X       X       X            X
  Concomitant                                                                                               
  Medications                                                                                               

  Study                                         X                                                           
  Intervention                                                                                              

  Physical       Complete           X                                                          X            X
  Examination                                                                                               

                 Symptom-Directed               X          \(X\)       \(X\)   \(X\)   \(X\)                

                 Vital Signs                    \(X\)      \(X\)       \(X\)   \(X\)   \(X\)                

  Assessment of                                            \(X\)       \(X\)   \(X\)   \(X\)   X            X
  Adverse Events                                                                                            

  Clinical       Chemistry          X           X          \(X\)       \(X\)   \(X\)   \(X\)   X            X
  Laboratory                                                                                                

                 Hematology         X           X          \(X\)       \(X\)   \(X\)   \(X\)   X            X

                 Urinalysis         X           X          \(X\)       \(X\)   \(X\)   \(X\)   X            X

  Research       Immunology\                    X                      \(X\)           \(X\)   X            X
  Laboratory     \_\_mL whole blood                                                                         

  Other                                         \(X\)                  \(X\)           \(X\)   \(X\)        \(X\)
  Procedures                                                                                                
  ---------------------------------------------------------------------------------------------------------------------------

+-----------------------------------------------------------------------+
| \(X\) -- As indicated/appropriate.                                    |
|                                                                       |
| Note: List the tests applicable to your specific protocol.            |
|                                                                       |
| Provide a list of tests to be done, eg:                               |
|                                                                       |
| [Hematology]{.underline} -- Hemoglobin, hematocrit, WBC and           |
| differential count, platelet count.                                   |
|                                                                       |
| [Biochemistry]{.underline} -- 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]{.underline} -- Protein and glucose, as appropriate for   |
| the study.                                                            |
|                                                                       |
| [Immunology]{.underline} -- Specimen types for nonstandard laboratory |
| assays.                                                               |
|                                                                       |
| [Other]{.underline} -- Other procedures that are done to evaluate     |
| outcome measures (eg, photographs, x-rays).                           |
|                                                                       |
| Study intervention -- Modify as appropriate if intervention is        |
| administered more than once throughout the study.                     |
|                                                                       |
| Specify time points for follow-up in days, weeks, or months, as       |
| appropriate for protocol.                                             |
|                                                                       |
| At baseline, all procedures should be done before study intervention. |
|                                                                       |
| Indicate volume of blood if frequent or large phlebotomies are part   |
| of the protocol over 2 months.                                        |
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