Tool Summary Sheet

Tool:	Manual of Procedures (MOP) Template
Purpose:	This document provides a template to assist investigators with the preparation of a study Manual of Procedures (MOP). The purpose of the MOP is to facilitate consistency in protocol implementation and data collection across participants and clinical sites. Use of the MOP increases the likelihood that the results of the study will be scientifically credible and provides reassurance that patient safety and scientific integrity are closely monitored.
Audience/User:	Investigators and Study Coordinators may use this template as a basis for customizing an appropriate Manual of Procedures to support individual studies.
Details:	A MOP (also known as Manual of Operations [MOO]) is a handbook that guides a study’s conduct and operations. It supplements the study protocol by detailing a study’s organization, operational data definitions, recruitment, screening, enrollment, randomization, intervention procedures and follow-up procedures, data collection methods, data flow, case report forms (CRFs), and quality control procedures. Procedures in the MOP should be followed with the same degree of vigor as those documented in the protocol.
Best Practice Recommendations:	This template is intended for use as a guide during development of a study-specific MOP. Review this template and customize to the specific needs and requirements of the study. Sample text is provided for reference and may be updated as needed. Remove or mark as “not applicable” those elements that are not required. In the template, the instructions and explanatory text are indicated by {blue italics} (“CROMS_Instruction” style). Instructional text will also be enclosed in braces to signify this text for screen-readers used by the visually impaired. Text enclosed with <> is a placeholder for a specific detail (e.g., <protocol title>); replace as appropriate. Because the MOP is used in tandem with the protocol, it is not necessary to repeat major sections of the protocol in the MOP (e.g., the summary of events). It is also good practice to avoid redundancy within the MOP itself. In both cases, use document and section references when necessary, remembering to revise these references when either document is updated. The first version of the MOP should be available at the time of study start. Sections of the MOP should be prepared by the subject matter experts (e.g., clinical procedures should be prepared by a clinician and data management procedures should be written by the data manager). The MOP is a dynamic document and tends to be updated more frequently than the protocol. Ensure that the MOP has a section on version control of the document and dissemination of updated versions. It is easiest and cleanest to use the styles that are embedded in the document, rather than to create your own. (In MS Word 2007: From the Home menu, select the bottom right arrow key to bring up the styles box, select “Options”, under “Select Styles to Show” select “in current document”.) Please retain the MOP Template identifier in the lower left hand section of the footer. You may choose to add “Based on” in front of “Template Version”.

Tool Revision History:

Version Number	Version Date	Summary of Revisions Made:
2.0	01OCT2010	Approved version. Includes styles and accommodations for 508 compliance.
3.0	22JUL2011	Edits to website hyperlinks.
4.0	01JUN2012	Clarified instructions to modify sample text as needed; corrected Essential Documents heading; revised ICF references to consent document; added table for documenting each chapter’s current version number and date; clarified versioning instructions; added additional explanatory text in Lab chapter; used “Essential Documents binder” as consistent terminology throughout; completed minor administrative edits.
5.0	21AUG2014	Updated hyperlinks, removed numbered memo text from section 1.2, revised safety oversight section to remove SMC and add MM, and completed administrative/clarifying edits throughout.
6.0	22DEC2014	Revised Document Maintenance section text to reflect current requirements.

{Instruction: Delete the Tool Summary Sheet and this Preface at the time of study-specific implementation.

Preface to the Manual of Procedures Template

Version 6.0 (22Dec2014)

Purpose of the Manual of Procedures (MOP)

A Manual of Procedures (MOP) is a handbook that guides a study’s conduct and operations. It supplements the study protocol by detailing a study’s organization, operational data definitions, recruitment, screening, enrollment, randomization, intervention procedures and follow-up procedures, data collection methods, data flow, case report forms (CRFs), and quality control procedures. The purpose of the MOP is to facilitate consistency in both protocol implementation and data collection across participants and clinical sites. Use of the MOP increases the likelihood that the results of the study will be scientifically credible and provides reassurance that participant safety and scientific integrity are closely monitored.

The MOP Template and Mechanics

This MS Word template can be used as the starting point for development of a study-specific MOP.

In the template, the instructions and explanatory text are indicated by {blue italics} (“CROMS_Instruction” style). Instructional text will also be enclosed in braces to signify this text for screen-readers used by visually impaired persons.

This text should be deleted during the study-specific customization of the MOP. Example text that appears in the MOP template in regular font may be retained and edited as appropriate to the study. Text within any section should be formatted using CROMS_Text style. Bulleted lists should be formatted using CROMS_Text Bullet (listing) style. Text included in <> is a placeholder for a specific detail (e.g., <protocol title>); replace as appropriate. Use CROMS_Heading 1-5 to format headings.

The MOP sections listed and described in the template are intended as guidelines and should be adapted to each study’s specific needs. If a section in the template does not apply to a study (e.g., randomization in a study with no randomization), it should not be included in the MOP.

Refer questions regarding use of this Manual of Procedures template to the appropriate NIDCR Program Official or the NIDCR Office of Clinical Trials Operations and Management (OCTOM).

A number of useful tools are available in the NIDCR website (http://www.nidcr.nih.gov/Research/toolkit/) and Clinical Tool Box section of the CROMS website. Please peruse the website to identify those that would be applicable for your study. Several of those tools are also referenced in the MOP template. Please note that all hyperlinks were functional at the time this template was published. If you find a link that is no longer active, please feel free to email anyone on the CROMS team, and it will be corrected with the next release of the template.

MOP Development

Because the MOP is used in tandem with the protocol, it is not necessary to repeat major sections of the protocol in the MOP (e.g., the summary of events). It is also good practice to avoid redundancy within the MOP itself. In both cases, use document and section references when necessary, remembering to revise these references when either document is updated.

The primary audience for the MOP is the site investigators and other research staff. Administrative documents, such as the data management plan, safety management plan, or statistical analysis plan are not commonly included in the MOP. Instead, only the site-relevant details are captured in the MOP and the other documents are maintained separately. These documents may be referred to in the MOP as “dynamic references.”

Development of the MOP requires the involvement of investigators and study staff (clinicians, laboratory staff, pharmacists, statistician data manager, regulatory specialist, etc.) to ensure that the guidelines accurately reflect how the study procedures will be performed. In multi-site clinical studies, a Steering Committee, comprised of the principal investigators from each of the sites, is often appointed to finalize the protocol and elements of the MOP.

The MOP finalization requires completion of the final protocol, CRFs, consent documents, and administrative forms (e.g., subject screening log, subject enrollment log, delegation of responsibilities log, etc.). Additionally, if the study is to be submitted to the Food and Drug Administration (FDA) under an Investigational New Drug Application (IND), an Investigator's Brochure, package insert or comparable product description may be required. Development of study materials could take up to six months. The MOP must be completed and be available to study staff before a study commences; please plan accordingly.

The National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH) must ensure compliance with Federal laws and regulations, including procedures and policies to protect the safety of all participants in the clinical studies it supports. In preparing a study protocol and a Manual of Procedures (MOP), the NIDCR grantee must be aware of the terms of award with respect to required reporting, data and safety monitoring, and Institutional Review Board (IRB) approval. For additional information, see website below: http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/NIDCRClinicalTermsofAward.htm

Maintenance and Updating of the MOP

The MOP should be maintained in a format that allows it to be easily updated; it may be filed in a three-ring binder, separated by dividers or sheets of paper, or stored in electronic format.

The MOP is a dynamic document that will be updated throughout the conduct of a study to reflect any protocol or consent amendments as well as the refinement of the CRFs and study procedures. It is useful to maintain a log in the front of the MOP that summarizes changes to the document. It is the responsibility of the MOP development team to implement appropriate version control procedures. As sections/chapters are revised, update the MOP version information on the cover page and Table of Contents; use the Summary of Changes table on the cover page to list the chapters that have changed and to provide a general summary of those changes. You may choose to update the version date on all pages or only on those chapters that have been modified, for ease of identification. If you choose the latter strategy, please use the sample “Chapter/Appendix Version Tracker” table (included after the revision history table) to clarify the chapter/appendix version information. Describe the chosen revision strategy in the version control section of the MOP. All previous versions should be archived.

Instruction: End of Preface. To be deleted at the time of study-specific implementation.}

Manual of Procedures (MOP)

for

<Protocol Title>

NIDCR Protocol Number: <#>

Draft or Version Number: <#.#>

{0.x (for draft) or x.0 (for final). Refer to NIDCR Guidance for assigning version numbers; when the version number and date change, be sure to update them in the header of every page of the MOP.}

<Day Month Year>

{(e.g., 23 January 2014)}

Summary of Changes:

Number	Date	Affected Chapter(s)	Summary of Revisions Made:

{Include this sample table if the MOP version control procedures entail updating and
up-versioning individual chapters, rather than the whole document.}

Chapter/Appendix Version Tracker

Chapter Number / Appendix	Title	Current, Approved Version Number	Current, Approved Version Date

Table of Contents

{This table uses the Table of Contents function in Microsoft Word that will automatically update headings and page numbers used throughout the report. In the body of the report, add, delete, or modify headings as needed in order to best reflect your study. To update the Table of Contents and all cross-references in the document, press CTRL-A to select the entire document, then press F9.}

Page

1	INTRODUCTION TO THE MANUAL OF PROCEDURES	13

1.1	Purpose	13

1.2	Updating and Version Control	13

2	ADMINISTRATIVE	14

2.1	Study Leadership Structure	14

2.1.1	Organizational Chart	14

2.1.2	Roles and Responsibilities	14

2.1.3	Steering Committee	15

2.2	Policies and Procedures	15

2.2.1	Conflict of Interest (COI) and Financial Disclosure Policies	15

2.2.2	Protocol Amendment Procedures	16

2.2.3	Version Control of Study Documents	16

2.2.4	Communication Plan	16

2.2.5	Clinical Trial Registry/ClinicalTrials.gov and PubMed	19

2.2.6	Data Request Policy	20

2.2.7	Publication and Presentation Policy	20

2.2.8	Organizational Chart	20

2.2.9	Roles and Responsibilities	20

2.2.10	Qualifications	21

2.3	Safety Oversight Committee (or Safety Oversight)	21

2.3.1	Roles and Responsibilities	21

2.3.2	Membership	21

2.3.3	Frequency of Meetings	21

2.4	Scientific Advisory Board	21

2.4.1	Roles and Responsibilities	22

2.4.2	Membership	22

2.5	Community Advisory Board	22

2.5.1	Roles and Responsibilities	22

2.5.2	Membership	22

3	REGULATORY	23

3.1	Regulations and Regulatory Bodies	23

3.2	Federalwide Assurance Documentation	23

3.3	Protection of Human Subjects	24

3.3.1	Informed Consent / Assent Process	24

3.3.2	Documentation of Consent / Assent	25

3.3.3	Translation of Consent and Assent Documents	25

3.3.4	Re-consenting for Protocol Changes or Safety Updates	25

3.3.5	HIPAA Privacy Rule	26

3.4	Essential Documents	26

3.4.1	Required Documents	26

3.4.2	Document Maintenance	27

4	SITE QUALITY MANAGEMENT PLANS	28

4.1	Informed Consent	28

4.2	Data Management	28

4.3	Research Specimen Management	28

5	SITE PREPARATION	29

5.1	Facilities Requirements	29

5.1.1	Clinical Research Area	29

5.1.2	Secure Document Storage	29

5.1.3	Diagnostic Services	30

5.1.4	Pharmacy Services	30

5.1.5	Laboratory Services	30

5.1.6	Courier Services	30

5.1.7	Research Sample Storage	30

5.2	Staff Training	30

5.2.1	Human Subjects Protection Training	30

5.2.2	Good Clinical Practice Training	30

5.2.3	Protocol Training	30

5.2.4	Study-Specific SOP Training	31

5.2.5	Clinical Operations	31

5.3	Equipment and Supplies	31

6	PROTOCOL IMPLEMENTATION	32

6.1	Recruitment, Screening, and Enrollment	32

6.1.1	Recruitment Methods	32

6.1.2	Pre-Screening	32

6.1.3	Screening	32

6.1.4	Rules for Re-screening	32

6.1.5	Establishing Eligibility	32

6.1.6	Assigning Participant Identification (PID) Numbers	32

6.2	Enrollment Procedures	33

6.3	Randomization	33

6.4	Masking/Blinding	33

6.5	Detailed Description of the Study Intervention	33

6.6	Detailed Description of Study Procedures	34

6.6.1	Schedule of Events	34

6.6.2	Visit Windows	34

6.6.3	Rules for Rescheduling Visits	34

6.6.4	Order of Visit Activities	34

6.6.5	Rules for Rescheduling Events	34

6.6.6	Missed Visits and Procedures	34

6.7	Protocol Deviations and Violations	34

7	PROCEDURES FOR MANAGING TRIAL PROGRESS	34

7.1	Enrollment	34

7.2	Visit Completion	35

7.3	Outstanding and Missing Data	35

7.4	Data Entry Errors	35

7.5	Protocol Deviations/Violations	35

7.6	Serious Adverse Events	35

8	TEST ARTICLE	36

8.1	Obtaining Test Article	36

8.2	Storage Conditions and Stability	36

8.3	Reconstitution (if applicable)	36

8.4	Ordering Test Article	36

8.5	Dispensation of Test Article to Clinical Staff	36

8.6	Treatment Regimen and Administration	36

8.7	Participant Counseling	36

8.8	Monitoring Subject Compliance	36

8.9	Test Article Accountability	36

8.10	Return and Destruction of Test Article after Study Completion	36

8.11	Compliance with Good Manufacturing Practice Standards	36

9	SAFETY ASSESSMENT AND REPORTING	37

9.1	SAE Reporting	37

9.2	Expected Adverse Events	37

9.3	Toxicity Tables	37

9.4	Prohibited Medications	37

9.5	Unanticipated Problems	37

9.6	Pregnancy Testing and Counseling	37

10	DATA MANAGEMENT	38

10.1	Data Collection Methods	38

10.2	Source Documentation Requirements	38

10.3	Study Forms	39

10.4	Case Report Form Completion Guidelines	39

10.5	Data Error Detection and Correction	39

10.6	Data Quality Management	39

10.7	Data Provided from an Entity Other than the Clinical Site	39

10.8	Data Collection and Data Processing Flowchart	40

10.9	Creating and Distributing Revised Case Report Forms	40

10.10	Long Term Storage of Case Report Forms	40

10.11	Maintaining Data Privacy	40

11	SPECIMEN AND LABORATORY MANAGEMENT	41

11.1	Specimen Collection	41

11.1.1	Overview	41

11.1.2	Detailed Information for Each Specimen	41

11.1.3	Specimen Tracking	41

11.2	Overview of Tests to be Performed in Each Lab	42

11.3	Laboratory Staff	42

11.3.1	Roles and Responsibilities	42

11.3.2	Good Clinical Lab Practice Training	42

11.3.3	IATA Training and Certification	42

11.4	Laboratory Certifications and Quality Assurance Plans	42

11.5	Laboratory Procedures	42

11.5.1	Specimen Acquisition	42

11.5.2	Specimen Storage and Tracking	42

11.5.3	Detailed Instructions for Processing Individual Specimen Types	42

11.5.4	Laboratory Data Management and Storage	42

12	SITE MONITORING	43

12.1	Purpose of Site Monitoring	43

12.2	Clinical Monitoring Logistics	43

12.2.1	Frequency of Visits	43

12.2.2	Scope of Monitoring Activities	43

12.2.3	Monitoring Reports	43

12.2.4	Communication Plan	43

12.3	Facilitating the Site Monitoring Visit	43

12.3.1	Scheduling the Visit	43

12.3.2	Securing Space for Monitors	43

12.3.3	Preparing Study Documentation for Review	43

12.3.4	Arranging for Access to Medical Records	43

12.3.5	Wrap-Up Meeting	44

12.3.6	Responding to Request for Corrective Action	44

12.4	Preparing for Audits by Regulatory Authorities	44

12.4.1	Sponsor Notification	44

12.4.2	Communicating and Interacting with Auditors	44

12.4.3	Responding to Audit Findings	44

13	STUDY COMPLETION AND CLOSE-OUT PROCEDURES	45

13.1	Participant Notification	45

13.2	Site Procedures	45

13.2.1	Data Locking Procedures	45

13.2.2	Return / Destruction of Remaining Test Article	45

13.2.3	Final Disposition of Study Supplies	45

13.2.4	Close-Out Monitoring Visit	46

13.2.5	Final Study Report (regulated studies only)	46

13.2.6	Long Term Storage of Study Documentation	46

14	APPENDICES	47

15	Appendix A: List of Abbreviations	48

16	Appendix B: Dynamic References List	50

INTRODUCTION TO THE MANUAL OF PROCEDURES

{Example text:}

Purpose

A Manual of Procedures (MOP) is a handbook that guides a study’s conduct and operations. It supplements the study protocol by detailing a study’s organization, operational data definitions, recruitment, screening, enrollment, randomization, intervention procedures and follow-up procedures, data collection methods, data flow, case report forms (CRFs), and quality control procedures. The purpose of the MOP is to facilitate consistency in protocol implementation and data collection across participants and clinical sites. Procedures in the MOP should be followed with the same degree of vigor as those documented in the protocol. Use of the MOP increases the likelihood that the results of the study will be scientifically credible and provides reassurance that participant safety and scientific integrity are closely monitored.

This MOP is to be used as a reference document for policies and procedures related to the study entitled <insert protocol title>.

All staff members participating in the conduct of this study at participating institutions should have ready access to the MOP and be familiar with its contents. The current version of the MOP and archived versions are posted to the study web site: <insert website address, if applicable>.

Updating and Version Control

The MOP is a dynamic document that will be updated throughout the conduct of a study to reflect any protocol or consent amendments as well as the refinement of the CRFs and study procedures. As sections/chapters are revised, the MOP version information and date on the cover page and Table of Contents will be updated; the Summary of Changes table on the cover page will list the chapters that have changed and will include a general summary of those changes.

{You may choose to update the version date on all pages or only on those chapters that have been modified, for ease of identification. Document your study-specific choice herein.}

As the study progresses, <responsible party> will be responsible for documenting any recommended and approved changes to the MOP. <Responsible party> will incorporate all of the approved changes and will update the MOP periodically. When the revisions are final, the MOP will be posted to the study’s website or otherwise made available to all study personnel. All clinical sites will be notified that the MOP has been updated and is on the website via a numbered memo (see MOP Section 2.2.4), which will also summarize the changes that were made. Additionally, study coordinators will be reminded of the MOP update during the regularly scheduled monthly teleconference.

The author of an updated MOP chapter will ensure that all necessary changes are captured in the update and that the <document is -- or chapters are> up-versioned.

The Webmaster is responsible for document control of the MOP on the study website and for filing updates in a timely manner. The Webmaster will post updated MOP chapters on the website within 2 business days of receipt.

The site principal investigator or designee is responsible for on-site document control of the MOP and for filing updates in a timely manner.

If paper copies of the MOP are maintained in the Essential Documents binder, the study coordinator will print and store the updated materials in the binder. Outdated materials will be removed from the binder and filed in another location clearly marked “obsolete.”

ADMINISTRATIVE

Study Leadership Structure

{This section describes the study’s organizational scheme and provides a roster of members of the Coordinating and Clinical Centers and study committees. The study organization for large studies is generally depicted by an organizational chart. This section also describes the roles and responsibilities of the Clinical Centers, Data Management, Coordinating and/or Statistical Center, laboratories, and committees.}

Organizational Chart

{Include a chart if needed for large studies.}

Roles and Responsibilities

{The roster includes the names, roles, addresses, phone numbers, fax numbers, pager numbers, and e-mail addresses of study staff members, committee members, points of contact at the Data Coordinating Center and participating laboratories, the Safety Officer, and NIDCR staff.

Indicate who should be contacted for study issues, such as:

Protocol questions

Reporting an adverse event (AE)

Request for additional supplies

Enrolling/Randomizing a participant

Unmasking a participant (should not be done lightly)

Each site will maintain a Delegation of Responsibilities Log in the Essential Documents binder. This log associates investigator and/or site staff names with specific study responsibilities.

Relevant tools: Delegation of Responsibilities Log, Investigator Responsibilities and Good Clinical Practice Training Slides.}

Steering Committee

{Describe the composition and responsibilities of the Study Steering Committee or Executive Committee, as applicable.

The Steering Committee often fills the leadership role of large, multi-center studies, and is responsible for the overall direction of a study. The following areas typically fall under the purview of the Steering Committee:

Responsibility for the general design and conduct of the study

Preparation of the essential study documents, including the protocol, protocol amendments, MOP, and data collection forms

Review of data collection practices and procedures

Changes in study procedures as appropriate

Appointments to and disbanding of study implementation subcommittees

Allocation of resources based on priorities of competing study demands

Review of study progress and implementation of necessary steps to ensure the achievement of study goals

Review and implementation of recommendations from those responsible for safety monitoring

Review and response to other general advice and/or recommendations (e.g., from the NIDCR Program Official)

In large, multi-center studies with multiple coordinating centers (e.g., clinical, data, and statistical centers), an Executive Committee is often responsible for reviewing study progress and identifying and resolving issues. The NIDCR Program Official may be a member of this committee. The Executive Committee is the small study leadership group that guides the study’s implementation and operation.}

Policies and Procedures

Conflict of Interest (COI) and Financial Disclosure Policies

{Refer to the following: http://grants.nih.gov/grants/peer/COI_Information.pdf}

Protocol Amendment Procedures

{Describe who will make decisions regarding protocol amendments. State the requirements for IRB approval and adherence to the amended protocol.

Relevant tools: IRB Amendment Checklist.

Example text:}

Protocol amendments require approval by <individuals and/or committees> prior to submitting the amendment to the IRB. Written IRB approval of protocol amendments is required prior to implementation. Any amendment to the protocol will be adhered to by all study staff and will apply to all subjects.

Version Control of Study Documents

{Example text:}

Version control procedures will be used to manage changes to all study documents. Version control directions are found at the following site:
http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/VersionControlGuidelines.htm.

{You may choose to include more detail about version control guidelines/processes for key documents such as protocol and/or consent document amendments.}

Communication Plan

{For multi-center studies, describe how information about study data, specimen management, and routine study activities will be communicated. The plan may include scheduled conference calls and routine data submission. Routine administrative communications are required for scheduling training sessions or meetings. As members of the Steering Committee or subcommittees, the study site investigators should have ongoing communication with other members of the study leadership team, especially during protocol finalization. Once a study is operational, routine telephone calls among the clinical site coordinators are useful to build an esprit de corps, discuss issues, and share successful strategies. The communications should be documented by the designated coordinating center. The Steering Committee may also participate in routine calls once the study is implemented to discuss progress, issues, and potential solutions to problems.

Specific tools that may be of use for study communication include:

Telephone Log

Telephone Contact Form

Some multi-center studies use a numbered memo strategy to communicate important study information across sites in a consistent and well-documented manner. If you choose to implement a numbered memo approach, the following text can be customized and included in the MOP.

Example text for numbered memos:}

Numbered Memos

The objective of numbered memos is to document and communicate important study information to all investigative sites in a consistent manner. The numbering of the memos is intended to facilitate reference to the memos, as well as tracking and archiving of the memos.

Responsibilities

<Name of responsible party> may identify issues that require across-site communication/clarification above and beyond discussion during a Study Coordinator or Steering Committee meeting.

<Name of responsible party (e.g., Operations Committee or PI)> will identify an author and reviewer(s) for the memo.

<Name of responsible party> or designee is responsible for approving the memo. (Approval may be communicated via email from a PI or by signature on a version of the memo itself.)

The facilitators of the Steering Committee and Study Coordinator Meetings are responsible for including a discussion of each new numbered memo on the agenda for the corresponding meeting.

The Site Correspondence Manager or designee will be responsible for the email distribution of the numbered memos.

The <Webmaster> will store the numbered memo tracking spreadsheet and all numbered memos under “Numbered Memos” on study website.

All Clinical Investigators and Site (Study) Coordinators are responsible for reviewing each numbered memo. In addition, all other individuals identified in the “TO” or “CC” lines of the memo are responsible for reading the memo (i.e., site pharmacists, regulatory coordinator, lab techs, etc.).

Study Coordinators will ensure that all relevant site staff members are aware of the memo and that all numbered memos are stored in the site’s Essential Documents binder.

Procedures

{Identifying the need for -- and the owners of -- a numbered memo}

If a study issue or new information is of enough complexity and importance to require a numbered memo, then the <Responsible individual or committee (e.g., Operations Committee or Executive Committee)> will identify an author and the reviewers for the memo. Examples of items that may trigger the generation of a numbered memo are 1) establishing a new process for distribution of study drug or 2) an update to the process for communicating Serious Adverse Events.

The Site Correspondence Manager will track all aspects of the generation, review, approval, and distribution of the numbered memos.

Creating, Reviewing, and Approving a New Numbered Memo

Structure of Memo: Memos will be numbered consecutively, starting with #001. The numbered memo will include a standard memo heading with TO, CC, RE, and the date of issuance. It will also contain a “Site Action Required” section in the header. This section is designed to communicate whether the memo requires some action on the part of the site or whether it is being provided for informational purposes only. The body of the memo will provide the details of the information.

The author will identify the required time frame for completion of the numbered memo and will be responsible for managing the production, review, and approval process. The author is responsible for confirming that he/she is using the appropriate number for the memo.

All memos must be approved prior to electronic distribution to the sites. It is not necessary to distribute the signed version of the memo to the sites.

A copy of the original numbered memo with the PI/designee’s email and signed approval will be kept at the coordinating center (i.e., the group responsible for maintaining the study master file).

Distributing a New Numbered Memo

An electronic version of each numbered memo will be emailed to the study coordinator(s), clinical investigators (CIs), and other relevant study personnel. (Note: It is not necessary to email the signed version of the memo.)

Each memo will also be posted on the website under “Numbered Memos” on the website.

Reading and Archiving Numbered Memos

The local PIs and study coordinators will read each numbered memo. Copies of the numbered memos will be stored in each site’s Essential Documents binder.

Amending Information in a Numbered Memo

If it becomes necessary to correct a numbered memo, a new memo will be distributed with the same memo number and will include a _Corrected_Date designation (e.g., Memorandum #005_Corrected_20JULY2010).

The nature of the corrections will be identified in the header of the memo.

If a study decision changes the guidance in a previous numbered memo, a new numbered memo will be issued and will refer to the numbered memo being superseded. This status of the previous numbered memo will be highlighted on the website as well.

Clinical Trial Registry/ClinicalTrials.gov and PubMed

{Prior to subject enrollment, interventional clinical trials must be registered with ClinicalTrials.gov via a web based data entry system called the Protocol Registration System (PRS), which is maintained by the National Library of Medicine. For more information, see http://prsinfo.clinicaltrials.gov.

For NIH Clinical Center (intramural studies), the Office of Protocol Services is responsible for registering studies with ClinicalTrials.gov. In addition, NIH Public Access Policy requires the principal investigator to submit journal articles that arise from NIH funds to the digital archive PubMed Central.

The International Committee of Medical Journal Editors (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 (e.g., Phase I trials), would be exempt from registering in a public registry such as ClinicalTrials.gov.

Following completion of the study, the investigator is expected to publish the results of this research in a scientific journal. The ICMJE has adopted a trials-registration policy as a condition for publication. This policy requires that select clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals are considering adopting similar policies. For grants and cooperative agreements, it is the grantee Institution’s responsibility to determine the responsible party who must register the trial in an acceptable registry.

Results of select studies must be reported within one year of the completion of the final participant (see http://prsinfo.clinicaltrials.gov/results_definitions.html and US Public Law 110-85, Section 805 http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf for further details).

In this section, clarify the responsible parties and study-specific requirements for registration and results submission.}

Data Request Policy

{Describe the data request policy. Identify the individuals who can make a data request, the individuals responsible for handling the request, and the process for communicating the request status and delivering the data requested. The MOP should identify the types of data that may require a formal request, such as:

Data used for presentations

Data used for manuscripts or abstracts

Data used for unplanned analyses

The MOP should also describe the types of data that do not require a formal request, which may include:

Clinical data requested by the lab in order to determine the best method to analyze the data sample

Clinical data requested for quality control processing

Information regarding study monitoring, timelines, or other administrative needs

Information already listed in periodic reports}

Publication and Presentation Policy

{Investigators have a responsibility to the public to make study results available as soon as possible (see NIH Public Access Policy http://publicaccess.nih.gov/). The MOP should detail the publication policy so that data are not released inappropriately, authorship is predetermined, and manuscripts are subjected to rigorous review before they are submitted for publication. Please refer to your specific grant and/or Clinical Trials Agreement.

It is recommended that extramural grantee authors inform their Program Official of a manuscript or presentation prior to publication of presentation. For publications and presentations authored by an NIH employee or contractor, the author must submit the publication/presentation to the NIDCR Office of Communication for clearance prior to publication.}

Organizational Chart

{For large, multi-center trials, it is helpful to include an organizational chart, depicting the relationship of the clinical sites to the coordinating center and other support centers such as pharmacy and specimen repositories.}

Roles and Responsibilities

{The roster includes the names, roles, addresses, phone numbers, fax numbers, pager numbers and e-mail addresses of study staff members at each clinical site.}

Qualifications

{Example text:}

All CVs and licenses for participating site investigators and staff will be filed in the Essential Documents binder.

Safety Oversight Committee (or Safety Oversight)

{NIDCR requires safety oversight in one of four forms: Medical Monitor (MM), Independent Safety Monitor (ISM), Clinical Study Oversight Committee (CSOC), or Data and Safety Monitoring Board (DSMB; also known as Data and Safety Monitoring Committee [DSMC]). In this section, the type of safety oversight should be clearly identified and any study-specific oversight responsibilities should be described. A proposed safety monitoring plan should be included in the grant application for review by the NIDCR Medical Officer and Program Official.

Relevant tools: DSMB (or CSOC) Charter Template, NIDCR DSMB (or CSOC) COI Template.}

Roles and Responsibilities

{Describe the responsibilities of the MM, ISM, CSOC, or DSMB. ISMs and members of a CSOC/DSMB are selected because they possess the clinical expertise and knowledge of the design, monitoring, analysis, and ethical issues of the clinical research project that are necessary to protect participant safety and conduct a scientifically rigorous study. The CSOC/DSMB members must also ensure that they have no direct or indirect financial interest by signing a Conflict of Interest statement. (See http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/DataandSafetyMonitoring.htm).}

Membership

{A CSOC/DSMB charter describes membership. For studies with a CSOC/DSMB, include in this section the contact information for the members.}

Frequency of Meetings

{Describe the frequency of meetings, as stated in the charter.}

Scientific Advisory Board

{Example text:}

A scientific advisory board is responsible for concept review. Members are selected based on expertise in the area of investigation.

Roles and Responsibilities

{Describe any study-specific responsibilities of the scientific advisory board members.}

Membership

{Members are selected based on expertise in the area of investigation. List the contact information for members of the scientific advisory board.}

Community Advisory Board

{Example text:}

A community advisory board provides an opportunity for interested members of a community, especially clinical study participants, to understand the clinical research process and to share their input regarding the development, implementation and outcomes of specific clinical studies. The board may also provide technical assistance on issues related to recruiting and retaining study participants.

Roles and Responsibilities

{Describe the expected contributions of the community advisory board.}

Membership

{Members are selected based on interest or experience in the area of investigation. List the contact information for members of the community advisory board.}

REGULATORY

Regulations and Regulatory Bodies

{Example text:}

The National Institute of Dental and Craniofacial Research (NIDCR) supports clinical research and interventional clinical trials involving human subjects and must ensure compliance with human subjects regulations.

All clinical research and clinical trials supported by NIDCR shall comply with ICH and GCP guidelines.

Institutions engaged in research with NIDCR as a Federal Sponsor must comply with the Office of Human Research Protection (OHRP) regulations which include the relevant parts of 45 CFR 46 : Protection of Human Subjects (the Common Rule) and agree to the Terms of the Health and Human Services (HHS), OHRP Terms of the Federalwide Assurance (FWA).

NIDCR-supported clinical trials conducted under an FDA IND or IDE application must comply with relevant parts of CFR Title 21:

Title 21, Part 50, Protection of Human Subjects

Title 21, Part 54, Financial Disclosure by Clinical Investigators

Title 21, Part 56, Institutional Review Boards

Title 21, Part 312, Investigational New Drug Application

Title 21, Part 812, Investigational Device Exemptions

Refer also to:

http://www.nidcr.nih.gov/Research/toolkit/

Federalwide Assurance Documentation

{All studies requiring IRB oversight are subject to OHRP regulations and guidelines. See http://www.hhs.gov/ohrp/policy/engage08.html for a definition of engagement as noted below.

Example text:}

All institutions “engaged” in the conduct of the research will have in place a Federalwide Assurance (FWA) with the DHHS Office for Human Research Protections (OHRP). This assurance documents the institution’s commitment to the human subjects regulations.

Documentation of the following information will be stored in the sites’ files and will be confirmed prior to site activation:

IRB name

IRB OHRP registration number

IRB notification of protocol approval

Federalwide assurance number for institutions, sites, and other engaged participants

Protection of Human Subjects

{Example text:}

The National Institute of Dental and Craniofacial Research (NIDCR) supports clinical research and interventional clinical trials involving human subjects and must ensure compliance with human subjects regulations.

Informed Consent / Assent Process

{Informed consent is required for all subjects participating in an NIDCR-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 study, the investigator must have the IRB’s written approval for the protocol, and favorable opinion of the informed consent process and written form(s) and any other written information to be provided to the subjects.

The MOP should identify different consent forms that will be used for the study (e.g., screening, study participation, screening for human immunodeficiency virus, future use of specimens, plasmapheresis, assent form for minors).

Refer to ICH GCP E6, Section 4.8
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.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.html#46.116).

Refer also to Tips on Informed Consent

(http://www.hhs.gov/ohrp/policy/ictips.html).

Refer also to Informed Consent Checklist (http://www.hhs.gov/ohrp/policy/consentckls.html).

This section of the MOP also describes specific instructions regarding the process of obtaining informed consent. The MOP should delineate the necessary signatures based on the site's IRB requirements (i.e., the participant or legal representative, the investigator or person actually obtaining the consent, and a witness). The MOP should indicate where the consent document will be maintained and who will be provided with a copy of the document.

If there is a change in any of the study procedures that may affect the participant, the consent document must be revised and again approved by the IRB. Subjects who were enrolled in the study prior to such changes must sign the amended consent document.}

Documentation of Consent / Assent

{The International Committee on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines require that the participant or legal representative receive a copy of the signed and dated consent document. OHRP and the Food and Drug Administration (FDA) both require that the participant receive a copy, although it need not be a signed copy. The source documents should indicate that the consent document was signed, along with the date of signing. }

Translation of Consent and Assent Documents

{Consent documents must be in a language familiar to study participants. For further guidance on informed consent regulations see:

45 CFR 46.116

(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116), and

21CFR 50.20

(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=50.20).

If consent documents will be translated into another language, include information about the translated documents in this section.}

Re-consenting for Protocol Changes or Safety Updates

{Example text:}

If a consent document is revised due to changes in study procedures, subjects who were enrolled prior to the change, but are affected by the change, will be informed of the changes and will sign the amended consent document. If a consent document is revised due to changes in the risks or safety of the study, all active participants must sign the revised consent.

HIPAA Privacy Rule

{Investigators should review information provided in “Understanding the HIPAA Privacy Rule,” NIH Publication 03-5388 at http://privacyruleandresearch.nih.gov to determine how the Privacy Rule applies to them, their organization, and their specific research project. Insert the necessary guidelines into the MOP.}

Essential Documents

{Additional tools available: Essential Documents Binder Tabs; Guideline for Drug Master Files.

Example text:}

Essential documents are those documents that individually and collectively permit evaluation of both the conduct of a clinical trial and the quality of the data produced.

Paper versions of non-subject specific site documents will be filed in the study-specific Essential Documents binder.

Required Documents

{Example text (modify list as needed):}

The following essential documents must be retained at the study site, must be accurately maintained, and may be verified during study monitoring visits:

Site-specific documents:

The protocol and all protocol amendments

All versions of IRB approved consent documents

IRB documentation, approvals, and correspondence

Investigator brochure, product label, or drug information sheet

FDA Form 1572 and 1571

Financial disclosure forms

Study communication

Delegation of responsibilities log

Documentation of clinical research and study training

Screening and enrollment log

Study product records (e.g., pharmacy logs)

Specimen tracking logs

Serious Adverse Events (SAEs)/Unanticipated Problems

Protocol deviations

Documentation of clinical site monitoring visits

Subject-specific documents:

Completed case report forms

Data correction forms

Workbooks

Source documents (e.g., lab reports, ECG tracings, x-rays, radiology reports, etc.)

Signed consent documents

Questionnaires completed by the participant

Document Maintenance

{Specify the length of time for the investigator to maintain all records pertaining to this protocol and indicate whether permission is required (and from whom) prior to destruction of records. Please consider institutional requirements as well as federal laws when preparing this section.

Grantees generally must retain all study records for a period of 3 years from the date the grant federal financial report (FFR) is submitted to the NIH. Note that other laws or local IRB policies may mandate a longer period for record retention than NIH requires.

IND retention rules require that documents are maintained until 2 years either post-licensure or withdrawal of the IND.}

SITE QUALITY MANAGEMENT PLANS

{Data integrity and study credibility depend on factors such as ensuring adherence to the protocol, protecting the rights and safety of study participants, obtaining complete follow-up information on all enrolled subjects, and using quality control measures to establish and maintain high standards for data quality. A quality control (QC) plan should be developed before the study starts and should continue through completion. It may include standard operating procedures (SOPs), data and forms checks, monitoring, routine reports, and correction procedures. This section should name the individual responsible for the quality control plan, detail the various aspects of the plan, and describe any training and certification procedures.}

Informed Consent

{Describe the established quality procedures for confirming that informed consent was obtained prior to initiation of any study procedures. Suggest adding a cross-reference to section 3.3.}

Data Management

{Investigators should be aware that if they are conducting studies that will also be submitted to the FDA, electronic systems will need to be documented and validated. Guidance for electronic systems is found on the FDA website, Title 21 Code of Federal Regulations (21 CFR Part 11) Electronic Records; Electronic Signatures (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11).

Details of data validation efforts are located in Section 10.}

Research Specimen Management

{This section should include procedures for confirming the quality of the specimen collection, shipment, and tracking process (e.g., confirming that shipped specimens have been received, processed, and results provided to the clinical database).}

SITE PREPARATION

{Example text:}

NIDCR has a responsibility to ensure that mechanisms and procedures are in place to protect the safety of subjects in NIDCR-supported clinical research. Therefore, prior to subject accrual or enrollment the following elements of site preparation will be reviewed and approved by NIDCR:

IRB-approved clinical research protocol identified by version number and date

Documentation of IRB approval, including OHRP FWA number, IRB registration number, and IRB name

IRB-approved consent document that is used to document informed consent, identified by version number, date, or both

Plans for managing adverse events

Procedures for assessing and reporting adverse events

Plans for data and safety monitoring, and for monitoring of the clinical study site, pharmacy, and laboratory

Documentation that the grantee institution and all study staff responsible for the design or conduct of the research have received training in the protection of human subjects

Supplies for study conduct, including CRFs, specimen collection and lab materials, and shipping materials

Site initiation visit and study-specific training

Contract/grant, technology transfer, clinical trial agreements, and other agreements

Facilities Requirements

Clinical Research Area

{Provide details of the location(s) where subjects will be seen, including facility exam rooms, operating room, etc.}

Secure Document Storage

{Provide details of adequate locked storage space for study documents.}

Diagnostic Services

{Describe access to diagnostic services, including type, frequency of use, and location.}

Pharmacy Services

{Describe where and how the investigational product is to be stored, prepared, dispensed, and returned to the Coordinating Center or other designated organization. Provide instructions for completing drug accountability records and administration records.}

Laboratory Services

{Describe the laboratory services to be used for obtaining, processing, storing and shipping specimens, and for reporting of laboratory tests.}

Courier Services

{Describe courier services that may be used and indicate how records of shipments will be maintained. Include instructions on appropriate days during the week for shipping to ensure recipient will be available to receive delivery.}

Research Sample Storage

{Describe the storage facilities for research specimens and the procedures for specimen tracking.}

Staff Training

Human Subjects Protection Training

Good Clinical Practice Training

Protocol Training

{Example text (modify as needed):}

All study staff will receive training on all aspects of the protocol, to include:

Study Objectives

Inclusion/Exclusion Criteria

Protocol Deviations

Investigational Product

Treatment Timelines

Subject Visit Schedule

Screening, Treatment, and End of Study Visits

Laboratory Evaluations

Safety Monitoring and Stopping Rules

Treatment Interruptions or Discontinuation

Study-Specific SOP Training

Clinical Operations

{Example text:}

All study staff will receive training in the following areas of clinical operations:

Communication

Clinical Research Associate (CRA) Functions and Expectations for Sites

Site Visits

Investigator Responsibilities

Good Clinical Practice (GCP)

Essential Document Collection and Storage

IRB Reporting Requirements

Audits

Informed Consent Procedures

Query Process

Equipment and Supplies

{Describe the availability of adequate study equipment and supplies.}

PROTOCOL IMPLEMENTATION

{A primary purpose of the MOP is to ensure that study procedures are administered in the same way for all participants and across all sites. The following sections in the MOP describe procedures to ensure standardization in conduct of the clinical trial.}

Recruitment, Screening, and Enrollment

Recruitment Methods

{To assist clinical sites in recruiting study participants, this section of the MOP describes the target population and suggests recruitment strategies such as identifying primary care referral practices, publicizing the study at grand rounds, and using other forms of publicity.}

Pre-Screening

{To help ensure that clinical sites accrue participants with the same characteristics, this section provides a detailed discussion of the screening procedures utilized to identify and determine participant eligibility.}

Screening

{Describe procedures to be used for screening subjects based on inclusion and exclusion criteria listed in the protocol.}

Rules for Re-screening

{If applicable, describe rules and procedures for re-screening subjects after amelioration of conditions listed as exclusion criteria.}

Establishing Eligibility

{Potential study participants must meet all entry criteria described in the protocol prior to enrollment. This section defines the criteria, method for determination (e.g., blood pressure sitting down), and the specific forms needed to document eligibility (e.g., medical history form, physical examination form, criteria for diagnosis).}

Assigning Participant Identification (PID) Numbers

{Describe the system used to assign identification numbers to study participants.}

Enrollment Procedures

{Describe procedures for enrollment, including the use of web-based data entry systems and maintenance of an enrollment log and screening failure log, if applicable. Relevant tool: Site Screening and Enrollment Log.}

Randomization

{If applicable, describe the randomization process, including:

Process Responsibilities

Procedure for Randomizing a Participant

Documentation of Randomization}

Masking/Blinding

{Describe procedures to maintain masking. There is a movement to use the term “masking” rather than “blinding” because it is perceived to be more politically correct. In addition, using the term “blinding” in ophthalmologic studies takes on an entirely different connotation.

Describe the procedures for unmasking, along with procedures for documenting the unmasking event. The unmasking procedures should include:

ID of unmasked participant(s)

Reason for unmasking study staff

Person responsible for unmasking study staff

List of person(s) who are unmasked (including the subject/participant, if applicable)}

Detailed Description of the Study Intervention

{The MOP describes the study intervention, which may include drugs, surgery, devices, bio-behavioral activities (e.g., coping mechanisms), and/or lifestyle changes (e.g., diet, exercise). The intervention must be thoroughly described so that all sites, investigators and participants have the same information.

For a Drug intervention, a detailed description of the information that must be provided is documented in the ICH E6 Good Clinical Practice Guidelines. See: (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf).

Device studies require a detailed description of the device and its intended use. Information on device studies is provided in the Code of Federal Regulations (CFR) Title 21, Parts 800-1299, revised as of April 1, 2000. See: http://www.gpo.gov/fdsys/pkg/CFR-2000-title21-vol8/pdf/CFR-2000-title21-vol8-chap-id6.pdf.

Surgical studies require a detailed description of the procedure.

For bio-behavioral and lifestyle studies, describe how the intervention is to be carried out.}

Detailed Description of Study Procedures

{Include details of specific procedures in this section only if full clarification requires details above and beyond those provided in the protocol. You may choose to pull in existing SOPs or attach them as appendices and reference them here.}

Schedule of Events

{If not included in the protocol, provide a schedule of visits and evaluations that specifies what is to be done at each study phase and at each contact with the study participant. Specify the schedule for each evaluation (e.g., five hours after the last dose of study drug/placebo administration).}

Visit Windows

Rules for Rescheduling Visits

Order of Visit Activities

Rules for Rescheduling Events

Missed Visits and Procedures

Protocol Deviations and Violations

{Describe plans for detecting, reviewing, and reporting deviations from the protocol. Protocol deviations must be sent to the local IRB per their guidelines.}

PROCEDURES FOR MANAGING TRIAL PROGRESS

Enrollment

{Assign the responsibility for tracking enrollment and providing enrollment reports to study staff or to multiple clinical sites.}

Visit Completion

{Assign the responsibility for recording and reporting data on completed visits.}

Outstanding and Missing Data

{Assign the responsibility for detecting missing data and notifying clinic staff.}

Data Entry Errors

{Assign the responsibility for detecting and correcting data entry errors.}

Protocol Deviations/Violations

{Describe procedures for reporting and compiling information on protocol deviations.}

Serious Adverse Events

{Describe procedures for reporting and tracking serious adverse events.}

TEST ARTICLE

{This section is used to describe the test article for drug or device studies. Insert information for each applicable section below.

Relevant tool: Study Product Guidelines and Considerations}

Obtaining Test Article

Storage Conditions and Stability

Reconstitution (if applicable)

Ordering Test Article

Dispensation of Test Article to Clinical Staff

Treatment Regimen and Administration

Participant Counseling

Monitoring Subject Compliance

Test Article Accountability

Return and Destruction of Test Article after Study Completion

Compliance with Good Manufacturing Practice Standards

SAFETY ASSESSMENT AND REPORTING

{This section of the MOP details the procedures for assessing and reporting safety.

Relevant tools: Serious Adverse Event Form and Completion Instructions; Adverse Event Form; Adverse Event Log; Unanticipated Problem Form; Safety Definitions for Clinical Research.}

SAE Reporting

{Provide a definition of a serious adverse event (SAE) and describe the procedures for reporting SAEs.}

Expected Adverse Events

{Describe adverse events that are expected to occur with the study intervention.}

Toxicity Tables

{If the protocol uses toxicity tables for determining toxicity from treatment as measured by clinical laboratory values, describe the grading system and the procedures for reporting toxicity due to study treatment.}

Prohibited Medications

{This section could include a detailed list of names of excluded medications, which are often named by category in the protocol (e.g., NSAIDS).

Describe a process for recording/reporting the on-study use of prohibited medications.}

Unanticipated Problems

{Provide a definition of unanticipated problems and describe the reporting procedures. See the OHRP guidance at http://www.hhs.gov/ohrp/policy/advevntguid.html.}

Pregnancy Testing and Counseling

{Describe procedures for pregnancy testing prior to study enrollment and counseling of subjects who become pregnant during the study.}

DATA MANAGEMENT

{This section describes the data collection, management and validation that will support the study and details how data are to be entered, edited and corrected. For studies that involve a large number of sites and/or participants, the investigators may wish to consider a computerized approach. In this case, the MOP should include a description of the computer system used to support the study and a copy of the User’s Guide.

Whether using a computerized or manual approach for data management, the MOP should describe procedures for data flow, transfer of data from sites in a multi-center study, handling of error identification and resolution, identification of useful reports, and deriving a frozen analytic database from edited or "clean" records.}

Data Collection Methods

{Describe the management of participant medical data collected on source documents, such as lab reports, ECG tracings, medical records, standardized test forms, and laboratory reports.}

Source Documentation Requirements

{Example text:}

The source document is defined as the first place the data are recorded. The <Responsible Party> may (will) provide source document templates, derived from the CRFs, to support data collection. However, these templates should only be used if the data are not originally recorded elsewhere. That is, data from one source should never be transcribed onto a worksheet and then subsequently entered into the CRF. This unnecessarily increases the risk of transcription errors.

In some instances, staff might need documentation from their own or other institutions (e.g., laboratory reports or a hospital report for an SAE). In this case, please request a copy of the record from the institution. It is also recommended that copies of records from outside the clinical research site be added to the subject’s binder.

All source documents should be completed by the clinician (or other appropriate study personnel). Data entries into source documents should be made in blue or black ink. Corrections should be made with a single line through the entry and the change initialed and dated. Original entries should remain legible (i.e., they should never be erased or covered with correction fluid to obscure the original entry). Late entries (e.g., laboratory results on the Eligibility Checklist) should be initialed and dated at the time entered.

Data should be handled in accordance with GCP, U.S. federal regulations, local regulations (if applicable), and instructions from NIH. All source documents should be filled out completely by the examining personnel or the study coordinator and should be signed by the person collecting the data on that form. The source documents are reviewed, signed and dated by the principal investigators or study staff designated by the principal investigators.

Source documents for subjects who are screened but not enrolled must be retained following the same guidelines as other study source documents.

Study Forms

{Study forms, also called case report forms (CRFs), provide the vehicle for consistent data collection. Describe who is responsible for producing and distributing forms; how the forms are manifested (e.g., electronic data capture or paper), packaged or placed in a binder for each participant; how they are to be maintained; and who should be contacted in the event that additional forms are needed.}

Case Report Form Completion Guidelines

{Describe study-specific requirements for completion of case report forms or note when these guidelines are printed on the paper CRF or embedded in the EDC system.}

Data Error Detection and Correction

{Provide specific instructions for detecting and correcting errors on source documents and on paper CRFs, if applicable.}

Data Quality Management

{This section describes the data management approach that will support the study and details how data are to be entered (if eCRF), edited, and corrected. The MOP may describe:

Data Tracking

Data Entry

Data Editing

Updating

Reporting

If applicable, include a description of the computer system used to support the study and a copy of the User’s Guide.}

Data Provided from an Entity Other than the Clinical Site

{External data refers to data not obtained directly at/from the clinical site and entered onto the CRF. Some examples are laboratory data, MRI assessment reviewed and recorded by a central reviewer, and other data evaluated by an adjudication committee.

This section of the MOP should describe how this information will be gathered, integrated into the clinical database, and validated.}

Data Collection and Data Processing Flowchart

{Provide a flowchart or description of data flow between the study site(s), laboratories and data coordinating center.}

Creating and Distributing Revised Case Report Forms

{Assign the responsibility for revising case report forms and distributing them to the study site(s).}

Long Term Storage of Case Report Forms

{Investigators should retain case report forms and all other study documents for the longest applicable period, stated in Section 3.4.2 of the MOP. Provide instructions to site and study staff that they will need to determine how documents will be maintained (electronic copies, paper files in boxes), location and length of time documents will be maintained.}

Maintaining Data Privacy

{Describe the precautions put in place to ensure that data are handled in ways that protect the privacy of personal health information. See Section 3.3.5.}

SPECIMEN AND LABORATORY MANAGEMENT

{This section should describe processes for collecting and managing the shipment of laboratory samples, MRIs, photographs, audio tapes, and other study participant samples and data to facilities external to the clinical site. Describe how specimens and the information obtained from them will be collected, labeled, handled, shipped, and tracked so that study data are not lost. Personal identifiers such as name, geographic location, social security number, and fifteen other specific individual identifiers should not be used. Refer also to: (http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html).

Ensure that each different type of specimen is considered. In this context, “Lab” refers to the institution that processes a specific type of specimen.}

Specimen Collection

{This chapter includes a suggested organizational structure. However, as with other areas of this template, you may choose an alternate structure to meet the needs of the study and/or the materials you have available. For example, you may prefer to include your SOPs in this section and divide Section 11.1.2 by specimen type, such that each specimen section includes the listed details from 11.1.2.1-11.1.2.5.}

Overview

{Clarify the general scope of the specimen collection and tracking process.}

Detailed Information for Each Specimen

Equipment and Supplies

Collection Procedures

Specimen Labeling

Shipping and Handling Procedures

Contact Information for the Laboratory(ies)

Specimen Tracking

Overview of Tests to be Performed in Each Lab

Laboratory Staff

Roles and Responsibilities

Good Clinical Lab Practice Training

IATA Training and Certification

{This training is required for individuals who prepare shipments of biological specimens that are sent outside of an institution.}

Laboratory Certifications and Quality Assurance Plans

Laboratory Procedures

{This section describes the procedures once specimens have been collected from subjects.}

Specimen Acquisition

Specimen Storage and Tracking

Detailed Instructions for Processing Individual Specimen Types

Laboratory Data Management and Storage

SITE MONITORING

{Based upon a monitoring plan, this section of the MOP describes the timing of monitoring visits, the logistical needs and activities involved in site monitoring, and the requirements for responses to monitoring reports or regulatory audits. At a monitoring visit, the monitor may review study documents to ensure that:

Adverse events have been identified and recorded

Information recorded on the case report forms is complete and accurate

There are no omissions of specific data elements in the reports

Missing examinations are indicated on the case report forms

Participant disposition at study exit is accurately recorded}

Purpose of Site Monitoring

Clinical Monitoring Logistics

{For most studies, a separate Clinical Monitoring Plan will be issued. This section should include only those logistical details of clinical monitoring that are relevant for the clinical sites.}

Frequency of Visits

Scope of Monitoring Activities

Monitoring Reports

Communication Plan

Facilitating the Site Monitoring Visit

Scheduling the Visit

Securing Space for Monitors

Preparing Study Documentation for Review

Arranging for Access to Medical Records

Wrap-Up Meeting

Responding to Request for Corrective Action

Preparing for Audits by Regulatory Authorities

Sponsor Notification

Communicating and Interacting with Auditors

Responding to Audit Findings

STUDY COMPLETION AND CLOSE-OUT PROCEDURES

{Describe study close-out activities performed to confirm that the site investigator’s study obligations have been met and post-study obligations are understood. Such close-out activities may include:

Verification that study procedures have been completed, data have been collected, and study drug and supplies have been returned to the responsible party or prepared for destruction

Review of investigator’s correspondence and study files against the coordinating center's records for completeness

Assurance that all data queries have been completed

Assurance that correspondence and study files are accessible for external audit

Reminder to investigators of the ongoing responsibility to maintain study records and to report any relevant study information to NIDCR

Meeting with the site investigators to ensure that they are aware of regulatory obligations and requirements for record retention

Assurance that the investigator notifies the IRB of study completion and obtains a copy of the notification

Preparation of a report summarizing study conduct}

Participant Notification

{Based upon the protocol, this section of the MOP may describe the plan to notify participants that the study is over, ask whether they would like to be informed of the results, and thank them for their participation.}

Site Procedures

{The MOP may describe procedures at end of study that include:}

Data Locking Procedures

Return / Destruction of Remaining Test Article

Final Disposition of Study Supplies

Close-Out Monitoring Visit

{Describe the activities that will occur during the close-out monitoring visit, which may include reviewing:

Informed consent documentation

Investigator site file

Source documentation and CRFs

SAEs and unanticipated problems reporting

Laboratory samples

Records retention

Additional details may also be included in the clinical monitoring plan.}

Final Study Report (regulated studies only)

Long Term Storage of Study Documentation

APPENDICES

Appendix A: List of Abbreviations

{Abbreviations on this list are examples. Please modify the list to include terms specific to your Protocol and Manual of Procedures.}

AE	Adverse Event/Adverse Experience
CDCC	Clinical Data Coordinating Center
CFR	Code of Federal Regulations
CIOMS	Council for International Organizations of Medical Sciences
CONSORT	Consolidated Standards of Reporting Trials
CRF	Case Report Form
CRO	Contract Research Organization
CSOC	Clinical Study Oversight Committee
DCC	Data Coordinating Center
DHHS	Department of Health and Human Services
DMFS	Decayed, Missing, and Filled Tooth Surfaces
DSMB	Data and Safety Monitoring Board
DSMC	Data and Safety Monitoring Committee
eCRF	Electronic Case Report Form
FDA	Food and Drug Administration
FWA	Federalwide Assurance
GCP	Good Clinical Practice
HIPAA	Health Insurance Portability and Accountability Act
IATA	International Air Transport Association
IB	Investigator’s Brochure
ICH	International Conference on Harmonisation
ICMJE	International Committee of Medical Journal Editors
IDE	Investigational Device Exemption
IND	Investigational New Drug Application
IRB	Institutional Review Board
ISM	Independent Safety Monitor
JADA	Journal of the American Dental Association
JAMA	Journal of the American Medical Association
MedDRA	Medical Dictionary for Regulatory Activities
MOP	Manual of Procedures
N	Number (typically refers to subjects)
NDA	New Drug Application
NEJM	New England Journal of Medicine
NIDCR	National Institute of Dental and Craniofacial Research, NIH, DHHS
NIH	National Institutes of Health
OCTOM	Office of Clinical Trials Operations and Management, NIDCR, NIH, DHHS
OHRP	Office for Human Research Protections
OHSR	Office of Human Subjects Research
PHI	Protected Health Information
PI	Principal Investigator
QA	Quality Assurance
QC	Quality Control
QM	Quality Management
SAE	Serious Adverse Event/Serious Adverse Experience
SOP	Standard Operating Procedure
US	United States
WHO	World Health Organization

Appendix B: Dynamic References List

{Include the list of dynamic references here. These are items that are not included in the MOP. Some may be developed to guide non-site-specific activities. Others may change too often to be included in the MOP proper. Some examples include:

Key Roles/Contact Information

Data Management Plan

Safety Management Plan

Clinical Monitoring Plan

Statistical Analysis Plan

Data Safety and Monitoring Plan}