**National Institute of Dental and Craniofacial Research\***

**Guidelines for Developing a Manual of Procedures (MOP)**

***November 15, 2002***

\*Adapted with permission from National Institute of Arthritis and
Musculoskeletal and Skin Diseases Revised Guidelines for Developing a
Manual of Operations and Procedures (MOP); June 5, 2002

  -----------------------------------------------------------------------
  **TABLE OF CONTENTS**

  -----------------------------------------------------------------------

**1.0** **INTRODUCTION** 4

**2.0** **OVERVIEW** 6

**3.0** **MOP CONTENTS AND ORGANIZATION** 7

3.a Study Protocol 8

3.b Schedule of Visits and Evaluations 8

3.c Study Organization, Centers, Committees 10

3.c.1 Study Chair 10

3.c.2
Roster\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....10
3.c.3 Coordinating Center 11

3.c.4 Clinical Sites 11

3.c.5 Pharmacy Activities 12

3.c.6 Steering Committees [12](#c.6-steering-committee)

3.d Recruitment, Screening, and Eligibility Criteria
[13](#d-recruitment-screening-and-eligibility-criteria)

3.d.1 Screening [13](#__RefHeading___Toc530198554)

3.d.2 Eligibility Criteria [13](#d.2-eligibility-criteria)

3.e Informed Consent [14](#e-informed-consent)

3.e.1 Informed Consent Process [16](#e.1-informed-consent-process)

3.e.2 Informed Consent Document [16](#e.2-informed-consent-document)

3.f Randomization [17](#f-randomization)

3.f.1 Blocked Randomization [17](#f.1-blocked-randomization)

3.f.2 Stratified Randomization [18](#f.2-stratified-randomization)

3.f.3 Blocked and Stratified Randomization 18

3.f.4 Randomization Procedures [18](#f.4-randomization-procedures)

3.g Masking and Unmasking 19

3.h Study Intervention 19

3.i Participant Evaluations and Follow-Up 21

3.j Study Completion [21](#j-study-completion)

3.k Concomitant Medications 21

3.l Adverse Events 21

3.l.1 Adverse Event Reporting 22

3.l.2 Serious Adverse Event Reporting 22

3.m Data and Safety Monitoring Activities
[26](#m-data-and-safety-monitoring-dsm-activities)

3.m.1 Monitoring Plans [27](#m.2-dsmb-membership)

3.m.2 DSMB Membership 27

3.n Study Compliance 27

3.o Data Collection and Study Forms 28

3.o1 Study Forms 30

3.o2 General Instructions for Completing Forms 30

3.o3 Performing a Quality Control (QC) Check 30

3.o.4 Submitting Forms 31

3.o.5 Retention of Study Documentation 31

3.o.6 Administrative Forms 31

3.p Data Management [32](#p-data-management)

3.p.1 Data Collection Options 32

3.p.2 Data Management Process [33](#p.2-data-management-process)

3.q Good Clinical Practice [33](#q-good-clinical-practice)

3.q.2 Monitoring [33](#q.1-monitoring)

3.r Reports [34](#r-reports)

3.s Policies [34](#s-policies)

3.s.1 Confidentiality Procedure [34](#s.1-confidentiality-procedure)

3.s.2 Publications [36](#s.2-publications)

3.t MOP Maintenance [36](#t-mop-maintenance)

**4.0 SUMMARY** [36](#summary)

**REFERENCES** [37](#references)

**RELEVANT WEB SITES** 39

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  **FIGURES**

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**Figure 1:** Generic Time and Events for Clinical Research Study 9

**Figure 2:** Sample Adverse Event Form 24

**Figure 3:** Sample Serious Adverse Event Report Form 25

**Figure 4:** Sample Protocol Violations Log 29

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  **WEB LINKS**

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NIH and the Academic Research Community: Partnerships for Clinical
Trials (<http://www.nih.gov/about/director/Speeches/aamc57.htm>)

> Further Guidance on Data and Safety Monitoring for Phase I and Phase
> II Trials
> (<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html>)
>
> *NIH Policy for Data and Safety Monitoring*
> (<http://grants.nih.gov/grants/guide/notice-files/not98-084.html>)
>
> Guidelines for Writing Informed Consent Documents

(<http://ohsr.od.nih.gov/info/finfo_6.php3>)

> *Clear and to the Point: Guidelines for Using Plain Language at NIH*
>
> (<http://www1.od.nih.gov/execsec/guidelines.htm>)

ICH E6 Good Clinical Practice Guidelines
<http://www.ich.org/pdfICH/e6.pdf>

> Code of Federal Regulations (CFR) Title 45, Part 46 Protection of
> Human Subjects
> (<http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm>)

[]{.mark}

> Guidance for Industry -- Medical Device Reporting -- Alternative
> Summary Reporting (ASR) Program
> (<http://www.fda.gov/cdrh/osb/guidance/315.html>)

# 1.0 INTRODUCTION

The National Institute of Dental and Craniofacial Research (NIDCR) is
the primary agency within the National Institutes of Health (NIH) for
research on dental, oral, and craniofacial diseases and disorders. As
part of its mandate, NIDCR supports numerous clinical research
activities. As our understanding of disease processes has grown along
with an expanded armament of potential interventions, the numbers of
clinical studies NIDCR supports have increased. In addition to the
increased numbers of clinical studies, their complexity has also
increased. The increased emphasis on studies that involve human
participants has stimulated a focus on the protection of human
participants and on study integrity. Thus, this document includes recent
policies and guidelines on protection of human participants and
conducting studies of the highest quality. A recent talk entitled *NIH
and the Academic Research Community: Partnerships for Clinical Trials*
by then Acting Director of the NIH, Ruth Kirchstein, M.D., summarized
the human participant protection issues and strategies of the NIH
\[<http://www.nih.gov/about/director/Speeches/aamc57.htm> (5/00)\].

A clinical study is a planned systematic investigation of a particular
problem (e.g., a disease or risk factors). A clinical trial is a planned
prospective human experiment that compares the outcomes of one or more
treatment, device, or behavioral interventions in a group of
participants with the outcomes of a control or comparison group
(Friedman, Furberg, and Demets, 1996; Gallin, 2002). Investigators can
initiate clinical trials through Investigator-Initiated Clinical Trial
grant applications that are funded using the Cooperative Agreement
mechanism. NIDCR may also support clinical trials through the Request
for Applications (RFA) or the Request for Proposals (RFP), both designed
to assist investigators in preparing an application for a clinical
trial. Because of the complexity of clinical trials, NIDCR recommends
that Investigators include a planning phase of up to 2 years in their
application \[*NIDCR Policy: Planning Grants for Clinical Trials*
(<http://grants1.nih.gov/grants/guide/pa-files/PAR-03-042.html>)\].

NIDCR must ensure compliance with Federal law and regulations, including
procedures and policies to protect the safety of all participants in the
clinical studies it supports. In preparing a grant application,
investigators must be aware of the terms of award with respect to
required reporting, data safety and monitoring, and Institutional Review
Board (IRB) approval
(<http://www.nidcr.nih.gov/clinicaltrials/clinical_trials_program.asp>).
Funded applicants must meet and adhere to the ***terms and conditions of
award*** that are incorporated into each cooperative agreement. This
process is summarized at
<http://www.nidcr.nih.gov/clinicalTrials/terms_conditions.asp>.

NIH monitoring policies for Phase I and II studies are described in the
NIH policy *Further Guidance on Data and Safety Monitoring for Phase I
and Phase II Trials*
\[<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html>
(6/00)\]. *NIH Policy for Data and Safety Monitoring* describes
requirements for Phase III studies \[[http://grants.nih.gov/grants/
guide/notice-files/not98-084.html](http://grants.nih.gov/grants/guide/notice-files/not98-084.html)
(6/98)\]. As of October 2000 grant applicants are required to submit an
IRB approved data safety and monitoring plan with provisions for
independent monitoring. Note the following:

-   ***Data Safety and Monitoring Plan -*** The Principal Investigator
    must include a data safety and monitoring plan in each new protocol.

-   ***Institutional Review Board (IRB) Approval -*** The IRB must
    approve the data safety and monitoring plan and must determine what
    kind of safety monitoring process (if any) is required.

-   ***Independent Monitor --***In consultation with the NIDCR Program
    Director/Project Officer, the Principal Investigator is responsible
    for appointing an independent monitor or convening a Data Safety and
    Monitoring Board (DSMB) if one does not already exist.

-   ***Provision of Data -*** The Principal Investigator or Coordinating
    Center is responsible for providing all required data to the study
    monitor or DSMB and for responding to any of their findings.

The clinical trial protocol provides a brief scientific rationale for
the proposed investigation, defines the study objectives and target
population, provides a detailed description of all study procedures and
interventions, defines end points, outlines the statistical plan, and
establishes procedures aimed to ensure patients safety and well-being.
Frequently, clinical trials are conducted at multiple clinical centers
in order to enroll an adequate number of participants into the study. A
study Manual of Procedures (MOP) is developed to facilitate consistency
in protocol implementation and data collection across patients and
clinical sites. Further, the MOP provides reassurance to all
participants that scientific integrity and patient safety are closely
monitored and increases the likelihood that the results of the study
will be scientifically credible. The NIDCR recognizes the importance of
a MOP. Thus, the purpose of this document is to assist investigators
that are conducting clinical studies by providing them with a template
for the preparation of a study\'s MOP.

# 2.0 OVERVIEW

During a study\'s planning phase, the investigators and their
institutional colleagues delineate the protocol. The study overview and
justification, study objectives, patient population and numbers, patient
eligibility, randomization, end points, assessments, treatment regimens,
definitions, data to be collected, statistical plan, endpoints, data
management plans, and data safety monitoring plans may be expanded and
refined. The protocol must be approved by the IRBs of all Institutions
that are participating in the study.

The MOP is analogous to a cookbook in that it details the study conduct
and operations. It transforms the study protocol into a guideline that
describes the study organization, operational definitions of the data,
patient recruitment, screening, enrollment, randomization, and follow-up
procedures, data collection methods, data flow, case report forms
(CRFs), and quality control procedures.

MOP development requires that the final protocol, CRFs, informed consent
documents, and administrative forms such as screening log, enrollment
log, etc., be completed. Additionally, if the study is conducted with a
pharmaceutical sponsor and is to be submitted to the Food and Drug
Administration (FDA), an Investigator\'s Brochure must be included.
Parenthetically, the timeline for development of study materials must be
planned for and typically takes several months to a year.

The MOP development process must involve the investigators and
coordinating center staff to ensure that the study will be performed as
intended. In multiple 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 must be 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. The MOP should be
maintained in a format that allows it to be easily updated. Further, it
is helpful to have each page of the MOP contain the version number and
date. As pages are revised, an updated version number and associated
date will replace the original page(s) in the MOP. All previous versions
should be archived.

# 3.0 MOP CONTENTS AND ORGANIZATION 

The MOP details the study procedures. At a minimum, it should include
the following sections:

a.  Study Protocol

b.  Schedule of Visits and Evaluations

c.  Study Organization, Centers, Committees

d.  Recruitment, Screening, and Eligibility Criteria

e.  Informed Consent

f.  Randomization

g.  Masking and Unmasking

h.  Study Intervention

i.  Participant Evaluations and Follow-up

j.  Study Completion

k.  Concomitant Medications

l.  Adverse Events

m.  Data Safety and Monitoring Activities

n.  Study Compliance

o.  Data Collection and Study Forms

p.  Data Management

q.  Good Clinical Practice

r.  Reports

s.  Policies

t.  MOP Maintenance

The above sections apply to all treatment, prevention, and diagnostic
trials. It also applies to all trials involving an intervention
regardless of whether the intervention involves drugs, surgical or
non-surgical procedures, behavioral activities or devices. In studies
where a section does not apply (e.g., concomitant medications), the
study investigators need not include it in the MOP. Each of the above
MOP sections is now described.

## 3.a Study Protocol

The protocol describes a statement of the problem, objectives, research
questions and hypotheses and should clearly articulate:

-   the study design

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-   primary and secondary endpoints

-   type and number of sites and centers, e.g., coordinating center

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-   patient population, including type of patient groups and associated
    numbers

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-   inclusion and exclusion criteria

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-   randomization plan

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-   screening process, baseline evaluation, study treatment and final
    evaluation

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-   masking /unmasking issues

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-   safety issues

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-   confidentiality/privacy issues

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-   internal review board (IRB) approval procedures

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-   informed consent procedures

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-   plans for and responsibilities of internal and/or external data and
    safety monitoring board (DSMB) or safety monitor

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-   statistical plan

The final version of the study protocol with the date of approval and
version number is included in the MOP.

## 3.b Schedule of Visits and Evaluations

A useful component of the MOP is a schedule of visits and evaluations.
This schedule delineates what is to be done at each study phase and at
each contact with the patient. An example of a schedule is provided in
Figure 1.

**FIGURE 1: Generic Time and Events for Clinical Trial\***

**\*Most Phase III trials will last more than 2 years given the need for
long-term follow-up.**

### 

## 3.c Study Organization, Centers, Committees

This section describes the study organization and provides a roster of
the coordinating and clinical centers, and study committees. The study
organization for large studies generally includes an organizational
chart and describes the roles of the study chair, clinical centers,
coordinating center, laboratories, committees and NIDCR.

3.c.1 Study Chair

The Study Chair is typically the person who conceived the idea for the
clinical trial and took the initiative to start the process of
developing the idea into a full-scale investigation. The Study Chair
provides the overall leadership for the clinical trial to ensure the
proper conduct and coordination among the different groups involved in
the conduct of the trial. The responsibilities of the Study Chair may
include but are not limited to:

-   serves as the scientific spokesperson for the clinical trial;

-   oversees and monitors the progress of the clinical trial;

-   oversees the development of the Manual of Procedures;

-   assists in resolving problems related to trial conduct at any of the
    centers;

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-   chairs the Steering Committee;

-   serves as the trial contact with the NIDCR on issues related to
    trial conduct ; and

-   coordinates the development of a roster of personnel involved in the
    clinical trial (see section 3.c.2).

### 3.c.2 Roster

The roster includes the names, roles, addresses, phone numbers, fax
numbers, pager numbers and e-mail addresses of study staff members,
committee members, Safety Office, and NIDCR staff.

A notation of whom to contact regarding the following special situations
should also be included:

-   reporting an adverse event

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-   request for an exemption to entry criteria

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-   randomizing a participant

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-   unmasking a participant

### 3.c.3 Coordinating Center

The responsibilities of the Coordinating Center may include but are not
limited to:

-   development and maintenance of the MOP

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-   randomization scheme and procedures

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-   development and implementation of data flow, schedules for
    transferring data from sites, and data tracking

-   development of procedures for data entry, error identification and
    error correction

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-   adverse event monitoring and reporting

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-   communications with clinical sites - scheduling of meetings and
    training sessions; responding to and documenting ad hoc
    communications

-   site visits to ensure adherence to the protocol and procedures

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-   quality control procedures (calibration of Clinical Examiners)

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-   reports - enrollment, adverse events, participant status (e.g.,
    drop-outs)

-   distribution of all changes, updates and policies of above mentioned
    reports and documents to all participating clinical sites

### 3.c.4 Clinical Centers

The roles and responsibilities of the Investigators and Clinical Centers
may include:

-   assuring that the study is conducted according to the protocol and
    MOP

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-   identifying, recruiting, screening and enrolling participants

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-   protecting participants\' rights

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-   obtaining informed consent from each participant

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-   collecting study data and following participants through study
    completion

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-   for drug treatment studies, controlling the distribution of the drug
    intervention under study

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-   retaining specific records, (e.g., laboratory drug distribution
    records)

-   preparing and sending required reports to coordinating center (e.g.,
    recruitment and enrollment, gender and minority breakdowns, adverse
    event reports)

-   assuring IRB review and approval of the protocol annually

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-   communicating questions, concerns, and/or observations to the Study
    Chair and/or Coordinating Center

### 3.c.5 Pharmacy Activities 

"Pharmacy" refers to the unit responsible for the storage, dispensing
and accountability for an investigational agent used in the trial, if
any. An actual pharmacy may or may not be directly involved in a study
at the clinical level (e.g., the investigational agent may be delivered
directly to the clinic or office participating in the study in
pre-labeled, sealed packages).

This section of the MOP describes how the investigational agent is to be
stored, prepared, dispensed, and returned to the Sponsor. It provides
instructions for completing drug accountability records and
administration records.

### 3.c.6 Steering Committee

In multicenter studies, the Steering Committee is generally responsible
for the overall direction of a study and is the main leadership
committee of the study. Frequently, the Steering Committee is comprised
of the study chair and the clinical and coordinating center Principal
Investigators.

The following areas typically fall under the purview of the Steering
Committee:

-   Responsibility for the general design and conduct of the trial and
    preparation of the essential study documents, including the
    protocol, MOP, and data collection forms

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-   Review of data collection practices and procedures

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-   Changes in study procedures as appropriate

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-   Appointments to and disbanding of study implementation subcommittees

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-   Allocation of resources based on priorities of competing study
    demands

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-   Review of study progress in achieving goals and taking necessary
    steps to enhance the likelihood of achieving those goals

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-   Review and implementation of recommendations from the DSMB approved
    by NIDCR

## 3.d Recruitment, Screening, and Eligibility Criteria

The goals of participant recruitment and screening are to quickly and
efficiently enroll eligible patients into the study. This section of the
MOP describes the target population, recruitment strategies, screening
procedures and eligibility criteria. The target population defines the
patients to be identified during the recruitment and screening process
and amplifies the disease or condition. The eligibility and exclusion
criteria are specifically defined and delineated to capture the target
population. []{#__RefHeading___Toc530198554 .anchor}

**3.d.1 Screening**

This section provides a detailed discussion of all screening procedures
outlined in the protocol to determine if a participant is eligible to
participate in the study. Frequently, there is a *pre-screening* phase
during which the study coordinator reviews medical or dental records,
hospital admissions or discharges, or responds to initial patient or
dentist/physician telephone inquiries.

A Screening Log may be used to monitor recruitment and document the
enrollment status of prospective study participants. The Screening Log
generally contains the patient\'s initials, age, gender, race, date and
time of hospitalization or office visit, participant status (whether the
participant is eligible for study participation, ineligible for study
participation and reason, or refused consent) and screening and
randomization number (if applicable). The MOP describes how sites will
maintain the Screening Log and its contents.

### 

### 3.d.2 Eligibility Criteria

Inclusion and exclusion criteria are protocol specific and are outlined
in the study protocol. Participants must meet all entry criteria prior
to being enrolled in the study. It should also delineate the necessary
procedures in seeking an exception, who is responsible for granting the
exemption, and the relevant forms used to document eligibility (e.g.,
medical history form, oral and / or physical examination form,
laboratory form). All data captured on the forms to support the
participant\'s enrollment in the study must be verifiable in the source
documents.

If the patient appears to be eligible for participation in the study,
informed consent must be obtained in order to accomplish screening
procedures, such as performing a physical exam and obtaining the
participant\'s demographic information, medical history and laboratory
results.

## 3.e Informed Consent

According to the *Guidelines for Writing Informed Consent Documents*,
\[<http://ohsr.od.nih.gov/info/finfo_6.php3> (08/00)\], informed consent
gives patients the opportunity to choose whether they want to
participate in a study. Informed consent requires:

-   Disclosure of relevant information to prospective participants about
    the research;

-   The participant's comprehension of the information; and

-   The participant's voluntary agreement to research participation
    without coercion or undue influence.

Informed consent is a process that involves:

-   Providing patients with adequate information concerning the study
    procedures and scope

-   Providing adequate opportunity for the patient to consider all
    available options

-   Responding to the patient's questions and concerns

-   Ensuring that each patient understands all information provided

-   Obtaining the patient's written voluntary consent to participate.

As required by 45 CFR 46
<http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm> when
obtaining informed consent, the following eight basic elements must be
addressed:

-   a statement that the study involves research, an explanation of the
    purposes of the research and the expected duration of the
    participant\'s participation, a description of the procedures to be
    followed, and identification of any procedures which are
    experimental;

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-   a description of any reasonably foreseeable risks or discomforts to
    the participant;

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-   a description of any benefits to the participant or to others which
    may reasonably be expected from the research;

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-   a disclosure of appropriate alternative procedures or courses of
    treatment, if any, that might be advantageous to the subject;

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-   a statement describing the extent, if any, to which confidentiality
    of records identifying the participant will be maintained and that
    notes the possibility that authorized persons may inspect the
    records;

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-   for research involving more than minimal risk, an explanation as to
    whether any compensation and an explanation as to whether any
    medical treatments are available if injury occurs and, if so, what
    they consist of, or where further information may be obtained;

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-   an explanation of whom to contact for answers to pertinent questions
    about the research and research participants\' rights, and whom to
    contact in the event of a research-related injury to the subject;
    and

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-   a statement that participation is voluntary, that refusal to
    participate will involve no penalty or loss of benefits to which the
    participant is otherwise entitled, and that the participant may
    discontinue participation at any time without penalty or loss of
    benefits to which the participant is otherwise entitled.

When appropriate, one or more of the following elements of information
shall also be

provided to each subject:

-   a statement that the particular treatment or procedure may involve
    risks to the subject (or to the embryo or fetus, if the subject is
    or may become pregnant) which are currently unforeseeable;

-   anticipated circumstances under which the subject\'s participation
    may be terminated by the investigator without regard to the
    subject\'s consent;

-   any additional costs to the subject that may result from
    participation in the research;

-   the consequences of a subject\'s decision to withdraw from the
    research and procedures for orderly termination of participation by
    the subject;

-   a statement that significant new findings developed during the
    course of the research which may relate to the subject\'s
    willingness to continue participation will be provided to the
    subject; and

-   the approximate number of subjects involved in the study.

### 3.e.1 Informed Consent Process

Specific instructions regarding the process of obtaining informed
consent must be detailed in this section*.* In offering participation in
the study to a patient, there should be ample time for the patient to
read the informed consent form. Additionally, the investigator,
coordinator or individual obtaining informed consent must discuss the
nature of the study, randomization and masking, study procedures,
importance of compliance, potential risks and benefits, and duration of
the study. The patient must be informed that he/she is not obligated to
participate in the study. The informed consent process should ensure
that there is no penalty for **NOT** participating in a clinical trial
and that treatment will not be compromised if patients do not
participate or cease participation at any time. Further, there should be
adequate time for the patient to ask questions. The instructions must
discuss the following:

-   *Describing study withdrawal* - the study withdrawal process based
    on the specific protocol, emphasizing that study participation is
    voluntary.

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-   *Signing the Informed Consent Form* - the necessary signatures based
    on the site\'s IRB requirements (i.e. the patient\'s signature/legal
    representative, the investigator or person actually obtaining the
    consent, and a witness).

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-   *Maintaining the Informed Consent Form* - where the informed consent
    form should be maintained and to whom a copy of the form should be
    provided.

### 3.e.2 Informed Consent Document

The written Informed Consent should be short and written in plain
language so that an individual or patient who has not graduated from
high school can understand the contents. According to *Clear and to the
Point: Guidelines for Using Plain Language at NIH*
\[[[http://www1.od.nih.gov/execsec/guidelines.htm]{.underline}](http://www1.od.nih.gov/execsec/guidelines.htm)
(8/00)\], it is recommended that public information materials be written
on a 4^th^ -- 8^th^ grade reading level.

NIDCR recommends that the Principal Investigator, study nurse and/or a
witness be present when the patient signs the informed consent document.
The International Committee on Harmonization (ICH) Good Clinical
Practice (GCP) guidelines require that the patient or legal
representative receive a copy of the signed and dated informed consent
form. Additionally, the investigator must maintain a signed copy of the
informed consent document for each patient in the study. The source
documents should indicate that informed consent was obtained.

If there is a change in any of the study procedures that may affect the
participant, the informed consent document must be revised and approved
by the IRB. Any patients enrolled in the study prior to a change in
procedures must sign the amended consent form.

NIH policy requires that studies conducted under a grant retain
participant forms for three years, while studies conducted under
contract must retain participant forms for seven years. Individual IRBs
may have different requirements for record retention. The FDA requires
that informed consent forms be retained for two years after a marketing
application is approved for a product or, if an application is not
approved, until two years after shipment and delivery of the product is
discontinued for investigational use and the FDA is notified.
Investigators should retain forms for the longest applicable period, and
this period should be stated in the MOP.

## 3.f Randomization 

The MOP should describe the randomization approach for the study. In
randomized, controlled clinical trials, participants are assigned to a
treatment group based upon a pre-determined randomization scheme
developed by the coordinating center. Randomization is introduced to
reduce bias in treatment selection.

Simple randomization assigns treatment groups without regard for
previous assignments. This approach can yield imbalance among groups.
The following is a brief description of randomization approaches.

### 3.f.1 Blocked Randomization

Blocked randomization reduces the likelihood of imbalance between
treatment groups. A block, which is an exact integer multiple of the
number of treatment groups, contains a balance of treatment assignments.
The order of the assignments is randomly assigned within the block, but
the block maintains a balanced assignment among groups.

### 

### 3.f.2 Stratified Randomization

To balance factors that may influence treatment outcome, such as age,
gender, or disease severity, randomization can be stratified. Each
combination of factors form a

Stratum, and randomization is allocated within each stratum. Thus, if
age and gender are the factors upon which to stratify, study stratum
could include:

-   men under age 60

-   men ages 60 and older

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-   women under 60

-   women ages 60 and older

    Within this study stratum, treatment allocation can be blocked to
    assure balance.

### 3.f.3 Blocked and Stratified Randomization

Blocking and stratification can also be combined to assure adequate,
relative size of treatment groups.

### 3.f.4 Randomization Procedures

This section of the MOP provides a full discussion of the randomization
procedures including:

-   ***[Process Responsibilities]{.underline}***: An individual who
    maintains the master randomization list must be identified. This
    person is responsible for assigning randomization codes, notifying
    appropriate study staff that the participant has been randomized and
    securely storing all randomized files.

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-   ***[Procedure for Randomizing a Participant]{.underline}:*** At each
    site, an individual who is responsible for initiating the
    randomization procedure must be identified. This individual must
    know who to contact once a participant is determined eligible for a
    study and which forms must be completed prior to randomization
    (e.g., informed consent form and participant eligibility form).

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-   ***[Documentation of Randomization]{.underline}:*** The person who
    will be responsible for completing the randomization log must be
    named at each site.

## 3.g Masking and Unmasking

In most studies with randomization, participants and the treating health
professional are \"blind\" or \"masked\" to the treatment and do not
know if the participant is receiving drug or placebo. The study
statistician and/or a designated study staff member keeps the
randomization assignment under \"lock and key\" so that the study
treatment assignments are not known. Randomization and masking/unmasking
procedures are typically determined prior to the enrollment of the first
participant *.*

Unmasking is a serious action and should be limited to reduce potential
bias. The DSMB and the NIDCR Project Officer must be involved in the
decision to

unmask and must grant approval for unmasking. In the event that
unmasking occurs, the following should be recorded:

-   ID of unmasked patient,

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-   reason for unmasked study staff,

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-   person responsible for unmasked study staff, and

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-   list of person(s) who are not masked.

Procedures for unmasking should be clearly specified in the MOP.

## 

## 

## 3.h Study Intervention

This section describes the study intervention in clinical trials. A
study intervention can be described as an effort to change the natural
course of a disease or condition by attempting to alter the risk factors
or precursors associated with that disease or condition. Interventions
include drugs, surgery, procedures, devices, biobehavioral activities
(e.g., coping mechanisms), and/or lifestyle changes (e.g., diet,
exercise).

All intervention studies require valid scientific evidence in order to
determine if the intervention is safe and effective. Types of
intervention studies are summarized as follows:

-   ***Phase I:*** Safety studies test a treatment for the first time in
    humans with a small group of participants in order to determine a
    safe dose range, identify side effects, and observe the treatment's
    effect on the participants. Phase I studies usually test the
    intervention using normal healthy volunteers and often do not
    involve a comparison group.

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-   ***Phase II:*** The study treatment is given to a larger group of
    participants with the disease or condition of interest to estimate
    effectiveness and further evaluate safety data. The main purpose is
    to provide preliminary information on treatment efficacy and to
    supplement information on safety obtained from Phase I trials. Phase
    II studies may be randomized and controlled.

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-   ***Phase III:*** Clinical trial done to determine efficacy of a
    treatment. Such a trial is usually designed to include a control
    treatment, some form of investigator and patient blinding, random
    allocation to treatment, and usually involves a few hundred
    participants.

Phase III trials usually involve several hundred or more human subjects
and may involve new drugs, treatments, devices or new ways of using
existing interventions for disease prevention, prophylaxis, diagnosis,
or therapy. Often the aim of such trials is to provide evidence leading
to a scientific basis for consideration of a change in health policy or
standard of care.

-   ***Phase IV:*** A study of an intervention that is designed to
    evaluate the long-term safety and efficacy of a treatment for a
    given indication after it has been accepted for use following phase
    III trials.

The intervention, whether medical treatment, device or behavioral
intervention, should be described comprehensively:

-   For ***drug intervention*** studies, the distribution, preparation
    and handling, labeling, and administration are detailed along with
    the duration of treatment and criteria for treatment
    discontinuation. A detailed description of the information that must
    be provided is documented in the ICH E6 Good Clinical Practice
    Guidelines. This document is available on the internet at Guidelines
    <http://www.ich.org/pdfICH/e6.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.access.gpo.gov/nara/cfr/waisidx_00/21cfrv8_00.html>).

-   For studies involving ***surgical or non-surgical interventions,***
    the procedure is delineated in sufficient detail to clearly and
    unambiguously define the procedure.

-   ***Biobehavioral*** and ***life style*** studies describe how the
    intervention is to be carried out.

## 3.i Participant Evaluations and Follow-Up

This section describes the baseline and follow-up evaluations and tests
for enrolled participants. All evaluations, as well as their schedule
and procedures for obtaining data, must be clearly stated in this
section. All efficacy (e.g., measures of oral or other diseases) and
safety evaluations (e.g., blood chemistries) should be delineated. The
schedule of when evaluations are to be obtained must be specific (e.g.,
every 3 months after the intervention was delivered).

## 

## 

## 3.j Study Completion

This section of the MOP must describe the evaluations that take place at
study completion, along with follow-up of participants who stop study
treatment or drop out of the study. Some studies are designed to follow
participants who stop treatment through the end of the study. The
approach to following participants who discontinue treatment and the
data that are to be collected should be detailed. A discussion of the
forms that are to be completed at each visit is discussed in Section
3.o.2, Study Forms.

## 

## 3.k Concomitant Medications

The MOP should discuss which concomitant medications are allowed or
restricted, if any in the protocol. The form used to collect concomitant
medication information and the period of time for which this information
will be collected must be described. Concomitant medication information
must be verifiable in the source documents.

## 3.l Adverse Events

This section of the MOP details the definitions of and procedures for
reporting adverse events. Relevant definitions, based on FDA Guidelines
for drug treatments (21CFR312.32, 21CFR314.80), guidances (ICHE6, Good
Clinical Practices), and devices (21CFR803 Subpart B and 21CFR803.20;
*Guidance for Industry - Medical Device Reporting - Alternative Summary
Reporting (ASR) Program 21CFR 803 Subpart B-End 803.20-End)* may be
found at *([http://www.fda.gov/cdrh/osb/guidance/
315.html](http://www.fda.gov/cdrh/osb/guidance/315.html)).*

Definitions include the following:

-   ***Adverse Event (AE)*** - An AE is any unfavorable and unintended
    diagnosis, sign (including an abnormal laboratory finding), symptom,
    or disease temporarily associated with the study intervention,
    whether or not related to the intervention.

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-   ***Serious Adverse Event (SAE)** -* An SAE is any untoward medical
    occurrence that results in death, is life-threatening, requires or
    prolongs hospitalization, causes persistent or significant
    disability/incapacity, results in congenital anomalies/birth defects
    or, in the opinion of the investigators, represents other
    significant hazards or potentially serious harm to research
    participants or others.

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-   ***Unexpected Adverse Event** -* An unexpected adverse event is an
    adverse reaction, the nature or severity of which is not consistent
    with the applicable product information (e.g., Investigator\'s
    Brochure for an unapproved investigational product/device or package
    insert/summary of product characteristics for an approved product or
    device).

### 

### 3.l.1 Adverse Event Reporting

Procedures for reporting adverse events are described in this section of
the MOP. All adverse events are collected, analyzed, and monitored by
using an Adverse Event Form, a sample of which is shown in Figure 2. All
adverse events experienced by the participant during the time frame
specified in the protocol (e.g., from the time study drug administration
to thirty days following the last administration of study drug) should
be reported. AEs include new events not present during the
pre-intervention period or events that were present during the
pre-intervention period but have increased in severity. Adverse events
and/or laboratory abnormalities identified in the protocol as critical
to safety evaluations should be reported as specified in the protocol.

### 3.l.2 Serious Adverse Event Reporting

Procedures for reporting serious adverse events are described in this
section of the MOP. All SAEs, unless otherwise specified in the protocol
and approved by the IRB, must be immediately reported by the Principal
Investigator to the study\'s responsible group, e.g., DSMB or safety
monitor, and NIDCR*.* All interventional studies, independent of phase
or type, must report SAEs. The immediate reports should be followed
promptly by detailed, written reports.

As shown on the sample SAE form in Figure 3 that is used for NIH
Intramural Programs, the following information must be provided with the
initial adverse event report:

-   Protocol number and title

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-   Name of principal investigator and site where SAE occurred

> \- Participant\'s I.D. number (site-specific reports only -- not to be
> submitted to IRB/DSMB)

\- Date and time of onset of the event

\- Description of the event and attribution to study drugs or
intervention

-   Brief description of participant, including gender and age

***FIGURE 2: SAMPLE ADVERSE EVENT FORM***

**Has the patient had any Adverse Events during this study?** **Yes**
**No *(If yes, please list all Adverse Events below)***

+-----------+---------+------------+------------+-------------+-----+
| **S       | **Study | **Action   | **Other    | **Outcome   | **  |
| everity** | Inter   | Taken      | Action     | of AE**     | Ser |
|           | vention | Regarding  | Taken**    |             | iou |
|           | Relatio | Study      |            |             | s** |
|           | nship** | Inte       |            |             |     |
|           |         | rvention** |            |             |     |
+-----------+---------+------------+------------+-------------+-----+
| 1 = Mild  | 1 =     | 1 = None   | 1 = None   | 1           | 1 = |
|           | Un      |            |            | =Resolved,  | Yes |
| 2 =       | related | 2 =        | 2          | No Sequela  |     |
| Moderate  |         | Di         | =Remedial  |             | 2 = |
|           | 2 =     | scontinued | The        | 2 =AE still | No  |
| 3 =       | U       | Perm.      | rapy-pharm | present- no |     |
| Severe    | nlikely |            |            | tx          | (If |
|           |         | 3 =        | 3          |             | y   |
|           | 3 =     | Di         | =Remedial  | 3 =AE still | es, |
|           | P       | scontinued | Therap     | pr          | co  |
|           | ossible | Temp.      | y-nonpharm | esent-being | mpl |
|           |         |            |            | tx          | ete |
|           | 4 =     | 4 =        | 4 =        |             | SAE |
|           | P       | Reduced    | hospi      | 4 =Residual | fo  |
|           | robable | Dose       | talization | effects     | rm) |
|           |         |            |            | present-no  |     |
|           | 5 =     | 5 =        |            | tx          |     |
|           | Def     | Increased  |            |             |     |
|           | initely | Dose       |            | 5 =Residual |     |
|           |         |            |            | effects     |     |
|           |         | 6 =        |            | present- tx |     |
|           |         | Delayed    |            |             |     |
|           |         | Dose       |            | 6 =Death    |     |
|           |         |            |            |             |     |
|           |         |            |            | 7 =Unknown  |     |
+-----------+---------+------------+------------+-------------+-----+

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Event</td>
<td>Start Date</td>
<td><p>Stop</p>
<p>Date</p></td>
<td>Severity</td>
<td>Relatedness</td>
<td><p>Action Taken</p>
<p>W/Study Drug</p></td>
<td>Other Action Taken</td>
<td>Outcome</td>
<td>Serious?</td>
<td>Initials</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

**FIGURE 3:**

**SAMPLE SERIOUS ADVERSE EVENT REPORT FORM**

1.  Protocol number: Protocol title:

2.  Principal Investigator:

    Institution: Office:

    Phone: FAX:

    E-mail:

3.  Date of serious adverse event:

4.  Location of serious adverse event:

5.  Was this an unexpected adverse event? Yes \[ \] No \[ \]

6.  Brief description of participant(s) with no personal identifiers:
    Sex: Age: Diagnosis:

7.  Brief description of the nature of the serious adverse event (attach
    description if more space needed):

8.  [Category (outcome) of the serious adverse event]{.underline}:

    \[ \] death \[ \] disability / incapacity

    \[ \] life-threatening \[ \] congenital anomaly / birth defect

    \[ \] hospitalization-initial or prolonged \[ \] required
    intervention to prevent permanent impairment

    \[ \] other:

9.  [Relationship of Serious Adverse Event to research]{.underline}:

\[ \] 1 = Unrelated (clearly not related to the research)

\[ \] 2 = Unlikely (doubtfully related to the research)

\[ \] 3 = Possible (may be related to the research)

> \[ \] 4 = Probable (likely related to the research)

\[ \] 5 = Definite (clearly related to the research)

10\. Have similar adverse events occurred on this protocol? Yes \[ \] No
\[ \]

If \"Yes\", how many? \_\_\_\_ Please describe.

11. What steps do you plan to take as a result of the adverse event
    reported above? Provide documentation to the IRB for review and
    approval of any of the steps checked below.

\[ \] no action required \[ \] amend protocol

\[ \] amend consent document \[ \] inform current participants

\[ \] terminate or suspend protocol

\[ \] other (describe)

> Signature of Principal Investigator:
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Date:
> \_\_\_\_\_\_\_\_\_\_\_

## 3.m Data and Safety Monitoring (DSM) Activities

With the increased concerns for patient safety, NIDCR has established
Data and Safety Monitoring Guidelines. These guidelines may be found at:
<http://www.nidcr.nih.gov/clinicalTrials/data_safety_guidelines.asp>.

All clinical trials supported by NIDCR must have a Safety Officer or a
Data Safety Monitoring Board (DSMB), that are independent of the study.
Phase I studies, which may be small single site studies, often have a
Safety Officer, while multi-center studies may require a DSMB. For Phase
II and III studies, the monitoring group is responsible for reviewing
the study data at regular intervals, including the interim analysis, and
determining if it is safe to continue with the study according to the
protocol.

DSM activities are established in order to protect the safety of human
participants and maintain and ensure the scientific integrity of the
study. The individual or group selected to monitor a study should
reflect the appropriate clinical expertise and knowledge of the design,
monitoring, and analysis of the project necessary to conduct an ethical
and scientifically rigorous study.

DSM activities include a review of the protocol with emphasis on data
integrity and patient safety issues, monitoring of adverse events,
protection of the confidentiality of the data and results, and
recommendations to the NIDCR and Principal Investigator regarding
continuation or conclusion of a study.

A description of the roles and responsibilities of the Safety Officer
and/or Data Safety and Monitoring Board (DSMB) should be described in
this section and generally include the following:

-   review protocol, informed consent documents, plans for data and
    safety monitoring;

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-   evaluate study progress, including periodic assessments of data
    quality, participant recruitment and retention, participant risk
    versus benefit, site performance, and other factors that may affect
    study outcome;

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-   consider external factors such as scientific or therapeutic
    developments that may impact on the safety of the participants or
    the ethics of the trial;

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-   protect the safety and scientific progress of the trial;

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-   make recommendations to the Principal Investigator, NIDCR, and, if
    required, to the FDA regarding continuation, termination, or other
    modifications to the study based on observed beneficial or adverse
    effects of the treatment under study; Recommendations should be in
    accordance with stopping rules, which are clearly defined prior to
    data analysis and have the approval of the DSMB;

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-   ensure data integrity;

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-   ensure the confidentiality of the trial data and the results; and

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-   assist NIDCR by providing recommendations on any problems with study
    conduct, enrollment, sample size, and/or data collection.

### 

### 3.m.1 Monitoring Plans

This section of the MOP should describe the specific study plans for
monitoring for patient safety and data integrity. A monitoring plan must
be submitted to and approved by the NIDCR Program Director prior to the
award for a clinical trial.

### 3.m.2 DSMB Membership

Members of a DSMB (and Safety Officers) are selected to reflect a mix of
appropriate clinical expertise and knowledge of the design, monitoring,
analysis and ethical issues of the clinical research project necessary
to protect patient safety and conduct a scientifically rigorous study.
([[http://www.nidcr.nih.gov/clinicalTrials/data_safety_guidelines.asp#membership]{.underline}](http://www.nidcr.nih.gov/clinicalTrials/data_safety_guidelines.asp#membership))

## 3.n Study Compliance

Clinical trials are expensive endeavors, and procedures should be
implemented to maximize adherence to the protocol, minimize participant
non-compliance and enhance participant retention in the study. Drug
accountability and other study procedures, such as ongoing communication
between study staff and participant, participant visits, etc. to
encourage patient compliance are described in this section. Likewise,
protocol violations and deviations as well as procedures to track them
and notify appropriate parties must also be described in this section.

Protocol violations include, but are not limited to, the following:

-   Randomization of an ineligible patient

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-   Failure to obtain Informed Consent

-   Entering a participant into another study

-   Failure to keep IRB approval up to date

-   Wrong treatment administered to participant

The MOP should state that these violations will be reported to the Study
Chair, the Coordinating Center, and to the NIDCR within 24 hours of
occurrence or as soon as they are discovered. In addition, if monitors
discover any of these violations during a monitoring visit, they should
notify the NIDCR of the occurrence.

The study Coordinating Center or responsible person in a single site
study should maintain a log of all protocol deviations and violations
and should report them routinely to the DSMB or Safety Officer. A sample
log is presented as Figure 4. While it is assumed that there may be
rational clinical reasons for an occasional violation, a site with
serious continual problems is at risk for losing its funding. Similarly,
subcontractors of the awarder may be made aware of repetitive violations
or deviations in this section.

## 3.o Data Collection and Study Forms

This section describes details of the data study collection and data
management procedures and should include copies of all forms. All study
documents must be retained by the investigator as described in Section
3.o5 below. The following are considered participant file documents:

-   Case report forms

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-   Data correction forms

-   Workbooks

-   Signed participant consent forms

Source documents are any documents on which study data are recorded for
the first time. Source documents include but are not limited to medical
records, study-specific source documents supplied by the coordinating
center or sponsor, standardized test forms and laboratory reports.

+---------+-------------+-------+------------+------------+-----------+
| P       | Participant | P     | Date       | Date       | Contact   |
| rotocol | Initials    | artic | Violation  | Protocol   | Person    |
| De      |             | ipant | Occurred:  | Violation  |           |
| viation |             | ID#   |            | Form       | (if       |
| Code:   |             |       | mm/dd/yyyy | Completed: | ap        |
|         |             |       |            | mm/dd/yyyy | plicable) |
+---------+-------------+-------+------------+------------+-----------+
|         |             |       |            |            |           |
+---------+-------------+-------+------------+------------+-----------+
|         |             |       |            |            |           |
+---------+-------------+-------+------------+------------+-----------+
|         |             |       |            |            |           |
+---------+-------------+-------+------------+------------+-----------+
|         |             |       |            |            |           |
+---------+-------------+-------+------------+------------+-----------+
|         |             |       |            |            |           |
+---------+-------------+-------+------------+------------+-----------+

+-----------------------------------+-----------------------------------+
| SAMPLE PROTOCOL VIOLATION CODES:  |                                   |
+-----------------------------------+-----------------------------------+
| 1.  Randomization of an           | 15. Consent form used was not     |
|     ineligible participant        |     current IRB-approved version  |
|                                   |     at time of participant        |
| 2.  Failure to obtain informed    |     registration                  |
|     consent                       |                                   |
|                                   | 16. Consent form was not protocol |
| 3.  Entering a (trial name)       |     specific                      |
|     participant in another type   |                                   |
|     of study                      | 17. Consent form does not include |
|                                   |     updates or information        |
| 4.  Failure to keep IRB approval  |     required by IRB               |
|     up to date                    |                                   |
|                                   | ADDITIONAL POTENTIAL PROTOCOL     |
| 5.  Participant receives wrong    | VIOLATION CODES:                  |
|     treatment                     |                                   |
|                                   | 18. Not reporting a serious       |
| 6.  Participant is randomized     |     complication within 24 hours  |
|     prior to Baseline Diagnosis,  |                                   |
|     Imaging Report                | 19. Completing a survey outside   |
|                                   |     the acceptable window for     |
| Form, Baseline Assessment, etc.   |     that survey                   |
|                                   |                                   |
| 7.  Participant seen outside      | 20. Missing data                  |
|     window of normal follow-up    |                                   |
|     visits                        | 21. Enrollment of an ineligible   |
|                                   |     patient                       |
| 8.  Missing radiology and/or      |                                   |
|     operative report              | 22. Randomization occurring       |
|                                   |     outside normal window         |
| 9.  Registration and/or treatment |                                   |
|     of participant prior to IRB   | 23. Center fails to submit and    |
|     approval                      |     transport data from their     |
|                                   |     onsite computer to the        |
| 10. Registration of participant   |     Coordinating Center           |
|     on protocol during a period   |                                   |
|     of delayed re-approval        | 24. Baseline Data (e.g. x-rays)   |
|                                   |     for participants were not     |
| 11. Reportable monitored events   |     obtained                      |
|     not reported to IRB           |                                   |
|                                   |                                   |
| 12. Consent form missing          |                                   |
|                                   |                                   |
| 13. Consent form not signed and   |                                   |
|     dated by participant          |                                   |
|                                   |                                   |
| 14. Consent form does not contain |                                   |
|     all required signatures       |                                   |
+-----------------------------------+-----------------------------------+
|                                   |                                   |
+-----------------------------------+-----------------------------------+

### 

### 3.o.1 Study Forms

This section details how study forms (also called case report forms) are
to be completed on a question-by-question basis. Each of the study forms
are included in the section with explanatory comments.

It also identifies who is responsible for producing and distributing
forms, how they are packaged (e.g., placed in a binder for each
participant), how the forms are to be maintained, and who should be
contacted in the event additional forms are needed. In addition, a list
of all study forms and the collection schedule is included.

This section should also describe where the forms are to be sent or
transmitted once they are complete.

### 

### 3.o.2 General Instructions for Completing Forms

All data recorded on forms must be verifiable in the source documents
maintained by the clinical site(s) according to FDA guidelines and good
clinical practice. This section should include instructions for
completing study forms.

### 

### 3.o.3 Performing a Quality Control (QC) Check

This section of the MOP describes the study quality control procedures.
With increased emphasis on scrutiny of clinical data, it is important to
conduct a quality control check of the study forms before entering the
data or submitting the forms to the coordinating center. Part of Good
Clinical Practice, discussed below in Section 3.q, is establishing
quality control procedures. The Coordinating Center and sites should
develop quality control procedures. Such procedures may specify the
following types of checks:

-   Numbers are not transposed in the site I.D and participant\'s I.D.
    number.

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-   Same participant I.D. number and initials recorded on all forms.

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-   There are no illegible handwritten items, spelling errors, etc.

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-   Placement of responses are clearly within designated spaces.

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-   All fields of a \"completed form\" are actually completed with
    participant data or reason for no data is noted in or near the
    field.

All required forms have been completed or reason for no data collection
is noted on the form.

### 3.o.4 Submitting Forms

It is the sites\' responsibility to ensure that all forms are complete.
Identify which copies of forms are to be maintained at the site and
which copies are to be submitted for data entry. In addition, identify
the data flow, data entry, and data correction procedures.

### 3.o.5 Retention of Study Documentation

The length of time all study files are to be maintained is specified in
this section. NIH policy requires that studies conducted under a grant
retain participant forms for three years while studies conducted under
contract must retain participant forms for seven years. Individual IRBs
may have different requirements for record retention.

FDA requires that informed consent forms be retained for two years after
a marketing application is approved for a product or, if an application
is not approved, until two years after shipment and delivery of the
product is discontinued for investigational use and the FDA is notified
(see Code of Regulations (CFR) Title 21, Parts 312.62c, revised April 1,
2001). Investigators should retain forms for the longest period in
accordance with the applicable regulatory requirements or by an
agreement with the sponsor. This period should be stated in the MOP.

### 

### 3.o.6 Administrative Forms

The MOP should contain a complete set of administrative forms.
Administrative forms may include the following:

> ***Facsimile Transmittal Sheet*** - This form serves as a cover page
> for all faxes, as required by a study.
>
> ***Telephone Contact Log -*** This form serves as a record of all
> conversations regarding the study and study participants.
>
> ***Screening Log*** - This form is a record of [all]{.underline}
> patients who are screened for participation in the study. It should be
> arranged chronologically and be kept up to date at all times.
>
> ***Record of Request for Exemption to Entry Criteria*** - This form is
> used to document a participant\'s exemption to an entry criterion.
>
> ***Participant Identification Code List*** -- According to the ICH
> Guidelines, it is recommended that the investigator or lead site
> maintain a confidential participant identification code list. This
> form is a record of the participant\'s name, medical record number,
> randomization number, and study entry and exit dates. The purpose of
> the code list is to "document that the investigators/institutions keep
> a confidential list of names of all participants allocated to trial
> numbers on enrolling in the trial. It allows the
> investigators/institutions to reveal identity of any participant" (ICH
> E6 section 8.3.21). Due to the confidential nature of this
> information, it is recommended that it be maintained in a secured
> location apart from forms and other participant data files. Although
> this form is not mandated by regulations, the information contained on
> it must be maintained by the site.
>
> ***Study Drug Accountability Record -*** This form should be
> maintained in the Pharmacy by the research pharmacist and must not be
> shared with other members of the study team.
>
> ***Record of Destruction of Clinical Product*** - This log is used to
> document destruction of any unused study drug. The date and time of
> incineration as well as how many vials were incinerated must be
> recorded. This record should be attached to the Study Drug
> Accountability Record.
>
> ***CRF Transmittal Sheet*** - This form serves as a cover page for
> each packet of CRFs submitted for data entry. It provides an inventory
> of the forms that are included in each mailing.

## 3.p Data Management

This section describes the data management approach that will support
the study. An issue that transcends clinical studies is how to collect
data accurately, quickly and cost-effectively from multiple sites. Each
study requires decisions regarding data handling options as discussed in
this section.

### 

### 3.p.1 Data Collection Options

Traditionally, data have been collected on paper forms. Recently,
however, technological advances support data entry directly into a
computer using electronic forms at clinical sites. The form of data
collection will depend on the nature of the trial, number of clinical
sites, complexity of data, and other factors. The data collection
process should be described in this section.

### 3.p.2 Data Management Process

In multicenter studies, data are sent from the clinical centers to a
Coordinating Center. The process used by the coordinating center to
receive and process the data should be described along with internal
quality control procedures.

## 3.q Good Clinical Practice

The integrity and ultimate credibility of the study depends on factors
such as ensuring adherence to the protocol, obtaining complete follow-up
information on all participants enrolled, and using quality control
measures to establish and maintain high standards for data quality. The
quality assurance plan should be developed before the study starts and
should be implemented over the life of the study. This section should
detail the various aspects of that plan and describe training and
certification procedures and the site monitoring and data monitoring
procedures.

### 3.q.1 Monitoring

This section should describe any site monitoring that will take place
during a study by the coordinating center. Monitoring typically takes
place through periodic site visits conducted during the study.

Periodic visits will be conducted throughout the course of the study.
The frequency of visits is dependent on the site\'s performance and the
number of participants enrolled. The purpose of monitoring visits is to:

-   assure the rights and safety of participants

-   confirm that study conduct follows the guidelines of Good Clinical

> Practice

-   assure maintenance of required documents

-   verify adherence to the protocol

-   monitor the quality of data collected

-   assure accurate reporting and documentation of all AEs

During the monitoring visits, the data recorded on the CRF's are
reviewed and verified against source documents to assure:

-   informed consent has been obtained and documented in accordance

> with federal regulations

-   the information recorded on the forms is complete and accurate

-   there are no omissions in the reports of specific data elements

-   missing examinations are indicated on the forms

-   participant disposition when exiting the study is accurately
    recorded

The investigator must allow the clinical monitor access to all study
documents, including informed consent forms, drug accountability
records, as well as source documents, including pertinent hospital or
medical records.

## 3.r Reports 

Once a study begins, the Coordinating Center, or Study Chair produces a
series of reports. The reports describe enrollment of participants at
each site and in aggregate form. The reports describe participants
screened, enrolled, refused participation, dropouts, adverse and
unexpected reactions to therapies, and participants completing the
study. Additionally, administrative reports can enumerate the forms
received at the Coordinating Center for multi-site studies, forms
entered, and missing and/or erroneous data and forms.

Data are also provided to DSMB. DSMBs can specify the format and content
of the reports they wish to receive.

## 3.s Policies 

The MOP also contains the study\'s policies, such as confidentiality and
publication policies.

###  3.s.1 Confidentiality Procedure

It is the responsibility of the study leadership to outline and enforce
patient confidentiality and data security guidelines for the study.
Study staff should be instructed in their responsibilities regarding
data safeguards and cautioned against the release of data to any
unauthorized individuals before they are allowed access to any study
data.

The following is a list of study participant confidentiality safeguards:

-   ***Data flow procedures*** - participant identifying information
    should not be transmitted from clinical site to the Coordinating
    Center.

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-   ***Electronic files -*** participant identifying information stored
    electronically should be maintained in an enciphered form or in a
    separate file.

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-   ***Forms -*** forms or pages containing personal identifying
    information should be separated from other pages of the data forms.

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-   ***Data distribution*** - data listings that contain participant
    name, name code, or other identifiers easily associated with a
    specific participant should not be distributed.

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-   ***Data listings -*** patient name, name code, hospital chart or
    record number, or other unique identifiers, such as Social Security
    number, should not be included in any published data listing.

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```
-   ***Data disposal*** - computer output from aborted runs that contain
    patient identifying information should be disposed of in an
    appropriate manner.

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```
-   ***Access*** - patient records stored in the data center should not
    be accessible to persons outside the center without the express
    written consent of the participant.

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```
-   ***Storage -*** study forms and related documents retained both
    during and after study completion should be stored in a secure
    location.

If computers are used to store and/or analyze clinical data, sponsors
should address the following elements of computer security to ensure
that the data remain confidential:

-   ***Passwords*** - Passwords provide limitations on general access to
    the systems and to the functions that individuals can use on the
    system. Passwords should be changed on a regular basis.

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```
-   ***User Training* -** Study staff who have access to clinical
    computer systems should be trained in their use and in related
    security measures. Training should include explanations of how to
    access the system and a discussion of the need for, and importance
    of, system security.

-   ***System Testing* -** Prior to the use of a new computer system,
    and if it is modified, the system should be tested to verify that it
    performs as expected. Testing should verify that password activated
    access system performance is as intended.

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```
-   ***System Backups*** - Backup copies of electronic data should be
    made at specified intervals. Backups should be stored in file
    cabinets or secure areas with limited access. Storage areas should
    have controlled temperature and humidity so that the backup tapes
    are not damaged.

### 3.s.2 Publications

Investigators have a responsibility to the public to make study results
available as soon as possible. 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.

## 3.t MOP Maintenance

This section describes the procedures for updating and distributing
updated MOP versions as well as staff responsible for this activity. The
MOP should be reproduced and distributed to appropriate staff. Each page
of the MOP should be numbered, dated and contain a version number to
facilitate any changes and/or additions. The MOP may serve as a history
of the project, documenting the time and nature of any changes in
procedures and policies.

The MOP should be continuously reviewed by study staff to ensure that
the operating procedures described are accurate. If any procedures have
been changed or modified, the MOP should be updated and the
appropriately modified pages distributed, with instructions, for
replacement in the MOP.

# 

# 4.0 SUMMARY

The development of study MOP is an important process that yields a
product that is critical in helping to assure a study that will yield
high quality results. Development of the MOP forces investigators to
consider the details of a study and to develop procedures that are
understood and can be followed by multiple clinical centers. Further,
the MOP assists with ensuring regulatory compliance.

# REFERENCES

Blumenstein BA, James KE, Lind BK, Mitchell HE. Functions and
Organization of Coordinating Centers for Multicenter Studies*.
Controlled Clinical Trials* 1995;16:4S-29S.

Bohaychuk W, Ball G, Lawrence G, Sotirov K. Good Clinical Practice: Data
Integrity Needs Upgrading*. Applied Clinical Trials*
1999(January):54-61.

Bucher HC, Guyatt GH, Cook, DJ, Holbrook A, McAlister FA. Users Guide to
the Medical Literature*.* JAMA 1999;282(8):771-778.

*Code of Federal Regulations & ICH Guidelines,* Revised April 1, 1998.

Collins JF, Williford WO, Weiss DG, Bingham SF, Klett CJ. Planning
Patient Recruitment: Fantasy and Reality. *Statistics in Medicine*
1984;3:435-443.

Data Safety Monitoring Boards Offer Credible Clinical Data Review, Says
Expert Panel. *Good Clinical Practice Monthly Bulletin* 1999;6(6):1.

Ellenberg SS, Myers MW, Blackwelder WC, Hoth DF. The Use of External
Monitoring Committees in Clinical Trials of the National Institute of
Allergy and Infectious Diseases. *Statistics in Medicine*
1993;12:461-467.

Ellenberg, SS, DeMets DL, Fleming T. *Data Monitoring Committees in
Clinical Trials -- A Practical Perspective*. Wiley, London, 2002.

Friedman LM, Furberg CD, DeMets DL. *Fundamentals of Clinical Trials.*
Mosby, Baltimore: 1996.

Gallin, J I. ed*. Principles and Practice of Clinical Research.*
Academic Press, San Diego, CA 2002

Gassman JJ, Owen WW, Kuntz TE, Martin JP, Amoroso WP. Data Quality
Assurance, Monitoring, and Reporting. *Controlled Clinical Trials*
1995;16:104S-136S.

Gibson D, Harvey AJ, Everett V, Parmar MKB. Is Double Data Entry
Necessary? *Cont Clin Tri* 1994;15:482-488.

*Guidelines for Quality Assurance and Data Integrity in NIAMS Clinical
Trials*, October 1997.

Greenwald et. al. *Human Participants Research, A Handbook for IRBs* at
81, 1982.

Hawkins BS. Data Monitoring Committees for Multicenter Clinical Trials
Sponsored by the National Institutes of Health. *Controlled Clinical
Trials* 1991;12:424-437.

Huster W, Shah A, Kaiser G, Dere W, DiMarchi R. Statistical and
Operational Issues Arising in an Interim Analysis When the Study Will
Continue. *Drug Information Journal* 1999;33:869-875.

Hyde AW. The Changing Face of Electronic Data Capture: From Remote Data
Entry to Direct Data Capture. *Drug Info Jour* 1998;32:1089-1092.

Knatterud GL, Rockhold FW, George SL, Barton FB, Davis CE, Fairweather
WR, Honohan T, Mowery R, O-Neill R. Guidelines for Quality Assurance in
Multicenter Trials: A Position Paper*. Controlled Clinical Trials*
1998;19:477-493.

Meinert CL. *Clinical Trials: Design, Conduct, and Analysis.* Oxford
University Press, New York: 1986.

*Protection of Human Participants,* Title 45 Code of Federal
Regulations, Part 46. PRR Reports, Revised June 18, 1991, Reprinted
April 2, 1996.

Psaty BM, Weiss NS, Furberg CD, Koepsell TD, Siscovick DS, Rosendaal FR,
Smith NL, Heckbert SR, Kaplan RC, Lin D, Fleming TR, Wagner EH.
Surrogate End Points, Health Outcomes, and the Drug-Approval Process for
the Treatment of Risk Factors for Cardiovascular Disease*. JAMA*
1999;282(8):786-795.

SenturiaYD, Mortimer KM, Baker D, Gergen P, Mithchell H, Joseph C,
Wedner J. Successful Techniques for Retention of Study Participants in
an Inner-City Population. *Controlled Clinical Trials* 1998;19:544-554.

van der Putten E, van der Velden JW, Siers A, Hamersma EAM, for the
Cooperative Study Group of Dutch Datamanagers. A pilot Study on the
Quality of Data Management in a Cancer Clinical Trial*. Controlled
Clinical Trials* 1987;8:96-100.

Weiss NS. *Clinical Epidemiology, The Study of the Outcome of Illness,
Second Edition.* Oxford University Press, New York: 1996.

Witkin KB. *Clinical Evaluation of Medical Devices* Humana Press,
Totawa, New Jersey: 1998.

Wittes J. Behind Closed Doors: The Data Monitoring Board in Randomized
Clinical Trials. *Statistics in Medicine* 1993;12:419-424.

# RELEVANT WEB SITES

***Food and Drug Administration:***

<http://www.fda.gov/default.htm>

<http://www.fda.gov/cber/guidelines.htm>

***International Conference on Harmonization (ICH) Guidelines***

<http://www.ich.org/pdfICH/e6.pdf>

<http://www.ifpma.org/ich1.html>

***Gene Therapy, Stem Cells and Fetal Tissue***

<http://grants.nih.gov/grants/policy/gene_therapy_20000307.htm>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-026.html>

***Information Required in NIH Grant Applications:***

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-031.html>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html>

<http://grants.nih.gov/grants/guide/notice-files/not98-024.html>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html>

***NIH Policies for Monitoring Clinical Research:***

<http://grants.nih.gov/grants/guide/notice-files/not99-044.html>

<http://grants.nih.gov/grants/guide/notice-files/not98-084.html>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html>

<http://grants.nih.gov/grants/guide/notice-files/not99-107.html>

<http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-053.html>