Protocol Development
and Preparation for a Clinical Trial
European University
Giorgi Lomidze, MD, PhD
2024
A clinical trial protocol - Definition
• A clinical trial protocol is a written document
that provides a detailed description of the
rationale for the trial, the hypothesis to be
tested, the overall design, and the methods to be
used in carrying out the trial and in analyzing its
results;
• A protocol has a structure and organization made
up of elements that follow the conception,
development, and conduct of a clinical trial in a
chronological fashion;
Protocol development
• A detailed protocol must be written before a clinical
trial starts. Its purpose is to state the aim of the study,
document its trial plan, its inclusion and exclusion
criteria, the treatments and clinical examinations, the
evaluation of response to treatment, randomization,
blinding, number of patients, plan for statistical
analyses and reporting of adverse events. Moreover, it
includes relevant practical and administrative
procedures. A protocol may be required to obtain
official approval to conduct a clinical trial as well as to
apply for funding of a trial, both vital aspects for the
researcher.
Protocol development
It is important to describe how the data are to be
processed (statistical analysis), how dropouts or
withdrawals will be treated and how deviations
from the protocol will be addressed;
In addition, patient information must be
compiled to provide the basis for an informed
consent statement to be signed by patients
before they take part in the study.
Protocol development
The principal parts of the protocol -
Trial plan
• The protocol shall describe the background for the study and state
why it should be done and how it shall be conducted;
• The first phase of planning should set three main aspects:
Which treatments will be compared?
Which patients will be included?
How will adverse events be recorded?
Moreover, the study design is defined and the required
number of patients estimated;
The principal parts of the protocol -
Trial plan
• Purpose of the study
• Trial plan
• Inclusion and exclusion criteria;
• Number of patients, Study power
• Description of treatment;
• Patient follow-up
• Randomization, blinding
• Outcome variables
• Adverse events
• Statistical analysis
• Administrative matters
• Ethics
Background and Rationale
• The background and rationale section of a
protocol is a brief but comprehensive
introductory section that should provide a
compelling argument to justify the proposed
research;
Components of the background and rationale
section of the clinical trial protocol
• General description of the disease being treated/managed and why improved
treatment/intervention/management is needed;
• Description of current treatment/management of the disease/condition and any
problems with available therapy/management;
• Description of known properties of the proposed treatment/management
intervention that justify its use;
• Brief summary of relevant preclinical and clinical experience with the proposed
treatment/management intervention;
• Rationale for the current study and its role in the overall research program;
• Statement of the hypothesis and objectives of the proposed research;
• Brief description of the significance of the study;
Statement of Hypothesis
• The section of the study protocol, stating the
hypothesis or hypotheses (there may be
more than one in a given study) typically
begins with a broad description of the overall
goal of the research within the context of the
investigators’ overall research program.
Statement of Hypothesis
• In addition to stating the broad programmatic goal of the
proposed research, the statement of the hypothesis also
presents a more specific broad objective of the research
followed by some more detailed specific aims of the research;
• For example, a broad objective might be to test the hypothesis
that a new drug improves symptoms in patients with the
disease of interest to the overall research program;
• The specific aims might be to determine whether certain of
those symptoms improve by a specified amount over a
specified period of time without producing major side effects;
Statement of Hypothesis - outcomes
• The specific aims typically include major
outcomes (primary endpoint) that essentially
drive the study design and other outcomes of
lesser importance (secondary endpoints) that
provide supportive information, as will be
discussed in greater detail below.
Statement of Hypothesis
Specific Major
Goal Objectives
Aims outcomes
Significance of the Research
Why study is significant?
• If the hypothesis is confirmed, what does that mean in terms of the
initial objectives?
• Is it conclusive or does it indicate a direction for future research?
• Results which are not confirmatory may lead to outright rejection of
the hypothesis or may imply a need for modification of the research
approach.
• Finally, some findings of the study may generate new hypotheses to be
addressed by future research.
Overview of Study Design Summary
• Summary is especially useful to certain
reviewers, e.g., research administrators,
funding agency officials, or institutional
review board (IRB) members, who may not
be scientists or may not require the level of
detail of the full protocol in order to perform
their specific review or critique functions;
Overview of Study Design Summary
• Statement of study type
- (e.g., controlled clinical trial)
• Overview of study design
– Parallel-group, crossover
– Level of blinding (e.g., open-label, single-blind, double-blind)
– Method of treatment assignment (e.g., randomization, stratification)
• Statement of treatment/intervention to be used
– Investigative drug or device
– Dosage of drugs or usage of devices
– Type of control (e.g., placebo, active drug, no treatment)
Overview of Study Design Summary
• Description of study population
– Planned sample size
– Source of patients; Number of centers
–Patient characteristics (age, race, sex) required
• Description of the disease or condition being studied and any
characteristics of that disease/condition that might affect patient
eligibility or study outcomes
– Duration; Etiology; Severity; Treatment
• Sequence and duration of study visits
• Description of study endpoints
General Description of the Study
Population
• The demographic characteristics typically
describe the sex and age group of patients and, if
appropriate, their race;
• If any of these characteristics are particularly
restrictive, the reason for that restriction should
also be given.
For example, if one is studying only Asian
females in their 20s, the reason for focusing on
that population should be presented;
General Description of the Study
Population
• The medical condition these patients must have in
order to participate in the study also should be
described in terms of its diagnostic criteria, duration,
etiology, treatment, present status, and severity;
• If normal subjects are included, then operational
criteria for defining the normal subject also must be
presented;
• This section also should include a description of the
number of patients to be studied (not sample size
calculation).
Patient Sources
• One should describe the number and location of
investigative sites that will provide patients and/or
participate in the trial;
• Methods to be used for finding patients should be
described.
• A detailed description of the screening process to
determine eligibility should be included, listing the
specific initial parameters that will be used
preliminarily to identify potential eligible patients;
Inclusion/Exclusion Criteria
• A list of all inclusion and exclusion criteria to be used
in determining eligibility of patients for the trial must
include a detailed description of all the requirements
a patient or subject must meet to be eligible for
enrollment in the trial, along with a detailed
description of all variables that would render the
patient ineligible for enrollment.
• It is important that the list be very detailed, leaving no
ambiguities for the study personnel who must use the
list to screen for potential patients;
Inclusion/Exclusion Criteria
For example, eligibility for inclusion in a trial of antihypertensive
treatment:
• Systolic blood pressure above 140 mmHg or a diastolic pressure above
90 mmHg, as determined by the average of 3 readings taken 5 min
apart with the patient seated and using a standard
sphygmomanometer;
The exclusion criteria might state that:
• “A patient may not be included if he/she has received any
antihypertensive drugs within the past 6 months, specifically any
diuretics, beta-blockers, calcium blockers, ACE-inhibitors, angiotensin-
receptor blockers, or alpha-blockers. For other agents with possible
antihypertensive activity, the investigator must obtain approval of the
study chairperson before enrolling the patient.”
Patient eligibility considerations
Category Inclusion criteria Exclusion criteria
Patient • Provision of written informed consent •Hypersensitivity/intolerance to study
characteristics • Demographics (age, sex, race) interventions
• Body weight • Medical history (current or preexisting
• Pregnancy or childbearing potential conditions and treatments)
• Behaviors (alcohol, smoking, activity, diet) • Allergies/food intolerance
• Mental status • Occupational risk/hazard
• Breast feeding
Characteristics Diagnostic criteria • Non-permitted treatment
of disease being • Duration /Etiology •Status/severity that might bias results
studied • Status/severity •Confounding concomitant conditions or
• Treatment (required, permitted) complications
Screening • Within limits specified •Outside of limits specified
examinations • Meets all run-in requirements (compliance, •Fails to meet run-in criteria
stability)
Other factors •Cooperative attitude •Inability to perform study requirements/
• Occupation procedures
• Availability for all study requirements • Lack of availability
for full duration • Increased risk of lack of cooperation
• Current/recent participation in another
clinical trial
Safety Monitoring Procedures
• A complete protocol should describe all
procedures that will be in place to ensure and
assess the safety of study participants;
• Whereas much of this information already is
included in different parts of the protocol,
e.g., on the schedule of visits and procedures,
it is recommended that a specific section be
devoted to summarizing all safety monitoring
procedures.
Ethical Considerations
• The protocol must state that all patients will provide
informed consent prior to being enrolled in the study;
• The consent form must be written in language the patient
can fully understand and must contain certain elements;
• These include a description of the study; what is expected
of the patient; what risks are involved with any tests,
procedures, and treatments; what alternative treatments’
are available; and assurance that the patient will be given
the best available treatment for his/her condition
whether or not he/she chooses to participate initially or
to terminate prematurely;
Statistical Considerations
• All protocols should contain a section that
describes trial-specific statistical evaluation
plans;
Resource Allocation and Management
• Key resources include funds, manpower, and supplies;
• Funding may be available prior to study initiation in
some settings with predetermined budgets, e.g.,
industry;
• Once funds are secured, the study leadership must
oversee their allocation, accountability, and continuing
availability, as well as identify the individuals who will
be responsible for these matters.
Recruitment of Study Participants
• The recruitment of eligible patients/subjects into
the study in a timely fashion is one of the key
rate-limiting processes that has a major impact
on study results;
• Failure to recruit patients in a timely manner
may have serious consequences by precipitating
retrospective protocol changes, such as relaxing
eligibility/exclusion requirements or modifying
procedures and observations;
Study Monitoring and data
processing
• Implementation of the protocol should be
carefully monitored.
• From the study conduct perspective, it is
important that adequate numbers of qualified
personnel are available for data processing
and management.
End of Study Procedures
• Once all study visits have been completed in
all subjects, the study itself can be
terminated;
• Procedures for terminating the study may
include a final monitoring visit to retrieve all
outstanding study materials such as case
report forms and study supplies;
