The Clinical Trial Protocol:
Writing Considerations
AMWA Northern California Chapter
04 Oct 2014
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Topics
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Relevant definitions, background
Protocol audiences
Purposes of protocols
Protocol components
– Per ICH E6
– Additional (synopsis, glossary, appendices)
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IRB (or equivalent) review
Uses for protocols
Resources
Writing tips
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What is a Clinical Trial?
• A clinical trial is any investigation in human
subjects intended to discover or verify the
clinical, pharmacological and/or other
pharmacodynamic effects of an investigational
product(s), and/or to identify any adverse
reactions to an investigational product(s), and/or
to study absorption, distribution, metabolism,
and excretion of an investigational product(s)
with the object of ascertaining its safety and/or
efficacy. The terms clinical trial and clinical study
are synonymous (ICH Guideline for Good Clinical
Practice E6[R1] 10 June 1996).
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What is a Protocol?
A protocol is a document that describes the
objective(s), design, methodology, statistical
considerations, and organization of a trial. . . . [It]
usually also gives the background and rationale for
the trial, but these could be provided in other
protocol referenced documents (ICH E6).
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Protocol Amendment
• A protocol amendment is a written description of a
change(s) to or formal clarification of a protocol (ICH
E6)
• A protocol amendment is
– Required for any change that significantly affects the safety
of subjects or the investigation’s scope or scientific quality,
eg, increase in drug dosage or duration of exposure, any
significant increase in the number of subjects under study
(21 CFR 312.30)
• A protocol can only be amended by the Sponsor
• Usually a new (amended) protocol is prepared that
includes or is accompanied by a list of descriptions of
the change(s) and the rationales for the changes
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Protocol Audiences (I)
• Sponsor (and Clinical Research Organization) personnel
(who are sometimes also contributors)
– Medical monitors
– Regulatory professionals
– Those responsible for interacting with persons at vendors
and clinical research sites and for monitoring the conduct
of the trial (eg, Clinical Research Associates)
– Writers of sample informed consent form (ICF), clinical
study report (CSR), and manuscript(s)
• Persons at regulatory agencies (multiple times, eg, at
initial review, when amended, when incorporated into
the CSR)
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Protocol Audiences (II)
• IRB (or equivalent) members
• Site personnel
– Investigators
– Clinical Research Coordinators
– Those preparing site-specific ICFs
– Physicians and those implementing trial
assessments and interventions
– Subjects (indirectly, through the ICFs)
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Purposes of Protocols
• Communicate the details of the clinical trial to
all audiences
• Contribute to the scientific soundness of the
trial by helping to insure uniformity in its
conduct
• Determine, in some instances, aspects of a
patients’ medical care
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Protocol Components (I)
• Per ICH E6:
– General information (title, sponsor [medical
expert, signatories], monitor, Investigator[s])
– Background information (investigational product,
previous nonclinical and clinical studies, risks,
benefits, rationale, population)
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Protocol Components (II)
– Objectives and purposes
– Design (scientific integrity and data credibility,
endpoints, type of trial, minimization of bias
[randomization, blinding], treatment[s], duration,
discontinuation criteria, study drug accountability
procedures, treatment randomization codes,
procedures for breaking codes, data recording)
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Protocol Components (III)
– Selection and withdrawal of subjects (inclusion,
exclusion, withdrawal criteria)
– Subject treatment (screening through follow-up)
– Prior and concomitant treatments (sometimes this
includes food and activities) permitted
– Compliance measurement
– Efficacy assessment (parameters, assessment
methods)
– Safety assessment (parameters, assessment
methods, follow-up)
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Protocol Components (IV)
• Statistics (methods; interim analyses; # of subjects; level
of significance; trial termination criteria; handling of
missing, unused, and spurious data and deviations from
the Statistical Analysis Plan; subjects included in
analyses)
• Direct access to source data/documents
• Quality control and quality assurance
• Ethical considerations
• Data handling, recordkeeping
• Financing, insurance, publication policy (if not in a
separate agreement)
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Additional Protocol Components
Protocol Synopsis
• Not mentioned in ICH E6 but usually is the
first part of a protocol
• Should not have anything in it that is not in
the protocol itself (though it may have
statements that summarize what is in the
protocol)
• Often in table format
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Additional Protocol Components
Protocol Synopsis
Content (I)
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Sponsor
Product name
Protocol title
Planned study center(s)
Objectives
Study design
Number of subjects
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Additional Protocol Components
Protocol Synopsis
Content (II)
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Test product information
Duration of treatment
Inclusion and exclusion criteria
Assessments
Endpoints
Statistical methods
Schedule(s) of Assessments and Procedures
(SOA[s]) (may be here, within the protocol itself,
or in an appendix to the protocol)
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Other Additional Protocol Components
• Glossary or List of Terms/Abbreviations
– Abbreviations/acronyms used in text and, for some
sponsors, tables (although also defined in table footnotes)
– When to use abbreviations/acronyms and include in list
varies by sponsor
• Reference list
• Appendices
– Examples
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Schedules of Assessments and Procedures
Sample ICF
Instruments used to measure efficacy
Specific laboratory tests to be performed
Sponsor and Investigator signature pages
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Protocols Inform the IRB
(or Equivalent Review Committee)
• An IRB
– An independent body constituted of medical, scientific, and
non-scientific members, whose responsibility is to ensure the
protection of the rights, safety, and well-being of human
subjects involved in a trial by, among other things, reviewing,
approving, and providing continuing review of the trial protocol
and amendments and of the methods and material to be used
in obtaining and documenting informed consent of the trial
subjects (ICH E6)
– Has authority to approve, require modifications in (to secure
approval), or disapprove all research activities (21 CFR 56.109)
at its associated institution
– Performs continuing review of ongoing research at least once
per year (21 CFR 56.109)
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Protocols Form the Basis for
Information Provided to Potential
Subjects and to Subjects
• Subject recruitment materials
• ICF
• Calendars and other instructions for subjects
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Protocols Inform Those Conducting the
Clinical Trial
Investigators and research site personnel use
protocols to find out about why the trial is being
conducted, what is to be learned, who is eligible
to participate, and when and how clinical trial
procedures are to be performed.
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Protocols Form CSR Content
• A CSR is a written description of a trial/study of any
therapeutic, prophylactic, or diagnostic agent
conducted in human subjects, in which the clinical and
statistical description, presentations, and analyses are
fully integrated into a single report (see ICH Structure
and Content of Clinical Study Reports E3, 30 November
1995) (ICH E6)
• Sections of the protocol are often copied into the CSR
(eg, introduction, objectives, investigational plan
sections) and then the future tense (used in the
protocol) is changed to past tense
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Protocols (Not Just Study Data) Are
Described in the Investigator’s
Brochure
• An Investigator’s Brochure is a compilation of
the clinical and nonclinical data on the
investigational product(s) that are relevant to
the study of the investigational product(s) in
human subjects (ICH E6)
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Resources (I)
• Guidances
– ICH Guideline for Good Clinical Practice E6(R1) 10
June 1996
– Disease-specific (eg, Guidance for Industry Acute
Bacterial Skin and Skin Structure Infections:
Developing Drugs for Treatment [describes
endpoints])
– Evaluation-specific (eg, Clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs)
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Resources (II)
• Published style manuals (eg, AMA Manual of
Style)
• Investigator’s Brochures
• Sponsors’ style guides, templates, and other
protocols
• Package inserts for commercially available drugs
• Web sites of indication-specific organizations, eg,
Infectious Diseases Society of America
• References obtained using search engines such as
PubMed
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Writing Tips (I)
• Clarity and accuracy (to reduce error by those
interpreting and implementing protocols) are of the
highest priority; protocol deviations, which affect the
scientific integrity of the results, should not occur
because of a lack of writing clarity or accuracy
– Write for understanding by all audiences
– Be particular about internal consistency; those
interpreting and implementing a protocol may not
study the entire document
– Make sure the SOA is complete as it may be the
primary source of what is to be done when
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Writing Tips (II)
• If possible, include additional elements that
can reduce protocol deviations:
– Windows around time points, eg, ± 10 minutes
around the time a sample is to be drawn
– Specification that no eligibility criteria waivers
(which are considered deviations) are permitted
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Writing Tips (III)
• Reduce redundancy (there is opportunity for error each time something is
described); if possible write it once:
– Write the synopsis after writing the body of protocol and excerpt sections
from the body of the protocol for the synopsis or write the synopsis and then
expand the synopsis text as necessary for the body of the protocol; writing
them simultaneously can mean a matching nightmare
– If assessments are repeated on multiple days, copy and past their first
mentions to the sections for the subsequent time points that they are to be
done
– Unless it reduces clarity, combine sections that are identical that describe
assessments at the various time points (eg, if assessments for Day 3, 7, and 9
are the same, combine all into 1 section for Days 3, 7, and 9)
– Write it the same way every time so there is no confusion about what is
meant; use search function to find all instances and paste in decided-upon
text wherever needed
– Unless it reduces clarity, use cross references whenever possible instead of
repeating large blocks of text; eg, if a questionnaire is used, describe it once
and reference this description elsewhere in the protocol
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Writing Tips (IV)
– If possible, save most of the work on the abbreviation
list and abbreviations in the text for the final draft and
let the reviewers know that you have done this
– Ditto for the reference list
– List procedures in the procedure section of the
protocol in the same order as in the SOA
• Complete the SOA, print it, and proceed from top to bottom,
line by line, to write the assessment and procedures sections
in the body of the protocol
– Write keeping in mind the CSR and the New Drug
Application (or similar) (eg, use the same definitions
across the protocols for a particular study drug)
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