Investigational Drug Products:
Protocol Development Resource &
Checklist
Protocol Development Guidance for Clinical
Investigations Using FDA Regulated Drug Products
ICTR Navigators
December 16, 2011
Version 1.0
1.0
TABLE OF CONTENTS
Section
1.0
Table of Contents
2.0
Introduction
3.0
Content Checklist
4.0
FDA Guidance Information
2.0
Page
2
2
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12
INTRODUCTION
The clinical protocol is the blueprint that directs the conduct of the clinical trial. The protocol
must contain concise and logically arranged information that fully describes the intent of the
clinical investigation. A comprehensive protocol is one of the central components of any FDA
submission (e.g. IND application and IND exemption request, etc.) involving the use of an
investigational device in a clinical trial as it provides specific and consistent direction to the study
team, ensures that the rights and welfare of the human participants are protected, and promotes
collection of quality research data. Conversely, a poorly written and incomplete protocol is likely
to encounter significant delay in both the IRB and FDA review processes as reviewers may not
completely understand the intent of the research or may not feel that sufficient attention has
been paid to patient safety or aspects of good clinical practice. Therefore, the more
comprehensive the protocol, the easier it will be for FDA and IRB reviewers to find the
information they need in order to complete their analysis of the project. Using regulatory
references including 21CFR50, 21CFR56, 21CFR312, ICH E:6, and the Johns Hopkins
Medicine Office of Human Subjects Research policies, the ICTR DDRS has developed this
resource in order to help ensure that the protocol being submitted contains essential information
that FDA and IRB reviewers need to see.
3.0
PROTOCOL CONTENT DEVELOPMENT RESOURCES AND CHECKLIST
The following table of suggested content may be used as a ‘checklist’ when drafting the clinical
protocol to help ensure that discussion of all applicable elements is included. Within the table,
the minimum suggested and optional information is noted. Also provided is the regulatory
reference from which the suggested information is cited. Ultimately, the content and format of
the protocol is left to the discretion of the sponsor-investigator.
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Protocol
Section
Description and Regulatory Reference (if applicable)
Title Page
Minimum
Suggested
Information
Optional
Information
Protocol title, Version Date, Phase, Investigation Product Name(s), IDE/IND number(s), IDE/IND
sponsor(s), Financial Sponsor, and Principal Investigator
(Regulatory Reference: ICH E:6, Section 6.1.1)
Short Protocol Title or Acronym, Protocol number, Version Number, IRB of Record (single site or
multisite with one IRB), and IRB application number.
(Regulatory Reference: ICH E:6, Section 6.1.1)
Amendments
When amendments are made to the protocol, the title page should include, at a minimum, the
date of the amendment and optionally, the amendment number.
(Regulatory Reference: ICH E:6, Section 6.1.1)
Table of Contents
Minimum
Suggested
Information
Include a table of contents for the protocol.
Signature Page(s)
Optional
Information
If this is a multicenter protocol, the sponsor should consider including a signature page that each
site’s Principal Investigator can sign and date the protocol stating she/he will conduct the
protocol as written by the Sponsor.
(Regulatory Reference: ICH E:6, Section 6.1.3)
List of Abbreviations
Optional
Information
Include a list of all abbreviations and/or acronyms used throughout the protocol.
Synopsis
Minimum
Suggested
Information
Optional
Information
Protocol title, Version Date, Phase, IDE/IND number(s), IDE/IND sponsor(s), Financial Sponsor,
Principal Investigator, Study Agent/Intervention Description, Sample Size, Study Population,
Study Design, Study Duration, Objective (primary, secondary, etc…), and Endpoints
Short Protocol Title or Acronym, Protocol number, Version Number, IRB of Record (single site or
multisite with one IRB), IRB application number, and Accrual Period
A schematic flow diagram or table of the study design
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General Information
Name and address of the sponsor and monitor (if other than the sponsor).
(Regulatory Reference: ICH E:6, Section 6.1.2 and 21 CFR 312.50)
Minimum
Suggested
Information
Name and title of the investigator(s) and sub-investigators who is (are) responsible for
conducting the trial, and the address and telephone number(s) of the trial site(s). Additionally,
indicate beside each name who is the qualified physician (or dentist, if applicable), who is
responsible for all trial-site related medical (or dental) decisions (if other than investigator).
(Regulatory Reference: ICH E:6, Section 6.1.5 & Section 6.1.6 and 21 CFR 312.23(a)(6)(iii)(a ))
Name(s) and address (es) of the clinical laboratory (ies) and other medical and/or technical
department(s) and/or institutions involved in the trial.
(Regulatory Reference: ICH E:6, Section 6.1.7 and 21 CFR 312.23(a)(6)(iii)(a ))
Key Study Team Members/Key Personnel/Key Roles
Optional
Information
Investigators may want to consider including names, titles, and contact information for other key
study team members. If not included in this section of the protocol, the names of other key study
team members should be documented in the Duties and Delegation Log, in a Manuel of
Procedures (MOP), or in the appendix. Examples of other key study team members include, but
are not limited to:

Protocol Data Manager(s)

Protocol Epidemiologist(s)

Protocol Pharmacologist(s)

Protocol Regulatory personnel

Protocol Statistician(s)

Protocol Behavioral Scientist (s)

NIH Representatives(s)

Industry Representative(s)

Other significant representative(s)

Major Collaborators, if not included as site investigators (add brief statement of role)

Medical Monitor (If applicable)

Independent Safety Monitor (If applicable)
(Regulatory Reference: 21 CFR 312.23(a)(6)(iii)(a ))
Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s)
for the sponsor.
NOTE: Only include this information if you include a signature page.
If applicable
(Regulatory Reference: ICH E:6, Section 6.1.3)
Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when
appropriate) for the trial.
NOTE: If there is no ‘medical expert’ besides the principal investigator, then this does
not need to be included.
(Regulatory Reference: ICH E:6, Section 6.1.4)
Abstract / Précis
Optional
Information
A written version of the synopsis that can be published where required and/or could be used in a
manuscript.
Background and
Significance
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Name and description of the investigational product(s).
(Regulatory Reference: ICH E:6, Section 6.2.1)
A summary of findings from nonclinical studies that potentially have clinical significance and
from clinical trials relevant to the trial.
(Regulatory Reference: ICH E:6, Section 6.2.2)
Summary of the known and potential risks and benefits, if any, to human subjects.
Minimum
Suggested
Information
(Regulatory Reference: ICH E:6, Section 6.2.3)
Description of and justification for the route of administration, dosage, dosage regimen, and
treatment period(s). If an investigational device will be used in the protocol, include a general
description here of the device and all major components as well as and how it will be utilized
throughout the course of the trial.
(Regulatory Reference: ICH E:6, Section 6.2.4)
Description of the population to be studied.
(Regulatory Reference: ICH E:6, Section 6.2.6)
If applicable
A statement that the trial will be conducted in compliance with the protocol, GCP and the
applicable regulatory requirement(s).
(Regulatory Reference: ICH E:6, Section 6.2.5)
Trial Hypothesis, Objectives, Specific Aims, and/or Purpose
Minimum
Suggested
Information
A detailed description of the objectives, hypothesis, specific aims, and/or the purpose of the
trial.
(Regulatory Reference: 21 CFR 312.23(a)(6)(i)-(ii),(iii)(a ) and ICH E:6, Section 6.3)
General study design
Minimization of potential bias
Describe the specific measures (e.g., randomization, blinding) that will be taken to
minimize/avoid bias on the part of the subjects, investigators, and analysts.
(Regulatory Reference: ICH E:6, Sections 6.4.3 & 6.5.3 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(d ))
Anticipated number of research subjects
Minimum
Required
Information
Define ‘enrollment’. Specify the estimated total number of subjects to be enrolled into the
clinical study and the anticipated number of subjects expected to complete the study.
(Regulatory reference: 21 CFR 312.23(a)(6)(i),(ii),(iii)(c ) and ICH E:6, Section 6.9.2)
Recruitment Plan
Federal regulations require that IRBs ensure that the selection of subjects for a study is
equitable. As such, each protocol must explain how subjects will be identified and recruited for
the study. Any approach to subjects must be non-coercive and the potential subjects must
voluntarily participate in the recruitment process.
(Regulatory Reference: Johns Hopkins Patient Recruitment and Referral for Research
guidelines)
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Informed Consent
As the FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to
assure the safety and rights of subjects the protocol should include discussion of the consent
processes to be followed.
(Regulatory references: ICH E:6, Section 4.8, 21CFR50, 21CFR60, 21CFR312.62(b), and
21CFR312.88)
Screening procedures
Describe or list the procedures that will be performed to verify a subject’s eligibility for
participation in the clinical study.
Study Treatment
Study treatment and/or diagnostic product procedures
Minimum
Suggested
Information
Describe, in detail, the study treatment or diagnostic products (e.g., the investigational device
and, if applicable, comparative devices or products) that will be administered to each study
group or arm of the proposed clinical investigation; to include, for each study treatment or
diagnostic product, the product name and FDA-approval status, dose or dose range (if
applicable), route/mode of administration, dosing or exposure schedule, and treatment or
exposure duration. Describe, if applicable, any plans for dose or exposure reductions or
increases based on the data accrued with study progression.
(Regulatory reference: ICH E:6, Section 6.6.1 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(e ))
Treatment adherence/ Study compliance
Specify the criteria and procedures for withdrawing subjects from study participation due to
non-compliance with the study treatment or diagnostic product regimen, if applicable, and/or
the study procedures or investigators instructions.
(Regulatory reference: ICH E:6, section 6.5.3 (a))
Investigational Drug Information
If applicable, include a description of the trial treatment(s) and the dosage and dosage regimen
of the investigational product(s) should be included. Also include a description of the dosage
form, packaging, and labeling of the investigational product(s).
Minimum
Suggested
Information,
If applicable
Insert Drug Name
Other names:
Classification:
How supplied:
Storage: (Where and how)
Stability:
Route of Administration:
Method of Preparation:
Drug Ordering and Drug Accountability:
Prohibited Medications and Procedures:
(Regulatory reference: ICH E:6, Section 6.4.4 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(e ) )
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Investigational Device Information
If applicable, provide a detailed description of each important component, ingredient, property,
and principle of operation of the device and of each anticipated change in the device during the
course of the investigation.
Insert Device Name
Classification:
Manufacturer:
Storage: (Where and how)
Accountability:
Instructions for Use:
(Regulatory reference: ICH E:6, Section 6.4.4 and 21 CFR 812.25)
Allocation to treatment
Incorporate only if the proposed clinical study involves multiple treatment arms.
Describe the plan and procedures for allocating subjects to the various treatment or diagnostic
arms of the study so as to ensure comparability between test groups and any control groups
with regard to pertinent variables such as gender, severity or duration of disease, and use of
therapy other than the investigational device.
(Regulatory Reference: ICH E:6, Sections 6.4.3 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(d-e ))
Breaking the blind
Incorporate only if the proposed clinical study is blinded. Describe the procedures for
breaking the blind should a given subject suffer a serious adverse event wherein knowledge of
the identity of the study treatment or diagnostic product received by the subject is necessary for
effective emergency treatment of the event
(Regulatory reference: ICH E:6, Section 6.4.8)
Treatment adherence/ Study compliance
If applicable, describe the procedures that will be used to assess subject
compliance/adherence with the assigned study treatment or diagnostic product regimen.
If applicable, specify whether or not subjects withdrawn from study participation due to
noncompliance will be replaced and, if so, the corresponding procedures for their replacement.
(Regulatory reference: ICH E:6 Section 6.6.3 & Section 6.5.3 (c))
Follow-up Procedures
Schedule of evaluations and study activities
Minimum
Suggested
Information
Incorporate, as a referenced attachment (i.e., Appendix ___), a table that summarizes the
protocol procedures that will be performed at screening, for treatment or diagnosis, and at
follow-up (if applicable).
(Regulatory reference: ICH E:6, Section 6.6.1 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(f-g))
Procedures to assess efficacy
If applicable
Specify the parameters (i.e., observations and/or measurements) that will be used to evaluate
the efficacy of the study treatment or diagnostic product(s); to include the methods and timing
for assessing, recording, and analyzing these parameters
(Regulatory reference: ICH E:6, Sections 6.7 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(f ))
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Procedures to assess safety
Specify the parameters (i.e., procedures, laboratory tests, or other measures) that will be used
to evaluate the safety of the study treatment or diagnostic product(s); to include the methods
and timing for assessing, recording, and analyzing these parameters.
(Regulatory reference: ICH E:6, Section 6.8 and 21 CFR 312.23(a)(6)(i),(ii),(iii)(g ))
Supportive care
Describe any supportive care (i.e., procedures, laboratory tests, or other measures) that will be
administered in the course of trial follow-up.
(Regulatory reference: ICH E:6, Section 6.6.1)
Statistical Considerations and Study outcome evaluations
Study endpoints
Summarize the primary and, if applicable, secondary endpoints or outcomes that will be
evaluated in the clinical study.
(Regulatory reference: ICH E:6, Section 6.4.1)
Sample size determination
Specify the number of subjects planned to be enrolled into the clinical study (i.e., to complete
the clinical study) and the reason(s) for the choice of this sample size. Include, if applicable,
calculations of the power of the study or provide an alternate explanation for the proposed
sample size. For example, if the purpose of the proposed clinical study is to obtain pilot data
upon which to base a subsequent pivotal study of the investigation device, state this and
provide a clinical justification for the sample size selected.
(Regulatory reference: ICH E:6, Section 6.9.2)
Minimum
Suggested
Information
Outcome data and data analysis
Describe the specific observations and/or measurements that will form the basis for evaluating
the primary and, if applicable, secondary endpoints or outcomes of the clinical study.
(Regulatory reference: ICH E:6, Section 6.7.1 & 6.8.1)
Efficacy analysis
Describe the analysis population(s) and statistical methods that will be employed in the analysis
(analyses) of primary and secondary (if any) endpoints related to evaluation(s) of the efficacy of
the study treatment or diagnostic product(s). Include the level(s) of significance to be used.
(Regulatory reference: ICH E:6, Section 6.7.2)
Safety analysis
Describe the analysis population(s) and statistical methods that will be employed in the analysis
of the safety of the study treatment or diagnostic product(s). Include the level of significance to
be used.
(Regulatory reference: ICH E:6, Section 6.9.3)
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Interim analysis
If applicable
Incorporate only if an interim analysis is planned. Describe the timing and nature of the
planned interim analysis. Address corresponding procedures; such as who will perform the
interim analysis and to whom the results of the analysis will be provided.
(Regulatory reference: ICH E:6, Section .9.1)
Data and Safety Monitoring (DSM) Plan
Data and Safety Monitoring (DSM) Plan
Describe the Data and Safety Monitoring Plan. If a Data Safety Monitoring Committee/Board
will provide oversight, describe the composition and operations or include DSM Charter as a
referenced attachment (i.e., Appendix ___).
(Regulatory reference: Johns Hopkins 103.6c Organization Policy on Data & Safety Monitoring
of Proposed Research and 21 CFR 312.50)
Minimum
Suggested
Information
Early stopping rules
Describe the early stopping rules of the trial.
(Regulatory reference: ICH E:6, Sections 6.4.6 & 6.5.3)
Study Interruption or withdrawal
Include any potential reasons for interruption or discontinuation of the protocol.
(Regulatory reference: ICH E:6, Section 6.9.4)
Risk Analysis
Anticipated risks
Describe all increased risks to which the subjects (patients-subjects and normal controls, if
applicable) will be exposed as a result of their participation in the clinical study.
Address the steps that will be taken to minimize these risks. Provide an analysis of the benefitto-risk ratio of study participation (i.e., for each of the study populations, as applicable) and a
corresponding justification for conducting the clinical study.
(Regulatory reference: ICH E: 6, Section 6.2.3)
Minimum
Suggested
Information
Adverse event recording/ reporting
Detail specific adverse event definitions (e.g. unanticipated adverse device effect (UDAE),
unexpected adverse effect, serious adverse effect, adverse effect, etc.)
(Regulatory reference: ICH E:6, Section 4.11)
Eliciting adverse effect information
Detail specifically how adverse effect information will be elicited from study participants.
(Regulatory reference: ICH E:6, Section 6.8.3)
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Recording and assessment of adverse effects
Specifically describe here what criteria will be used in order to classify an abnormal test finding
as an adverse effect (e.g. the test finding is accompanied by clinical symptoms, the test finding
necessitates additional diagnostic evaluations or interventions, the test finding leads to a
change in study dosing or exposure or discontinuation of subject participation, the test finding is
considered an adverse effect by the Sponsor-Investigator, etc.)
Detail specifically how adverse effect information will be documented (e.g. in research chart)
and plan to ensure that sufficient information will be pursued as to permit adequate
determination of the outcome of the effect and assessment of the causal nature of the
relationship between the investigational device and or other study treatment/products.
(Regulatory reference: ICH E:6, Section 6.8.2 & 6.8.3)
Assessment of causality and severity
Describe here the process to be followed by the sponsor-investigator for review of documented
adverse effects and abnormal test findings in order to determine classification as an adverse
effect, whether or not the adverse effect was caused by the investigational device or other
study treatment, or if the adverse effect meets the criteria for a serious adverse effect.
Additionally, describe how determinations of causality that are “unknown” and/or “questionable”
in relation to the investigational device will be addressed, documented and reported.
Reporting of adverse effects to the FDA
If the sponsor-Investigator will report any observed or volunteered adverse effects determined
to be an unanticipated adverse device effect to the FDA (e.g. via FDA Form 3500 (for voluntary
reporting), FDA Form 3500A (required reporting) describe the process for initial reporting, follow
up, and notification of co-investigators.
(Regulatory reference: http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085568.htm
and ICH E:6, Section 6.8.3)
Reporting of adverse effects to the responsible IRB
Describe the process to be followed for reporting of adverse effects to the IRB and time frames
in which this will be done.
(Regulatory reference: 103.6b Organization Policy on Reports of Unanticipated Problems
Involving Risks to Participants or Others and ICH E:6, Section 6.8.3))
Monitoring
Monitoring procedures
Minimum
Suggested
Information
Describe the nature and timing of any quality control/quality assurance reviews (i.e.,
independent of the previously described monitoring activities) that will be undertaken by the
Sponsor-Investigator to ensure appropriate conduct of the clinical study and quality and
completeness of the accrued study data. I.e., describe the data and safety monitoring plan for
the clinical study as outlined in the IRB application or include DSM plan/charter in the
appendices and reference same here.
(Regulatory reference: ICH E:6, Section 6.11 and 21 CFR 312.56)
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Additional Records and Reports
Data handling and record-keeping
Describe the procedures for management and retention of study data including accounting for
any missed, unused, and/or spurious data. In appendices, include a copy of Case Report
Forms (CRF) and reference “See Appendix__.
Minimum
Suggested
Information
(Regulatory reference ICH E:6, Sections 5.5 & 6.13)
Record maintenance and retention
Describe how the subject-specific data and Case Report Forms will be coded and how these
materials, and the subject identification code list, will be stored so as to protect the subjects
confidentiality. Specify that subject names or other directly identifiable information will not
appear on any reports, publications, or other disclosures of clinical study outcomes
(Regulatory reference ICH E:6, Sections 5.5 & 6.13)
Dissemination of Results and Publication Policy
Optional
information
The investigator may consider adding information describing the dissemination of results and
publication policy. When describing this section, include specific criteria set forth by the funding
agency, contracts with sponsor, and/or institutional polices. Additionally, the investigator can
also include information on Clinicaltrials.gov registration and result reporting requirements, if
applicable.
References
Minimum
Suggested
Information
List all references cited throughout the protocol. Where possible include DOI (Digital Object
Identifier) number, PMID (PubMed ID number), and/or PMCID (PubMed Central ID number) as
this may make it easier for reviewers to find electronic copies of publications if they want to
review the paper.
(Regulatory reference ICH E:6, Section 6.2.7)
Appendices
If applicable
Appendices can include but not limited to Site roster, Schedule of events, lab processing
procedures, case report forms, package inserts, manual of procedures, advertisements, patient
education materials, study diaries, behavioral evaluations/tests, or other signification
information.
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4.0 FDA GUIDANCE INFORMATION
Below are links to a number of FDA guidance documents and FDA guidance sites that may be
useful with regard to choice of study design and drafting of a clinical protocol involving use of an
investigational drug.
FDA Guidance Documents on Clinical Pharmacology:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064982.htm
FDA Guidance Documents on Clinical / Medical:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm
FDA Guidance Documents on Biopharmaceutics:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064964.htm
FDA Guidance Documents on Drug Safety:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064993.htm
FDA Guidance Documents on International Conference on Harmonisation – Efficacy:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065004.htm
FDA Guidance Document: Collection of Race and Ethnicity Data in Clinical Trials
http://www.fda.gov/cder/guidance/5656fnl.htm
International Committee on Harmonization (ICH) E: 6 Good Clinical Practices
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__
Guideline.pdf
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