M11 TEMPLATE: 
 CLINICAL ELECTRONIC STRUCTURED 
HARMONISED PROTOCOL  
(CESHARP)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact 
the FDA staff responsible for this guidance as listed on the title page.  The draft guidance has been 
left in the original International Council for Harmonisation format.  The final guidance will be 
reformatted and edited to conform with FDAs good guidance practice regulation and style. 
 
 
 
 
 
 
  
 
 
For questions regarding this draft document, contact (CDER) Veronica Pei, 240-402-7091, 
Veronica.Pei@fda.hhs.gov.    
   
FOREWORD 
 
 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained in 
the most resource-efficient manner.  By harmonizing the regulatory expectations in regions around 
the world, ICH guidelines have substantially reduced duplicative clinical studies, prevented 
unnecessary animal studies, standardized safety reporting and marketing application submissions, 
and contributed to many other improvements in the quality of global drug development and 
manufacturing and the products available to patients.  
 
 
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-based 
guidelines by regulators around the globe is critical to realizing the benefits of safe, effective, and 
high-quality medicines for patients as well as for industry.  As a Founding Regulatory Member of 
ICH, the Food and Drug Administration (FDA) plays a major role in the development of each of the 
ICH guidelines, which FDA then adopts and issues as guidance to industry.   
 
 
   
 
 
 
 
 
INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 
 
 
 
 
ICH HARMONISED GUIDELINE 
 
 
 
CLINICAL ELECTRONIC STRUCTURED HARMONISED 
PROTOCOL 
(CESHARP) 
 
M11 TEMPLATE 
 
 
Draft version 
Endorsed on 27 September 2022 
Currently under public consultation 
 
 
 
 
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH 
Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities of the 
ICH regions for internal and external consultation, according to national or regional procedures. 
   
M11 Template 
Document History 
 
Code  History  Date 
M11  Endorsement by the Members of the ICH Assembly  27 September 
under Step 2 and release for public consultation  2022 
(document dated 4 September 2022).  
 
 
 
 
 
 
 
 
 
 
 
 
Legal notice: This document is protected by copyright and may, with the exception of the ICH 
logo, be used, reproduced, incorporated into other works, adapted, modified, translated or 
distributed under a public license provided that ICH's copyright in the document is acknowledged 
at all times. In case of any adaption, modification or translation of the document, reasonable steps 
must be taken to clearly label, demarcate or otherwise identify that changes were made to or based 
on the original document. Any impression that the adaption, modification or translation of the 
original document is endorsed or sponsored by the ICH must be avoided.  
The document is provided "as is" without warranty of any kind. In no event shall the ICH or the 
authors of the original document be liable for any claim, damages or other liability arising from 
the use of the document.  
The above-mentioned permissions do not apply to content supplied by third parties. Therefore, 
for documents where the copyright vests in a third party, permission for reproduction must be 
obtained from this copyright holder. 
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1  Interventional Clinical Trial Protocol Template 
2  0  Foreword 
3  0.1  Template Revision History 
Date   Description of Revision 
(To be determined)  Initial template 
4  0.2  Intended Use of Template 
5  This template is intended for interventional clinical trials of drugs, vaccines, and drug/device 
6  combinations intended to be registered as drugs.  The template is suitable for all phases of 
7  clinical research and all therapeutic areas.  Existing ICH Guidelines and ISO 14155 were 
8  considered in its development. The template is designed to enable modification suitable for the 
9  particular trial.  Refer to the sections below for additional details and conventions related to 
10  flexibility. 
11  0.3  Template Conventions and General Instructions 
12  This template uses the typefaces described in the table below to distinguish between their 
13  intended use and applicability.  Use of consistent font sizes (12 point) throughout the document 
14  is recommended, but not required.   
Type of Text  Typeface Details  Description (Intended Use) 
(Applicability) 
Universal text   Black Times New Roman font  Text that should appear in all 
protocols 
Instructional text  Red Calibri font  Text that provides instructions, but 
which should not appear in a final 
(Delete for final document) 
protocol 
Suggested text  Blue Century font  Text that is suitable for many trials, 
but which may need to be modified, 
Restyle to Black Times New 
deleted, or replaced according to the 
Roman for final document 
specific aspects of the trial  
{braces} in the prevailing 
Variable text  Where a choice is suggested between 
typeface 
options in a passage of text, braces 
Select from choices by  are used to separate them 
eliminating unwanted options; 
remove braces and restyle 
remaining text to match other 
text in the final document 
Fields  [Square brackets] in the  Brackets with grey shading are used 
prevailing typeface with grey  to indicate variable text modelled as a 
shading  field in the electronic manifestation of 
the protocols   
3 
   
Type of Text  Typeface Details  Description (Intended Use) 
(Applicability) 
Populate field from available 
choices, or with free text if 
indicated; remove brackets and 
restyle text to match other text 
in the final document 
15   
16  Heading Structure and Flexibility  
17  This template uses the typefaces and numbering conventions described in the table below to 
18  distinguish between heading levels.  To ensure consistency and predictability for all readers, the 
19  numbering conventions should be strictly observed.  However, fonts, font sizes, and colour are 
20  not intended to be fixed requirements, and can be adapted as specific situations may dictate, 
21  or per country or regional requirements.   
Example  Heading  Typeface  Modification or Deletion  Addition 
Heading  Level  in this 
Template 
14 point 
Times 
New 
Roman 
LEVEL 1 
1  Do not add L1 Headings 
(L1)  Bold 
Black 
Do not delete or modify 
ALL  L1 or L2 headings 
CAPS  Retain heading and 
indicate Not Applicable 
14 point 
Times 
Level 2  New 
1.1 
(L2)  Roman 
Add L2 headings, if 
Bold  needed, at the end of the 
Black  higher-level section to 
preserve the established 
Do not delete or modify 
L1 and L2 heading 
12 point  Level 3 safety 
structure 
Level 3  Times New  subheadings (Section 8.4) 
1.1.1 
(L3)  Roman  Other Level 3 headings 
Bold Black 
may be deleted or 
modified as needed 
4 
   
Example  Heading  Typeface  Modification or Deletion  Addition 
Heading  Level  in this 
Template 
Level 4 
1.1.1.1 
(L4) 
Delete heading or modify 
Additional 
Non- Insert where needed 
as needed 
Non-
numbered 
Numbered 
heading 
Heading 
22   
23  Table and Figure Numbering 
24  Tables and figures should be numbered and include a title or caption, respectively.  No 
25  numbering convention is specified by this template, but a consistent approach should be 
26  applied throughout the document. 
27  Page orientation can be modified from portrait to landscape as needed. 
28  Terminology 
29  The following terminology has been selected for use within this template and is considered to 
30  be appropriate for all phases, trial populations, and therapeutic areas: 
31    Because the scope of this protocol template is focused on interventional clinical trials, 
32  the term clinical trials is used rather than clinical studies when referring to 
33  interventional clinical trials. 
34    Participant is used rather than subject, healthy volunteer, or patient when referring to 
35  an individual who has consented to participate in the clinical trial. Patient or individual is 
36  used to distinguish the population represented by the trial participants, when 
37  necessary.  
38    Trial intervention refers to any therapeutic, prophylactic, or diagnostic agent including 
39  pharmaceuticals, biologics, vaccines, cell or gene therapy products (when applicable), 
40  and drug-device combination products when registered as a drug. Trial interventions 
41  include the agent being tested or used as a control (for example, placebo or active 
42  comparator). Procedures conducted to manage participants or to collect data are 
43  excluded from the usage of this term. 
44    While blinding is the more commonly used term, masking is an alternative term which 
45  may be used in certain situations.   
46  Suggestions for Publishing a Paper or .pdf Document: 
47  Various formatting, typefaces, and instructional elements are used in this template to inform 
48  preparation activities, but these should not appear in final protocols.  Specific recommended 
49  steps for finalisation are as follows:   
5 
   
50    Delete Section 0 and all its contents 
51    Update the Table of Contents (TOC).   
52    Confirm that the Level 1 and Level 2 headings are visible in the navigation pane or 
53  bookmark view).  Visible Level 3 bookmarks are also recommended.   
54    Delete unneeded or non-applicable Level 3 or lower headings and ensure remaining 
55  Level 3 and lower headings are numbered appropriately 
56    Delete any unused variable text and related prompts 
57    Restyle any suggested, example, or variable text to match the regular text 
58    Remove all instructional text, and 
59    Remove brackets that denote variable or field text after making appropriate selections. 
60  As a reminder, protocols often become public through transparency requirements in various 
61  regions/countries.   
62  0.4  Abbreviations Used in this Template 
Abbreviation or Acronym  Definition 
AE  Adverse Event 
AESI  Adverse Events of Special Interest 
AxMP  Auxiliary Medicinal Product 
CDISC  Clinical Data Interchange Standards Consortium 
COAs  Clinical Outcome Assessment(s) 
CRF  Case Report Form 
DREs  Disease-Related Events 
ECG  Electrocardiogram 
EU  European Union 
EUDAMED  European Databank on Medical Devices 
European Union Drug Regulating Authorities Clinical Trials 
EudraCT 
Database 
IB  Investigators Brochure 
ICF  Informed Consent Form 
ICH  International Council for Harmonisation 
IDE  Investigational Device Exemption 
IEC  Independent Ethics Committee 
IMP  Investigational Medicinal Product 
IND  Investigational New Drug 
6 
   
Abbreviation or Acronym  Definition 
IRB  Institutional Review Board 
IVRS  Interactive Voice Response System 
IWRS  Interactive Web Response System 
jRCT  Japan Registry of Clinical Trials 
MedDRA  Medical Dictionary for Regulatory Activities 
N/A  Not Applicable 
NCT  National Clinical Trial  
NIMP  Non-Investigational Medicinal Product 
PD  Pharmacodynamics 
PK  Pharmacokinetics 
SAE  Serious Adverse Event 
SoA  Schedule of Activities 
TOC  Table of Contents 
WHO  World Health Organization 
63     
7 
   
Protocol Full Title:  [Protocol Full Title] 
The protocol should have a descriptive title that identifies the 
scientific aspects of the trial sufficiently to ensure it is 
immediately evident what the trial is investigating and on 
whom, and to allow retrieval from literature or internet 
searches. 
Sponsor  [Sponsor Confidentiality Statement] 
Confidentiality 
Insert the Sponsors confidentiality statement, if applicable, 
Statement: 
otherwise delete. 
Protocol Number:  [Protocol Number] 
A unique alphanumeric identifier for the trial, designated by the 
Sponsor, is a standard part of trial data, and should be included 
for most trials.   
Version:  [Version] 
An optional field for use by the Sponsor at their discretion. 
Amendment Number:   [Amendment Number] 
Enter the amendment number.  If this is the original instance of 
the protocol, indicate Not Applicable. 
Amendment Scope:  [Amendment Scope] [Country/Region Identifier] 
Acceptable entries for amendment scope are:  global or 
Country-specific/Regional 
Use the ISO-3166 region or country identifier (for example, DE 
or EU).  For global trials delete the Country/Region Identifier 
field. 
Compound Number(s):   [Compound Number] 
Enter the Sponsors unique identifier for investigational 
compound(s) in the trial.  Add or delete additional fields as 
needed. 
Compound Name(s):  [Nonproprietary Name], [Proprietary Name], [Additional 
Proprietary Name] 
Delete this line from the table if a nonproprietary name has not 
yet been assigned.  Omit proprietary name fields if not yet 
established. 
Trial Phase:   [Trial Phase] [Description of Trial Phase Other] 
Acceptable entries are:  Early Phase 1, Phase 1, Phase 
1/Phase 2, Phase 2, Phase 2/Phase 3, Phase 3, Phase 4,  
8 
   
or Other.  For trials combining investigational drugs or 
vaccines with devices, classify according to the phase of drug 
development.  
Acronym:   [Protocol Acronym]  
Acronym or abbreviation used publicly to identify the clinical 
trial, if any.  The acronym may include numerals, such as -1, -2, 
or I, II, III, or IV.  Delete this line from the table if not applicable. 
Short Title:  
[Protocol Short Title]  
Short title should convey in plain language what the trial is 
about and is suitable for use as Brief Title or Title in Plain 
Language in global clinical trial registries.  It can also be suitable 
for use with informed consents and ethics committee 
submissions.  
Sponsor Name and  [Sponsor Name]  
Address:  
[Sponsor Legal Address] 
Provide the legal name of the individual or pharmaceutical or 
medical device company, governmental agency, academic 
institution, private organisation, or other organisation who takes 
primary responsibility for and initiates a clinical investigation.  If 
more than one Sponsor, list the Primary Sponsor in this field.    
Local Sponsor Name and Address: 
[Sponsor Local Name] 
[Sponsor Local Address] 
In some countries, the clinical trial Sponsor may be the local 
affiliate company (or designee).  In such cases, indicate in the 
Sponsor Local Name and Address Field. 
Manufacturer Name 
[Device Manufacturer Name] 
and Address:  
[Device Manufacturer Address] 
Manufacturer name and address information is required only for 
protocols that include investigational device(s) and should not 
be included for other protocols. Include the manufacturer 
address only if the manufacturer is different than the Sponsor 
listed above.   
Add additional fields as needed if multiple investigational 
devices will be used in the trial.  Delete this line from the table if 
not applicable. 
9 
   
Regulatory Agency  [EUDAMED:  [EUDAMED Number]]  
Identifier Number(s): 
[EudraCT Number:  [EudraCT Number]]   
 
[EU Trial Number:  EU Trial Number]]  
[IDE:  [IDE Number]] 
[IND:  [IND]] 
[jRCT:  [jRCT Number]] 
[NCT:  [NCT Number]]:  
[NMPA IND:  [NMPA IND]] 
[WHO:  [WHO Number]]: 
[Other:  [Other Regulatory Agency Identifier Number]]  
Include all numbers that are applicable for the trial and available 
at the time of protocol or amendment finalisation.  Delete 
prompts for numbers not available at the time of document 
finalisation.  Delete unused fields.  Add fields for other if more 
than one is needed. 
Sponsor Approval Date:   [Approval Date] or [The approval date is included with the 
electronic signature, located {describe location}.] 
All versions should be uniquely identifiable.  Use the CDISC date 
format (dd/mmm/yyyy, for example 07/JUN/2015) to indicate 
the date the protocol (or amendment) was approved by the 
Sponsor. 
64   
65  Sponsor Signatory: 
66   
67   
[Name]    [Sponsor Signature Date] 
[Title of Sponsor Signatory] 
68  or 
69  [This protocol was approved via {describe method} as described on the approval 
70  page appended to the document] 
71  Where allowed, an electronic/digital signature may be used for approval rather than a wet 
72  signature.  In such cases, replace the signature block with appropriate description of the 
73  electronic/digital approval and the location of relevant information for traceability. 
10 
   
74  Medical Monitor Name and Contact Information: [Medical Monitor Institution Name], 
75  [Medical Monitor Institution Address] or [ is provided separately/can be found in 
76  {describe location}].  
77  Report Serious Adverse Events within 24 hours {via E-mail/fax provided in the site 
78  manual. /per the options below:}  
79  E-mail: [Rapid Alert E-mail Address] 
80  Fax: [Rapid Alert Fax Number] 
81  Amendment Details 
82  Delete this entire section for an original protocol. 
83  History of Amendments 
84  {#/A total of #} prior {global} amendments have occurred, as shown in the table below: 
Sponsor Approval Date       Approximate {(#/%)} 
Document  (dd/mmm/yyyy)  Enrolled     
[Amendment x]  [Amendment x Date]  {(#/%)} {globally/locally}} 
[Amendment x]  [Amendment x Date]  {(#/%)} {globally/locally} 
[Amendment x]  [Amendment x Date]  {(#/%)} {globally/locally} 
Original Protocol  [Original Protocol Date]  0 
85  Do not include the current amendment in the table above, as final approval dates are often 
86  difficult to predict during document preparation.  Previous amendments should appear in 
87  reverse chronological order with the most recent at the top (for example, Amendment 3, 2, 1).  
88  Delete lines not needed, add lines as needed.  Inclusion of regional-, country-, and site-specific 
89  amendments in the table is optional.  If included, ensure that the scope is clearly 
90  distinguishable from global amendments. 
91  If including the column with enrollment numbers, follow the instructions below. 
92    For global amendments, list approximate global enrollment total or percentage at the 
93  time of the amendment and select globally.   
94    For country/region amendments, list the approximate local enrollment total or 
95  percentage at the time of the amendment and select locally.  
96  Current Amendment 
97  The table below provides an overview of the current amendment. 
Amendment Number:  [Amendment Number] 
Approximate {%/#} 
[Estimated % or # Enrolled] enrolled [Globally/Locally]  
Enrolled: 
Enter the approximate number or percentage of participants 
enrolled as a percentage of the expected total.  If the number of 
expected participants is changing as a result of the current 
amendment, use the updated number of expected participants to 
11 
   
estimate the current percent of enrollment.  Estimates are 
adequate, as precise enrollment figures will likely be changing while 
an amendment is being prepared.  For a global amendment, 
provide the estimated global enrollment at the time of the Sponsor 
approved the amendment.  For a country/regional amendment, 
provide the estimated local or regional enrollment at the time the 
Sponsor approved the amendment. 
Reason(s) for  Primary: [Primary Reason for  Other: [Other Reason for 
Amendment:   Amendment] *  Amendment] * 
Select from the following  Select from the following 
(multiple selections allowed):  (multiple selections allowed): 
  Regulatory agency    Regulatory agency 
request to amend  request to amend 
  New regulatory guidance    New regulatory guidance 
  IRB/IEC feedback    IRB/IEC feedback 
  New safety information    New safety information 
available  available 
  Manufacturing change    Manufacturing change 
  Adaptive clinical trial IMP    Adaptive clinical trial IMP 
addition  addition 
  Change in strategy     Change in strategy  
  Change in standard of    Change in standard of 
care  care 
  New data available    New data available 
(other than safety data)  (other than safety data) 
  Investigator/site    Investigator/site 
feedback  feedback 
  Recruitment difficulty    Recruitment difficulty 
  Inconsistency and/or    Inconsistency and/or 
error in the protocol  error in the protocol 
  Protocol design error    Protocol design error 
  Other:  [Describe]     Other:  [Describe] 
  Not applicable 
Summary of the  [Summary of Amendment] 
Amendment:  Specify on the primary reason for the amendment with details 
specific to the trial.  If more than one key change prompted the 
amendment, discuss briefly.  Incidental changes which are included 
in the amendment but unrelated to the key changes do not need to 
be described here. 
Is this amendment likely to have a  [Yes/No] 
substantial impact on   Indicate whether the current amendment is 
  safety or rights of the participants, or  likely to have a significant impact on either of 
the criteria listed.   
12 
   
  on the reliability and robustness of the 
data generated in the clinical trial? 
98  * Choose from the available categories as the primary reason and secondary reason(s) for the 
99  amendment.  Select the closest match among the choices.  Changes to key measures or 
100  endpoints should be listed as a change of strategy.  If none of the choices apply, choose other 
101  and provide a description.  If no secondary reason, indicate not applicable for the secondary 
102  reason. 
103  Summary of Changes in the Current Amendment: 
Section # and 
Name  Description of Change  Brief Rationale for Change 
[Location of  [Description of Change]  [Rationale for Amendment 
Change]  Change] 
[Location of  [Description of Change]  [Rationale for Amendment 
Change]  Change] 
[Location of  [Description of Change]  [Rationale for Amendment 
Change]  Change] 
104  (Add lines as needed) 
105  Follow the steps below to prepare the summary of changes. 
106    If a Summary of Changes already exists from a prior amendment, move it to Section 
107  13.4, History of Previous Amendments, and populate a clean summary table for the 
108  present amendment.   
109    List the changes that apply to the current amendment.  Provide a brief description of 
110  the change(s) and a brief scientific rationale for specific changes (for example, change to 
111  individual inclusion/exclusion criteria).   
112  Tabular presentation is common but not required.  The page can be changed to landscape 
113  orientation if necessary.   
13 
   
114  Table of Contents 
115   
116  1  PROTOCOL SUMMARY .................................................................................................... 19 
117  1.1  Protocol Synopsis ........................................................................................................... 19 
118  1.2  Trial Schema .................................................................................................................. 22 
119  1.3  Schedule of Activities .................................................................................................... 22 
120  2  INTRODUCTION ................................................................................................................ 23 
121  2.1  Purpose of Trial .............................................................................................................. 23 
122  2.2  Summary of Benefits and Risks ..................................................................................... 23 
123  3  TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS ................................................ 25 
124  3.1  {Primary/Secondary/Exploratory} Objective + Associated Endpoint {and Estimand} 25 
125  4  TRIAL DESIGN ................................................................................................................... 26 
126  4.1  Description of Trial Design ............................................................................................ 26 
127  4.1.1  Participant Input into Design .................................................................................. 27 
128  4.2  Rationale for Trial Design .............................................................................................. 27 
129  4.2.1  Rationale for Comparator ....................................................................................... 27 
130  4.2.2  Rationale for Adaptive or Novel Trial Design ........................................................ 28 
131  4.2.3  Other Trial Design Considerations ......................................................................... 28 
132  4.3  Access to Trial Intervention After End of Trial ............................................................. 28 
133  4.4  Start of Trial and End of Trial ........................................................................................ 28 
134  5  TRIAL POPULATION ......................................................................................................... 29 
135  5.1  Selection of Trial Population ......................................................................................... 29 
136  5.2  Rationale for Trial Population ........................................................................................ 29 
137  5.3  Inclusion Criteria ............................................................................................................ 29 
138  5.4  Exclusion Criteria ........................................................................................................... 30 
139  5.5  Lifestyle Considerations ................................................................................................. 30 
140  5.5.1  Meals and Dietary Restrictions ............................................................................... 30 
141  5.5.2  Caffeine, Alcohol, Tobacco, and Other Habits ....................................................... 30 
142  5.5.3  Physical Activity ..................................................................................................... 30 
143  5.5.4  Other Activity ......................................................................................................... 30 
144  5.6  Screen Failures ............................................................................................................... 30 
145  6  TRIAL INTERVENTION AND CONCOMITANT THERAPY......................................... 31 
146  6.1  Description of Trial Intervention.................................................................................... 31 
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147  6.2  Rationale for Trial Intervention...................................................................................... 31 
148  6.3  Dosing and Administration ............................................................................................ 32 
149  6.3.1  Trial Intervention Dose Modification ..................................................................... 32 
150  6.4  Treatment of Overdose ................................................................................................... 32 
151  6.5  Preparation, Handling, Storage and Accountability ....................................................... 32 
152  6.5.1  Preparation of Trial Intervention ............................................................................ 32 
153  6.5.2  Handling and Storage of Trial Intervention ............................................................ 33 
154  6.5.3  Accountability of Trial Intervention ....................................................................... 33 
155  6.6  Participant Assignment, Randomisation and Blinding .................................................. 33 
156  6.6.1  Participant Assignment ........................................................................................... 33 
157  6.6.2  Randomisation ........................................................................................................ 34 
158  6.6.3  Blinding and Unblinding......................................................................................... 34 
159  6.7  Trial Intervention Compliance ....................................................................................... 34 
160  6.8  Concomitant Therapy ..................................................................................................... 34 
161  6.8.1  Prohibited Concomitant Therapy ............................................................................ 35 
162  6.8.2  Permitted Concomitant Therapy ............................................................................. 35 
163  6.8.3  Rescue Therapy ....................................................................................................... 35 
164  6.8.4  Other Therapy ......................................................................................................... 35 
165  7  DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
166  WITHDRAWAL FROM TRIAL ................................................................................................. 36 
167  7.1  Discontinuation of Trial Intervention ............................................................................. 36 
168  7.1.1  Criteria for Permanent Discontinuation of Trial Intervention ................................ 36 
169  7.1.2  Temporary Discontinuation or Interruption of Trial Intervention .......................... 36 
170  7.1.3  Rechallenge ............................................................................................................. 36 
171  7.2  Participant Withdrawal from the Trial ........................................................................... 37 
172  7.3  Lost to Follow-Up .......................................................................................................... 37 
173  7.4  Trial Stopping Rules....................................................................................................... 37 
174  8  TRIAL ASSESSMENTS AND PROCEDURES ................................................................. 38 
175  8.1  Screening/Baseline Assessments and Procedures .......................................................... 38 
176  8.2  Efficacy Assessments and Procedures ........................................................................... 38 
177  8.3  Safety Assessments and Procedures ............................................................................... 38 
178  8.3.1  Physical Examination.............................................................................................. 39 
179  8.3.2  Vital Signs ............................................................................................................... 39 
15 
   
180  8.3.3  Electrocardiograms ................................................................................................. 39 
181  8.3.4  Clinical Laboratory Assessments ............................................................................ 39 
182  8.3.5  Suicidal Ideation and Behaviour Risk Monitoring ................................................. 39 
183  8.4  Adverse Events and Serious Adverse Events ................................................................. 39 
184  8.4.1  Definitions of AE and SAE..................................................................................... 39 
185  8.4.2  Time Period and Frequency for Collecting AE and SAE Information ................... 40 
186  8.4.3  Identifying AEs and SAEs ...................................................................................... 40 
187  8.4.4  Recording of AEs and SAEs ................................................................................... 40 
188  8.4.5  Follow-up of AEs and SAEs ................................................................................... 40 
189  8.4.6  Reporting of SAEs .................................................................................................. 40 
190  8.4.7  Regulatory Reporting Requirements for SAEs ....................................................... 40 
191  8.4.8  Serious and Unexpected Adverse Reaction Reporting ........................................... 40 
192  8.4.9  Adverse Events of Special Interest ......................................................................... 41 
193  8.4.10  Disease-related Events or Outcomes Not Qualifying as AEs or SAEs .................. 41 
194  8.5  Pregnancy and Postpartum Information ......................................................................... 41 
195  8.5.1  Participants Who Become Pregnant During the Trial............................................. 41 
196  8.5.2  Participants Whose Partners Become Pregnant ...................................................... 42 
197  8.6  Medical Device Product Complaints for Drug/Device Combination Products ............. 42 
198  8.6.1  Definition of Medical Device Product Complaints ................................................ 42 
199  8.6.2  Recording of Medical Device Product Complaints ................................................ 42 
200  8.6.3  Time Period and Frequency for Collecting Medical Device Product Complaints . 42 
201  8.6.4  Follow-Up of Medical Device Product Complaints ............................................... 42 
202  8.6.5  Regulatory Reporting Requirements for Medical Device Product Complaints...... 42 
203  8.7  Pharmacokinetics ........................................................................................................... 43 
204  8.8  Genetics .......................................................................................................................... 43 
205  8.9  Biomarkers ..................................................................................................................... 43 
206  8.10  Immunogenicity Assessments ........................................................................................ 43 
207  8.11  Medical Resource Utilisation and Health Economics .................................................... 44 
208  9  STATISTICAL CONSIDERATIONS.................................................................................. 45 
209  9.1  Analysis Sets .................................................................................................................. 45 
210  9.2  Analyses Supporting Primary Objective(s) .................................................................... 45 
211  9.2.1  Statistical Model, Hypothesis, and Method of Analysis ......................................... 45 
16 
   
212  9.2.2  Handling of Intercurrent Events of Primary Estimand(s) ....................................... 45 
213  9.2.3  Handling of Missing Data ....................................................................................... 46 
214  9.2.4  Sensitivity Analysis ................................................................................................ 46 
215  9.2.5  Supplementary Analysis ......................................................................................... 46 
216  9.3  Analysis Supporting Secondary Objective(s) ................................................................ 46 
217  9.4  Analysis of Exploratory Objective(s) ............................................................................. 46 
218  9.5  Safety Analyses .............................................................................................................. 46 
219  9.6  Other Analyses ............................................................................................................... 47 
220  9.7  Interim Analyses ............................................................................................................ 47 
221  9.8  Sample Size Determination ............................................................................................ 47 
222  9.9  Protocol Deviations ........................................................................................................ 48 
223  10  GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND TRIAL 
224  OVERSIGHT ................................................................................................................................ 48 
225  10.1  Regulatory and Ethical Considerations .......................................................................... 48 
226  10.2  Committees..................................................................................................................... 48 
227  10.3  Informed Consent Process .............................................................................................. 48 
228  10.4  Data Protection ............................................................................................................... 49 
229  10.5  Early Site Closure or Trial Termination ......................................................................... 49 
230  11  GENERAL CONSIDERATIONS: RISK MANAGEMENT AND QUALITY 
231  ASSURANCE ............................................................................................................................... 50 
232  11.1  Quality Tolerance Limits ............................................................................................... 50 
233  11.2  Data Quality Assurance .................................................................................................. 50 
234  11.3  Source Data .................................................................................................................... 50 
235  12  APPENDIX:  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
236  DEFINITIONS, SEVERITY, AND CAUSALITY ...................................................................... 51 
237  12.1  Further Details and Clarifications on the AE Definition................................................ 51 
238  12.2  Further Details and Clarifications on the SAE Definition ............................................. 51 
239  12.3  Severity........................................................................................................................... 51 
240  12.4  Causality ......................................................................................................................... 51 
241  13  APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL DETAILS .............. 52 
242  13.1  Contraception and Pregnancy Testing............................................................................ 52 
243  13.1.1  Definitions Related to Childbearing Potential ........................................................ 52 
244  13.1.2  Contraception .......................................................................................................... 52 
17 
   
245  13.1.3  Pregnancy Testing ................................................................................................... 52 
246  13.2  Clinical Laboratory Tests ............................................................................................... 52 
247  13.3  Country/Region-Specific Differences ............................................................................ 53 
248  13.4  Prior Protocol Amendments ........................................................................................... 53 
249  14  APPENDIX:  GLOSSARY OF TERMS .............................................................................. 54 
250  15  APPENDIX:  REFERENCES............................................................................................... 54 
251   
252     
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253  1  PROTOCOL SUMMARY 
254  No text is intended here (header only).  
255  1.1  Protocol Synopsis 
256  The protocol synopsis is a short summary of the key points of the trial. 
257  No text is intended here (header only).  
258  Primary and Secondary Objectives and Endpoints 
259  Include a copy of the Objectives/Endpoints Table including primary and secondary endpoints 
260  only from Section 3 of the protocol and follow all the same instructions.  Not all trials will have 
261  a complete estimand.  Do not include exploratory endpoints in the synopsis.  
262  [Primary and Secondary Objectives and Endpoints] 
263  Overall Design 
264  Several key aspects of the trial  design are summarised below. 
Intervention Model:  [intervention  Population Type:  [population type] 
model] 
Control:  [control]  Population Diagnosis  [diagnosis or 
or Condition:  condition] 
Active Comparator:  [comparator]  Population Age:  Minimum:  
[minimum age]  
Maximum: 
[maximum age] 
Trial Intervention  [intervention  Site Distribution:  [geographic scope] 
Assignment  assignment 
Method:  method] 
265  Briefly state the following: 
266    Intervention model (for example, single group, parallel group, cross-over, factorial, 
267  sequential).  
268    Control (for example, placebo, active comparator, low dose, historical, standard of care, 
269  sham procedure, or none [uncontrolled]).  
270    Active comparator, if applicable; indicate N/A if not applicable. 
271    Trial intervention assignment method (for example, randomisation, stratification, or 
272  both). Do NOT state block size. If assignment to intervention is by randomisation, 
273  describe when randomisation occurs relative to screening. 
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274    Trial population type (for example, healthy volunteers, adult patients, paediatric 
275  patients).   
276    Population Diagnosis or Condition (for example, acute lung injury, or a specific 
277  biomarker profile); indicate N/A  Healthy for trials in healthy volunteers. 
278    Population age range (for example 3 mos, 18 to 80 years old).  List N/A if a maximum 
279  or minimum age limit does not apply.  For trials in which multiple age ranges may be 
280  eligible (for example, a younger cohort and an older cohort), indicate the minimum and 
281  maximum ages for the trial overall, with an additional comment for any excluded age 
282  ranges. 
283    Site distribution (select from: single-site, multi-site, or multi-site and multi-regional).  If 
284  none of these applies, indicate other and describe. 
285  Number of Arms: [Number of Arms]   
286  Enter the numeric value for the number of arms in the trial. For trials with a different number 
287  of arms in different periods, populate this field based on the period with the greatest number 
288  of arms.  
289  Blinding:  The following roles indicated below will not be made aware of the treatment group 
290  assignment during the trial:  [blinded roles].  
291  Select from the following blinded roles:   
292    Participant 
293    Care Provider 
294    Investigator 
295    Outcomes Assessor:  the individual who evaluates the outcome(s) of interest 
296    Not applicable (No blinding). 
297  For designs in which these details may differ in one or more trial periods, answer according to 
298  the portion of the trial in which the greatest blinding occurs.  More details can be provided in 
299  Section 6.6 of the protocol.  Note that this list does not include Sponsor staff or their designees 
300  who may be unblinded to complete ongoing safety oversight and surveillance reporting.  
301  Not Applicable (No blinding) indicates an open-label trial. 
302  Number of Participants:   
303  Number {randomly assigned to trial intervention/ enrolled}: {x} participants  [{Target/ 
304  Maximum}] 
305  State the expected number of participants to be assigned to trial intervention/enrolled.  
306  Indicate whether the number provided is the target or maximum number of individuals to be 
307  randomly assigned to trial intervention/enrolled. 
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308  Arms and Duration 
309  Total duration of trial intervention for each participant: 
310  [Approximately] [x] Year(s)/[x] Month(s)/[x] Day(s) 
311  or 
312  Duration will vary [Reason duration of trial intervention will vary] 
313  Total duration of trial participation for each participant:   
314  [Approximately] [x] Year(s)/[x] Month(s)/[x] Day(s) 
315  or 
316  Duration will vary [Reason duration of trial participation will vary] 
317  Select the text that applies to the trial.  Note that total duration of participation should include 
318  any washout and any follow-up periods in which the participant is not receiving trial 
319  intervention.  Where the total durations can be provided, indicate whether the duration is 
320  approximate, and delete terms that are not applicable (for example, for a trial of only a few 
321  days, delete the years and months terms).  When duration cannot be approximated, provide a 
322  short explanation (for example, event-driven or adaptive design). 
323  [Arms and Duration Description]  
324  Briefly state: 
325    Total duration of participation for each participant with sequence and duration of trial 
326  periods (for example, screening, run-in, fixed dose/titration, follow-up/washout periods) 
327    Dose regimens in each trial period and stage (if applicable) including frequency (for 
328  example, twice daily) and route of administration and criteria for individualised dosing 
329  (for example, participant weight or plasma concentrations), if applicable 
330    Rules/procedures for any dose changes/adjustments including flexible dosing; dose 
331  reductions, dose interruptions, or tapering; discontinuation; and any circumstances for 
332  resuming trial intervention, as applicable 
333  If sufficiently detailed, a cross-reference to the trial schema is appropriate in lieu of text 
334  description. 
335   
336  Committees:   
337  Indicate whether any committee(s) will be reviewing data while the trial is ongoing, and the 
338  type of committee.  Common examples include Data Monitoring Committee, Dose Escalation 
339  Committee, or Endpoint Adjudication Committee; describe others, if applicable.   List 
340  independent committees in the space indicated.  Other committees may be included at the 
21 
   
341  Sponsors discretion in the separate space provided.  Committees listed here should be fully 
342  described in Section 10.3, Committees Structure.     
343  Independent Committees:  [Independent Committees] 
344  Indicate N/A if no independent committees will be involved in the trial. 
345  Other Committees:  [Other Committees] 
346  Delete Other Committees if not applicable. 
347  1.2  Trial Schema 
348  The purpose of this section is to provide a visual depiction of the trial design, orienting users of 
349  the protocol to the key features of the design.  The schema depicts the trial arms, the flow of 
350  individual participants through the progression of trial period(s)/epochs (such as screening, 
351  washout/run-in, intervention, and key milestones [for example, randomisation, cross-over, end 
352  of treatment]).  For complex trials, additional schemas may be added to describe activities or 
353  trial periods in greater detail. 
354  [Schema] 
355  1.3  Schedule of Activities 
356  The schedule of activities must capture the procedures that will be accomplished at each trial 
357  visit, and all contact with participants, for example, telephone contacts. This includes any tests 
358  that are used for eligibility, participant randomisation or stratification, or decisions on trial 
359  intervention discontinuation. Allowable windows should be stated for all visits.  
360  [Schedule of Activities] 
361     
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362  2  INTRODUCTION 
363  No text is intended here (header only).  
364  2.1  Purpose of Trial 
365  Explain why the trial is needed, why the research questions being asked are important.  Do not 
366  restate the IB. 
367  [Purpose] 
368  Refer to the Section 1.2, Trial Schema, and Section 1.3, Schedule of Activities, for 
369  more information about the trial design. 
370  2.2  Summary of Benefits and Risks 
371  Include an assessment of known benefits and potential risks, including the basis of the risk (for 
372  example, preclinical studies or prior clinical trials).   
373  Benefit Summary 
374  The benefit summary should be written from the perspective of an individual participant, and 
375  should describe any physical, psychological, social, legal, or any other potential benefits to 
376  individual participants as a result of participating in the trial, addressing immediate potential 
377  benefits and/or long-range potential benefits.  Clearly state if no benefits to an individual 
378  participant can be anticipated, or if potential benefits are unknown.  For early clinical trials such 
379  as Phase 1, benefits for an individual participant (other than those of altruism) are expected to 
380  be minimal.  
381  Benefits to society in general may also be included but should be discussed separately.  
382  [Benefit Summary] 
383  Risk Summary and Mitigation Strategy 
384  Trial Intervention  Discuss risks related to trial-specific treatments and interventions.  For the 
385  protocol, focus discussion only on the relevant key risks for THIS trial.  Provide a brief 
386  description of strategies to mitigate identified risks or provide a cross-reference to the relevant 
387  protocol section. 
388  [Trial-specific Discussion of Intervention Risks and Mitigations] 
389  Trial Procedures  Consider risks associated with the design (for example, placebo arm) and 
390  procedures specific to THIS trial (for example, biopsies), and any measures to control the risks. 
391  Provide a brief description of strategies to mitigate identified risks or provide a cross-reference 
392  to the relevant protocol section.  This is not intended to be an exhaustive list of all possible risks 
393  associated with trial procedures but should focus on the unique risks inherent in the design or 
394  less common or high-risk procedures.  As above, provide a brief description of strategies to 
395  mitigate identified risks or provide a cross-reference to the relevant protocol section. 
396  [Trial-specific Discussion of Procedure Risks and Mitigations] 
23 
   
397  Other  Consider risks associated with other items (for example, comparators, challenge 
398  agents, imaging agents, medical devices).  Insert a line for each, as needed. 
399  [Trial-specific Discussion of Other Risks and Mitigations] 
400  Overall Benefit:Risk Conclusion 
401  Provide a succinct, concluding statement on the perceived balance between risks that have 
402  been identified from cumulative safety data, protocol procedures, and anticipated 
403  efficacy/benefits within the context of the proposed trial. Risks need to be assessed against the 
404  benefits for the individual participant at least once a year.  
405  [Overall Benefit:Risk Conclusion] 
406     
24 
   
407  3  TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS 
408  In this section, precisely define each clinical question of interest by stating each trial objective 
409  and specifying the endpoint(s) and estimand(s) that correspond to each objective. Ensure 
410  alignment with every other section of the protocol. 
411  Include additional level 2 headers under Section 3 Trial Objectives, Endpoints, and Estimands as 
412  needed. 
413  No text is intended here (header only).  
414  3.1  {Primary/Secondary/Exploratory} Objective + Associated Endpoint 
415  {and Estimand} 
{Primary/Secondary/Exploratory}  {Primary/Secondary/Exploratory} Endpoint 
Objective 
[Objective]  [Endpoint] 
416  {Primary/Secondary/Exploratory} Estimand 
417  Describe the attributes that construct the estimand: the treatment condition of interest, the 
418  population of participants targeted by the clinical question of interest, other intercurrent 
419  events (if applicable), a population level summary, and the endpoint (or variable) specified in 
420  the table above. 
421  [Estimand Description] 
422     
25 
   
423  4  TRIAL DESIGN 
424  In this section, describe the trial design with specific mention, as applicable, of the components 
425  of an adequate and well-controlled trial and reflect the principles of Quality by Design. The 
426  description of the design should be concise and consistent across Section 1.1, Protocol Synopsis 
427  and Section 1.2, Trial Schema. 
428  No text is intended here (header only).  
429  4.1  Description of Trial Design 
430  Describe the trial intervention model (for example, single group, parallel group, cross-over, 
431  factorial, sequential), the expected number of participants, and the control method (for 
432  example, placebo, active comparator, low dose, historical, standard of care, sham procedure, or 
433  none [uncontrolled]).  
434  If applicable, indicate the type of trial (for example, superiority, non-inferiority, dose escalation, 
435  or equivalence).  
436  If the trial will have an adaptive or novel design (for example, the trial will be conducted under 
437  a master protocol), provide a summary of these design aspects. 
438  [Description of Intervention Model] 
439  Describe the trial duration with reference to Section 1.2, Trial Schema. Explain what the overall 
440  duration for an individual participant is anticipated to be and why, including the sequence and 
441  duration of trial periods (for example, screening, run-in, randomisation, treatment [fixed 
442  dose/titration], follow-up/washout periods).  Where applicable, include discussion of sentinel 
443  dosing (or lack thereof), dose escalation, and cohort expansion.  If dose modification decisions 
444  are dependent upon review by a committee, include details in Section 10.2, Committees 
445  Structure. 
446  [Description of Trial Duration] 
447  Describe the method of assignment to trial intervention (for example, stratified randomisation). 
448  If assignment to trial intervention is by randomisation, describe when randomisation occurs 
449  relative to screening.  
450  Describe the level and method of blinding; for example, single-blind, double-blind, [including 
451  Sponsor unblinded], matching placebo, double-dummy, or open-label). Include mention of 
452  measures taken to minimise bias on the part of participants, investigators, and analysts.  
453  If applicable, describe within-trial transition rules, for example, transitions involving cohorts or 
454  trial parts. Dose escalation or dose-ranging details should also be described.  
455  [Method of Assignment to Trial Intervention] 
456  Discuss any other important aspects of the design, including but not limited to the following, 
457  where applicable: 
26 
   
458    Geographic scope of trial (for example, single-centre, multi-centre, or multi-centre and 
459  multi-national)  
460    Use of decentralised processes, tools, or features in the trial 
461    Planned use of a Data Monitoring Committee, or similar review group and cross-
462  reference Section 10.2, Committees, for details,  
463    Whether an interim analysis is planned and, if so, refer to details in Section 9.7, Interim 
464  Analysis, and/or 
465    Any planned extension trial, long-term follow-up/registry, or post-trial sample analysis 
466  or other data-related activities. 
467  [Additional Description of Design] 
468  4.1.1  Participant Input into Design 
469  If applicable, describe any participant involvement in the design of the trial and any participant 
470  suggestions implemented. 
471  [Participant Input] 
472  4.2  Rationale for Trial Design 
473  Provide a rationale for the trial intervention model selected in Section 4.1, Description of Trial 
474  Design. A rationale for the choice of comparator, if applicable, should be described separately 
475  in Section 4.2.1, Rationale for Comparator. 
476  [Rationale for Intervention Model] 
477  Provide a rationale that the trial duration is appropriate to show a reliable and relevant effect 
478  of the trial intervention per the trial objective(s).  
479  [Rationale for Duration] 
480  Provide a rationale that the trial endpoint(s) described in Section 3, Trial Objectives, Endpoints, 
481  and Estimands, are clinically relevant and provide a reliable and valid measurement of the 
482  intended intervention effect.  
483  [Rationale for Endpoints] 
484  If applicable, provide a rationale for any interim analysis planned with respect to its purpose 
485  (for example, stopping the trial early for efficacy or futility) and timing. 
486  [Interim Analysis] 
487  4.2.1  Rationale for Comparator 
488  If applicable, provide a rationale for the type of control selected for the trial (for example, 
489  placebo, active drug, combination, historical). Discuss any known or potential problems 
490  associated with the control group selected in light of the specific disease and intervention(s) 
491  being studied.  If comparators will differ by region, describe.  Describe prior trials that support 
492  the dose and/or dose regimen. 
27 
   
493  [Rationale for Comparator] 
494  4.2.2  Rationale for Adaptive or Novel Trial Design 
495  If applicable, provide a rationale for the use of an adaptive or novel design. 
496  [Rationale for Adaptive or Novel Design] 
497  4.2.3  Other Trial Design Considerations 
498  Discuss rationale for any additional aspects of the design not addressed above.   
499  [Other Design Considerations] 
500  4.3  Access to Trial Intervention After End of Trial 
501  If applicable, describe any possibilities for access to trial intervention, if any, beyond completion 
502  of the trial.  Planned extension trials, if described above in Section 4.1 do not need to be 
503  repeated. 
504  [Access to Trial Intervention after End of Trial] 
505  4.4  Start of Trial and End of Trial 
506  Define key timepoints in the trial, such as the start date, first act of recruitment, and site 
507  closure.  These definitions should consider local regulatory requirements. Delineate sponsor 
508  and investigator decision rights to close a site or end the trial, including criteria for early closure 
509  of a site.  List responsibilities of the sponsor and investigator following termination or 
510  suspension of the trial.  Provide a cross-reference to Section 10.5, Early Site Closure or Trial 
511  Termination for criteria and responsibilities related to early site closure or trial termination.  
512  [Trial Start and End] 
513     
28 
   
514  5  TRIAL POPULATION 
515  In this section, describe the trial population. Use the following guidance when developing 
516  participant eligibility criteria to be listed in Section 5.3, Inclusion Criteria, and Section 5.4, 
517  Exclusion Criteria. 
518    List the criteria necessary for participation in the trial. Ensure that each criterion can be 
519  easily assessed definitively and answered with yes/no responses. 
520    If participants require screening, distinguish between screening vs enrolling participants.  
521  Identify specific laboratory tests or clinical characteristics that will be used as criteria for 
522  inclusion or exclusion. If permitting existing medical diagnosis, imaging, genetic tests, or 
523  laboratory results, state any required window or acceptable test type. 
524    If measures to enrich the trial population for pre-specified subgroups of interest are 
525  used, these should be described. 
526  No text is intended here (header only).  
527  5.1  Selection of Trial Population 
528  Describe the population selected (for example, healthy volunteers, adult participants, 
529  paediatric participants) and how the enrollment criteria reflect the populations that are likely to 
530  use the drug if approved. Specify the population age range (for example, 3 months, 18 to 80 
531  years old) and any key diagnostic criteria for the population (for example, acute lung injury, 
532  or a specific biomarker profile).  If applicable, describe similar conditions or diseases and their 
533  differential diagnosis. 
534  [Selection of Trial Population] 
535  5.2  Rationale for Trial Population 
536  Provide a rationale for the trial population ensuring that the population selected is well defined 
537  and clinically recognisable. Justify whether the trial intervention is to be evaluated in children, 
538  in adults unable to consent for themselves, other vulnerable participant populations, or those 
539  that may respond to the trial intervention differently (for example, elderly, hepatic or renally 
540  impaired, or immunocompromised participants).  
541  [Rationale for Trial Population] 
542  Individuals who do not meet criteria for trial eligibility must not be enrolled via protocol waivers 
543  or exemptions. 
544  5.3  Inclusion Criteria 
545  Inclusion criteria are characteristics that define the trial population, for example, those criteria 
546  that every potential participant must satisfy, to qualify for trial entry.  
547  To be eligible to participate in this trial, an individual must meet all the following criteria: 
548  #  [Inclusion Criterion] 
549  #  [Inclusion Criterion] 
550  #  [Inclusion Criterion] 
29 
   
551  Add criteria as needed. Number sequentially. 
552  5.4  Exclusion Criteria 
553  Exclusion criteria are characteristics that make an individual ineligible for participation.  
554  An individual who meets any of the following criteria will be excluded from participation in this 
555  trial: 
556  #  [Exclusion Criterion] 
557  #  [Exclusion Criterion] 
558  #  [Exclusion Criterion] 
559  Add criteria as needed. 
560  5.5  Lifestyle Considerations 
561  In the following subsections, describe any restrictions during the trial pertaining to lifestyle 
562  and/or diet, intake of caffeine, alcohol, or tobacco, or physical and other activities. If not 
563  applicable, include a statement that no restrictions are required.  
564  [Lifestyle Considerations] 
565  5.5.1  Meals and Dietary Restrictions 
566  If applicable, describe any restrictions on diet (for example, food and drink restrictions, timing 
567  of meals relative to dosing).  
568  [Meals and Dietary Restrictions] 
569  5.5.2  Caffeine, Alcohol, Tobacco, and Other Habits 
570  If applicable, describe any restrictions on the intake of caffeine, alcohol, tobacco, or other 
571  restrictions.  
572  [Caffeine, Alcohol, Tobacco, and Other Habits] 
573  5.5.3  Physical Activity 
574  If applicable, describe any restrictions on activity (for example, in first-in-human trials, activity 
575  may be restricted by ensuring participants remain in bed for 4 to 6 hours after dosing).  
576  [Physical Activity]   
577  5.5.4  Other Activity 
578  If applicable, describe restrictions on any other activity (for example, blood or tissue donation); 
579  or any other activity restrictions, such as on driving, heavy machinery use, or sun exposure.  
580  [Other Activity]   
581  5.6  Screen Failures 
582  Indicate how screen failure will be handled in the trial, including conditions and criteria upon 
583  which rescreening is acceptable. If applicable, indicate the circumstances and time window 
30 
   
584  under which a repeat procedure is allowed for screen failure relating to specific 
585  inclusion/exclusion criteria for the trial. 
586  [Screen Failure] 
587  6  TRIAL INTERVENTION AND CONCOMITANT THERAPY 
588  In this section, describe the trial intervention being tested and any control product being used.  
589  If multiple trial interventions are to be evaluated, Section 6.1, Description of Trial Intervention, 
590  Section 6.3, Dosing and Administration, and Section 6.5, Preparation, Handling, Storage, and 
591  Accountability should differentiate between each product. 
592  No text is intended here (header only).  
593  6.1  Description of Trial Intervention 
594  Describe the intervention to be administered in each arm of the trial and for each period of the 
595  trial including route and mode of administration, dose, dosage regimen, duration of 
596  intervention, packaging, labelling, and storage conditions. Include information for all trial 
597  interventions (experimental, placebo, active comparator, sham comparator).  
598  The trial intervention should be designated as an investigational medicinal product (IMP) or 
599  non-investigational medicinal product (NIMP)/auxiliary medicinal product (AxMP).  
600  It is suggested that the trial intervention(s) be described concisely in a table. 
601  [Table of Trial Interventions] 
602  Indicate whether an additional product will be provided as part of the trial and its intended use 
603  (background intervention, challenge agent, rescue medication, diagnostic, or other). If use of an 
604  additional product is planned, include dosing information. Refer to approved regional labelling 
605  or describe any differences. 
606  For drug/device combination products, include details on the configuration and use of the 
607  device and device manufacturer. A device user manual may be referenced in this section. 
608  [Additional Text, if Needed] 
609  6.2  Rationale for Trial Intervention 
610  Provide a rationale for the selection of the dose(s) or dose range, the route of administration, 
611  and dosing regimen (including starting dose, dose titration, dose interval) of the trial 
612  intervention and any control product. This rationale should include relevant results from 
613  previous preclinical studies and clinical trials that support selection of the dose and regimen.  
614  Include any information about age or sex-based pharmacokinetic or pharmacodynamic 
615  differences known from previous trials. If applicable, justify any differences in specifications, 
616  dose regimen, or therapeutic use relative to approved labelling.   
617  Include a rationale for prospective dose adjustments incorporated in the trial, if any; for 
618  example, as a result of interim analysis. 
619  [Rationale for Dose and Regimen] 
31 
   
620  6.3  Dosing and Administration 
621  Describe the detailed procedures for administration of each participants dose of trial 
622  intervention and control product. This may include the timing of dosing (for example, time of 
623  day, interval), the duration (for example, the length of time participants will be administered 
624  the trial intervention), the planned route of administration (for example, oral, nasal, 
625  intramuscular), and the timing of dosing relative to meals.  
626  Include any specific instructions to trial participants about when or how to prepare and take the 
627  dose(s) and how delayed or missed doses should be handled.  
628  For an individual participant, describe dose modifications allowed.  State any minimum period 
629  required before a participants dose might be raised to the next higher dose or dose range. 
630  Include whether it is permissible to start and stop treatment and how dose reductions (if 
631  permitted) are to be managed. 
632  Discussion of dose escalation or cohort expansion as part of the overall design should be 
633  covered in Section 4.2 (Rationale for Trial Design). 
634  [Dosing and Administration] 
635  6.3.1  Trial Intervention Dose Modification 
636  If applicable, the protocol should state the conditions under which a dose modification will be 
637  made for an individual participant, particularly regarding failure to respond or to toxic or 
638  untoward changes in stipulated indicators. This section can also include discussion of dose 
639  titration.  Do not include information on stopping trial intervention for individual participants 
640  due to safety/other reasons as this is detailed in Section 7, Discontinuation of Trial Intervention 
641  and Participant Discontinuation/Withdrawal from the Trial.  
642  [Dose Modification] 
643  6.4  Treatment of Overdose 
644  Specify what is meant by trial intervention overdose and any known antidote or therapies. 
645  Although clinical experience with overdose is often limited in early phases of development, 
646  provide any available project-specific guidance and information; however, ensure consistency 
647  with and avoid unnecessary duplication with any overdose information in the Investigators 
648  Brochure /package insert. Cross-reference these documents if appropriate. Refer to the 
649  approved product label of the comparator (as applicable) for advice on overdose.  
650  [Treatment of Overdose] 
651  6.5  Preparation, Handling, Storage and Accountability 
652  No text is intended here (header only).  
653  6.5.1  Preparation of Trial Intervention 
654  Describe any preparation of the trial intervention and control product and by whom. Discuss 
655  the maximum hold time once thawed/mixed, if appropriate, before administration. Include 
656  thawing, diluting, mixing, and reconstitution/preparation instructions in this section, as 
32 
   
657  applicable. For drug/device combination products, include any relevant assembly or use 
658  instructions. 
659  If the instructions are lengthy or complicated, it is acceptable to reference the label (if 
660  applicable) or include them as a separate document(s) provided to the site (for example, a 
661  pharmacy manual). If instructions are provided to the site as a separate document(s), this 
662  should be noted in here.  
663  [Trial Intervention Preparation] 
664  6.5.2  Handling and Storage of Trial Intervention 
665  Describe storage and handling requirements (for example, protection from light, temperature, 
666  humidity) for the trial intervention and control product.  For trials in which multi-dose vials are 
667  utilised, provide additional information regarding stability and expiration time after initial use 
668  (for example, the seal is broken). 
669  [Trial Intervention Storage and Handling] 
670  State how the trial intervention and control product will be provided to the Investigator. If 
671  applicable, describe the kits, packaging, or other material of the trial intervention for blinding 
672  purposes. 
673  6.5.3  Accountability of Trial Intervention 
674  Describe the method by which the accountability will be achieved, including trial intervention 
675  will be distributed and related details, including: 
676    how and by whom the trial intervention will be distributed 
677    participation of a drug repository or pharmacy, if applicable,  
678    plans for disposal or return of unused product, and 
679    expectations for reconciliation. 
680  [Accountability] 
681  6.6  Participant Assignment, Randomisation and Blinding 
682  No text is intended here (header only).  
683  6.6.1  Participant Assignment 
684  Describe the method of assigning participants to trial intervention without being so specific that 
685  blinding or randomisation might be compromised. If assignment to trial intervention is by 
686  randomisation, describe when randomisation occurs relative to screening. If participants will be 
687  assigned to intervention sequences as in a cross-over trial, then describe these sequences.  
688  If adaptive randomisation or other methods of covariate balancing/minimisation are employed, 
689  include a cross-reference to the methods of analysis in Section 9, Statistical Considerations. As 
690  applicable, details regarding the implementation of procedures to minimise bias should be 
691  described. 
33 
   
692  [Participant Assignment] 
693  6.6.2  Randomisation 
694  Describe the randomisation procedures (for example, central randomisation procedures), the 
695  method used to generate the randomisation schedule (for example, computer generated), the 
696  source of the randomisation schedule (for example, sponsor, investigator, or other), and 
697  whether or not IVRS/IWRS will be used. To maintain the integrity of the blinding, do not include 
698  the block size. Describe the use and validation of any computer systems or programmes in 
699  randomisation, stratification, and unblinding. 
700  [Randomisation] 
701  6.6.3  Blinding and Unblinding 
702  Describe efforts to ensure that the trial intervention and control products are as 
703  indistinguishable as possible. Plans for the maintenance of randomisation codes and 
704  appropriate blinding for the trial should be discussed. Procedures for planned and unplanned 
705  breaking of randomisation codes should be provided.  
706  If the trial allows for some investigators or other designated staff to remain unblinded (for 
707  example, to allow them to adjust medication), the means of maintaining the blinding for other 
708  investigators or staff should be explained. Measures to prevent unblinding by laboratory 
709  measurements, if used, should be described. 
710  [Blinding and Unblinding] 
711  Emergency Unblinding 
712  Describe the criteria for breaking the trial blind or participant code. Discuss the circumstances 
713  in which the blinding would be broken for an individual or for all participants (for example, for 
714  SAEs) and who has responsibility. Include the procedure for emergency unblinding such as via 
715  IVRS/IWRS or code envelopes as well as documentation of unblinding. Indicate to whom the 
716  intentional and unintentional unblinding should be reported. 
717  [Emergency Unblinding] 
718  6.7  Trial Intervention Compliance 
719  Describe measures employed to ensure and document dosing information and trial 
720  intervention compliance (for example, accountability records, diary cards, or concentration 
721  measurements). Include a discussion of what documents are mandatory to complete (for 
722  example, participant drug log) and what source data/records will be used to document trial 
723  intervention compliance. 
724  [Additional Trial Intervention Compliance] 
725  6.8  Concomitant Therapy 
726  This section should be consistent with the medication restrictions in the inclusion/exclusion 
727  criteria previously listed.  Describe the concomitant medications, supplements, complementary 
728  and alternative therapies, treatments, and/or procedures which are allowed or prohibited 
34 
   
729  during the trial, and include details about when the information will be collected (for example, 
730  screening, all visits).   
731  [Concomitant Therapy ] 
732  6.8.1  Prohibited Concomitant Therapy 
733  If applicable, describe any prohibited concomitant therapy. 
734  [Prohibited Concomitant Therapy] 
735  6.8.2  Permitted Concomitant Therapy 
736  If applicable, describe any permitted concomitant therapy. 
737  [Permitted Concomitant Therapy] 
738  6.8.3  Rescue Therapy 
739  List all medications, treatments, and/or procedures which may be provided during the trial for 
740  rescue therapy and provide relevant instructions about the administration of rescue 
741  medications. Describe the circumstances under which use of rescue therapy is permitted. 
742  If administration of rescue therapy leads to the temporary discontinuation of trial intervention 
743  or a participants withdrawal from the trial, refer to Section 7, Discontinuation of Trial 
744  Intervention and Participant Discontinuation/Withdrawal from the Trial. 
745  [Rescue Therapy] 
746  6.8.4  Other Therapy 
747  If applicable, describe the use of other non-investigational or auxiliary therapy, for example, 
748  challenge agents. 
749  [Other Therapy] 
750     
35 
   
751  7  DISCONTINUATION OF TRIAL INTERVENTION AND 
752  PARTICIPANT WITHDRAWAL FROM TRIAL 
753  This section must align with the intercurrent events introduced in Section 3, Trial Objectives, 
754  Endpoints, and Estimands, and the treatment described in Section 6 Trial Intervention and 
755  Concomitant Therapy. 
756  No text is intended here (header only).  
757  7.1  Discontinuation of Trial Intervention 
758  Discontinuation of trial intervention for a participant occurs when trial intervention is stopped 
759  earlier than the protocol planned duration. 
760  7.1.1  Criteria for Permanent Discontinuation of Trial Intervention 
761  Describe the criteria for discontinuation of a participant from trial intervention, carefully 
762  evaluating which are appropriate for the participant population and therapy being studied. 
763  Specify whether participants who discontinue trial intervention can or cannot continue the trial 
764  (continue trial visits). Refer to the SoA for assessments to be performed at the time of and 
765  following discontinuation of trial intervention. 
766  [Criteria for Permanent Discontinuation of Trial Intervention] 
767  7.1.2  Temporary Discontinuation or Interruption of Trial Intervention 
768  Describe  
769    the criteria for temporary discontinuation or interruption of trial intervention for an 
770  individual participant  
771    what to do and which restrictions still apply if the participant needs to temporarily 
772  discontinue or interrupt trial intervention  
773    whether they will continue in the trial, and  
774    whether all, or specify which, assessments will be performed for the stated duration of 
775  the trial. 
776  Details of any rechallenge or restart after a safety-related event should be included in Section 
777  7.1.3, Rechallenge. 
778  [Temporary Discontinuation/Interruption of Trial Intervention] 
779  7.1.3  Rechallenge 
780  Describe the criteria for rechallenge/restarting trial intervention, how to perform rechallenge, 
781  number of rechallenges allowed during the trial, and whether all, or specify which, assessments 
782  will be performed for the stated duration of the trial. 
783  If rechallenge is not allowed, state this. 
784  [Rechallenge] 
36 
   
785  7.2  Participant Withdrawal from the Trial 
786  Describe the criteria for participant withdrawal from the trial. 
787  [Participant Withdrawal from Trial] 
788  7.3  Lost to Follow-Up 
789  Describe how the trial will define and address participants who are lost to follow-up to help 
790  limit the amount and impact of missing data. Describe the nature and duration of follow-up, as 
791  appropriate. 
792  [Lost to Follow-Up] 
793  7.4  Trial Stopping Rules 
794  If applicable, describe any trial-specific stopping rules, including guidance on when the trial 
795  should be stopped for safety reasons, when a cohort or dose escalation should be terminated, 
796  and/or when a given treatment arm should be terminated. 
797  [Trial Stopping Rules] 
798     
37 
   
799  8  TRIAL ASSESSMENTS AND PROCEDURES 
800    Describe the assessments and procedures required during each phase of the trial that 
801  are relevant to the stated endpoints. Provide details that are not already presented in 
802  the SoA, taking care not to duplicate information. 
803    Describe methods, training, tools, instruments/questionnaires, calibration methods, etc. 
804  that will be used to record and assess data and ensure consistency across centres and 
805  participants. Include instructions on timing/conditions of assessments and if a 
806  specifically qualified person should be performing these assessments. Describe whether 
807  centralised readings and measurements will be utilised. Describe procedures to be used 
808  to maintain the blind. 
809    Reference the literature for the validation of scales/instruments/questionnaires/assays. 
810    Instructions or protocols for specialised tests may be presented in an appendix or a 
811  separate document and cross-referenced. 
812    If the trial includes qualitative interviews, describe these evaluations. 
813    If COA measures are utilised, include instructions for the investigators per local 
814  guidance. All COA parameters should be fully integrated into the appropriate sections of 
815  the protocol; separate COA sections should not be created in the protocol. 
816    Include minimums and limits for procedures (for example, volume of blood draws, 
817  number of imaging procedures/biopsies, radiation exposure, etc.) if appropriate to the 
818  trial. 
819  8.1  Screening/Baseline Assessments and Procedures 
820  Describe any assessments and procedures that are unique to screening/baseline (for example, 
821  collection of data on participant characteristics, assessments/procedures performed for the 
822  purpose of determining eligibility or for stratification) in this section. 
823  [Screening/Baseline Assessments and Procedures] 
824  8.2  Efficacy Assessments and Procedures 
825  Describe efficacy assessments and procedures in this section. 
826  [Efficacy Assessments and Procedures] 
827  8.3  Safety Assessments and Procedures 
828  Describe safety assessments and procedures in this section. Level 3 headings can be added as 
829  needed. 
830    Identify any non-investigator party responsible for evaluation of laboratory or other 
831  safety assessments (for example, Sponsor or external Independent Data Monitoring 
832  Committee). 
38 
   
833    Include guidelines for the management of relevant laboratory or other safety 
834  assessment abnormalities. 
835  [Safety Assessments and Procedures] 
836  8.3.1  Physical Examination  
837  Include any specific instructions for the collection and interpretation of physical examinations. 
838  [Physical Examination] 
839  8.3.2  Vital Signs 
840  Include any specific instructions for the collection and interpretation of vital signs. 
841  [Vital Signs] 
842  8.3.3  Electrocardiograms 
843  Include any specific instructions for the collection, interpretation, and archiving of ECGs. 
844  [Electrocardiograms] 
845  8.3.4  Clinical Laboratory Assessments 
846  Include any specific instructions for the collection and interpretation of clinical laboratory 
847  assessments. 
848    Specify if and when the use of local laboratories is allowed. 
849    Specify which laboratory parameters should be included in each panel (for example, for 
850  haematology, chemistry, urinalysis). 
851  [Clinical Safety Laboratory Assessments] 
852  8.3.5  Suicidal Ideation and Behaviour Risk Monitoring 
853  If the trial meets any of the criteria requiring suicidal ideation and behaviour risk monitoring by 
854  the guidance/guideline in each region, include any specific instructions for the collection and 
855  interpretation of the assessment 
856  [Suicidal Ideation and Behaviour Risk Monitoring] 
857  8.4  Adverse Events and Serious Adverse Events 
858  No text is intended here (header only).  
859  8.4.1  Definitions of AE and SAE 
860  Specify the AE and SAE definitions. 
861  [AE definition] 
862  [SAE definition] 
863  Additional details and clarifications for AEs and SAEs are in Appendices 12.1 and 12.2. 
864   
39 
   
865  8.4.2  Time Period and Frequency for Collecting AE and SAE Information  
866  Specify the starting and ending time periods for collecting AEs and SAEs. 
867  [Time period and/or frequency for collecting AEs and SAEs] 
868  8.4.3  Identifying AEs and SAEs 
869  Specify how AEs and SAEs will be identified (for example, spontaneous reporting, solicited 
870  questions). 
871  [Identifying AEs and SAEs] 
872  8.4.4  Recording of AEs and SAEs 
873  Specify the Investigators actions for recording AEs and SAEs, including severity, causality, and 
874  the final outcome. 
875  [Recording of AEs and SAEs] 
876  Further details on assessing severity and causality of AEs and SAEs are in Appendices 12.3 and 
877  12.4. 
878  8.4.5  Follow-up of AEs and SAEs 
879  Specify the procedures for follow-up of AEs and SAEs until they are resolved or considered 
880  stable.  Include the assessment tools that will be used to monitor the events and the duration 
881  of follow-up after appearance of the events.  Specify any procedures to be used for trials in 
882  which death is not an endpoint. 
883  [Follow-up of AEs and SAEs] 
884  8.4.6  Reporting of SAEs 
885  Specify the SAE reporting method (for example, an electronic data collection tool or a paper 
886  CRF) to the Sponsor. 
887  [Reporting of SAEs] 
888  8.4.7  Regulatory Reporting Requirements for SAEs 
889  Specify: 
890    The Sponsors legal/regulatory responsibilities to report SAEs to regulatory authorities, 
891  ethics committees, and investigators. 
892    The investigators responsibilities for promptly reporting SAEs to the Sponsor (and to 
893  Ethics Committees, where required) to allow the Sponsor to meet their responsibilities. 
894  8.4.8  Serious and Unexpected Adverse Reaction Reporting 
895  Include this section, if applicable. 
896  [Serious and Unexpected Adverse Reaction Reporting] 
40 
   
897  8.4.9  Adverse Events of Special Interest 
898  Include this section, if applicable. 
899  Specify any Adverse Events of Special Interest (AESI): 
900    Other events that merit reporting to the Sponsor, trial leadership, IRB, and regulatory 
901  agencies (for example, secondary malignancies in oncology trials). 
902    Other reportable events not already included in the previous sections, such as 
903  cardiovascular and death events, medical device incidents (including malfunctions), 
904  laboratory test abnormalities, and trial intervention overdose. 
905  Include the following for each AESI: 
906    The definition of the event. Specify the MedDRA preferred terms to use to report the 
907  AESI. 
908    If it is a measurable quantity, specify how will the measurement be done. 
909    If it is a clinical event, specify how will it be confirmed. 
910  [Adverse Events of Special Interest] 
911  8.4.10  Disease-related Events or Outcomes Not Qualifying as AEs or SAEs  
912  Specify any Disease-Related Events (DREs), disease-related outcomes, or both that will not be 
913  reported as AEs or SAEs (for example, seizures in anticonvulsant trials). 
914  [Disease-related Events or Outcomes not Qualifying as AEs or SAEs] 
915  8.5  Pregnancy and Postpartum Information  
916  No text is intended here (header only).  
917  8.5.1  Participants Who Become Pregnant During the Trial 
918  Specify  
919    the assessments to be performed,  
920    type and duration of monitoring, and  
921    what information will be collected for a participant who becomes pregnant during the 
922  trial (for example, recording and reporting to the Sponsor, postpartum follow-up, trial 
923  intervention discontinuation or continuation, or trial withdrawal).  
924  For postpartum follow-up, include the time period (for example, initial child development) with 
925  the justification. 
926  If exposure to trial intervention during breastfeeding is applicable, specify  
927    the assessments to be performed,  
928    type and duration of monitoring, and  
41 
   
929    what information will be collected for both the participant and child. 
930  Specify that pregnancy is not an AE, unless a negative or consequential outcome occurs in the 
931  participant or child/foetus. If the negative event meets the seriousness criteria, then this is 
932  considered an SAE (for example, spontaneous abortion, foetal death, stillbirth, congenital 
933  anomalies, ectopic pregnancy, or pre-eclampsia) and reported per Section 8.4.5, Reporting of 
934  SAEs.  
935  [Participants Who Become Pregnant During the Trial] 
936  8.5.2  Participants Whose Partners Become Pregnant 
937  Specify: 
938    If the investigator will attempt to collect pregnancy information for a participants partner, 
939  who becomes pregnant while the participant is in the trial. 
940    The assessments to be performed, type and duration of monitoring, and what information 
941  will be collected. 
942  [Participants Whose Partners Become Pregnant] 
943  8.6  Medical Device Product Complaints for Drug/Device Combination 
944  Products 
945  Optional section to include for drug/device combination products. 
946  8.6.1  Definition of Medical Device Product Complaints 
947  [Definition of Medical Device Product Complaints] 
948  8.6.2  Recording of Medical Device Product Complaints 
949  Optional section to specify the investigators actions for recording product complaints, 
950  including the final complaint outcome. 
951  [Recording of Medical Device Product Complaints] 
952  8.6.3  Time Period and Frequency for Collecting Medical Device Product Complaints 
953  Optional section to specify the start and ending time periods for collecting Medical Device 
954  Product Complaints (for example, from when the medical device use begins to end of trial 
955  participation). 
956  [Time Period and Frequency for Collecting Medical Device Product Complaints] 
957  8.6.4  Follow-Up of Medical Device Product Complaints 
958  [Follow-up of Medical Device Product Complaints] 
959  8.6.5  Regulatory Reporting Requirements for Medical Device Product Complaints  
960  Optional section to specify the investigators responsibilities for reporting Medical Device 
961  Product Complaints (for example, within 24 hours) to the Sponsor. 
42 
   
962  [Reporting of Medical Device Product Complaints] 
963  8.7  Pharmacokinetics  
964  Include any specific instructions for the collection of samples and interpretation of PK 
965  assessments. 
966    Specific sample collection and processing instructions can be described in an appendix 
967  or a separate document and cross-referenced. 
968    Describe the biological sample(s) collected, the handling of samples, and the assay 
969  method. 
970  [Pharmacokinetics] 
971  8.8  Genetics 
972  Include any specific instructions for the collection of samples for genetic analysis. 
973    Include the biological samples that will be collected (for example, serum, plasma, etc.) 
974  and the retention time for the samples (ensuring alignment with the ICF). 
975    Indicate the types of analyses that may be studied for each sample. 
976    Specific sample collection and processing instructions can be described in an appendix 
977  or a separate document and cross-referenced. 
978  [Genetics] 
979  8.9  Biomarkers 
980  Include any specific instructions for the collection of samples and interpretation of biomarkers, 
981  including pharmacodynamics. 
982    Include the biological samples that will be collected (for example, serum, plasma, etc.) 
983  and the retention time for the samples (ensuring alignment with the ICF). 
984    Indicate the types of biomarkers that will be studied for each sample. 
985    Specific sample collection and processing instructions can be described in an appendix 
986  or a separate document and cross-referenced. 
987    Specify whether optional or required. Required samples must be based on a protocol 
988  objective. 
989  [Biomarkers] 
990  8.10  Immunogenicity Assessments 
991  Include any specific instructions for the collection of samples and interpretation of 
992  immunogenicity. If immunogenicity assessments are included within Efficacy Assessments or 
993  Safety Assessments, cross-reference to that section. 
994  [Immunogenicity Assessments] 
43 
   
995  8.11  Medical Resource Utilisation and Health Economics 
996  This section does not apply to COAs. Include this section only for any value evidence and 
997  outcomes assessments not included in either the efficacy or safety sections. 
998  Describe the health outcome measures, collection method (for example, diary, physician 
999  interview), and participant burden. 
1000  [Medical Resource Utilisation and Health Economics] 
1001     
44 
   
1002  9  STATISTICAL CONSIDERATIONS 
1003  Ensure that the data analysis complies with ICH E9 Guideline and ICH E9(R1) Guideline. 
1004  In general, all relevant data collected in the trial should be considered in this statistical 
1005  considerations section.  
1006  Provide a statement with regard to when the primary analyses will be conducted. For example: 
1007  The analysis will be conducted on all participant data at the time the trial ends.   
1008  [Statistical Considerations] 
1009  9.1  Analysis Sets 
1010  Analysis sets to support each analysis will be specified here and described in the Statistical 
1011  Analysis Plan. 
1012  [Analysis Datasets] 
1013  9.2  Analyses Supporting Primary Objective(s) 
1014  This section introduces the Statistical Analysis Plan, with the detail to be provided in the 
1015  subsequent subsections. This includes describing the methods of estimation (analytic approach) 
1016  in alignment with how the estimands are defined. Sensitivity analyses should be aligned with 
1017  how the estimands and estimators are defined. 
1018  [Analysis Supporting Primary Objectives] 
1019  9.2.1  Statistical Model, Hypothesis, and Method of Analysis 
1020  Ensure that the statistical hypothesis/model (and corresponding assumptions)/analysis is 
1021  aligned with the primary estimand(s). 
1022  For all applicable objectives (for example, primary, secondary), under the appropriate header, 
1023  state the null and alternative hypotheses, including the pre-planned type 1 error, or alternative 
1024  criteria to define trial success and relevant operating characteristics if appropriate. Describe the 
1025  statistical model used and the factors that will be included (covariates and interactions) and any 
1026  rules for handling these factors (for example, pooling of centres). If applicable, state and discuss 
1027  any adjustments to account for multiplicity.  
1028  If modelling and simulation methods are to be used, please describe the model (inputs and 
1029  outputs), the underlying assumptions, and the method of model fitting. 
1030  [Statistical Model, Hypothesis, and Method of Analysis] 
1031  9.2.2  Handling of Intercurrent Events of Primary Estimand(s) 
1032  For each intercurrent event of the primary estimand(s) (Section 3.1, Estimand[s] for the Primary 
1033  Objective[s]), explain how data will be handled for the statistical analysis in line with the 
1034  primary estimand. The handling of intercurrent events in statistical analysis should be aligned 
1035  with the specific estimand strategies being used.  
45 
   
1036  This section should describe with more detail the rationale and handling of the data rather than 
1037  repeating the guidance from the preceding sections.  
1038  [Handling of Intercurrent Events of Primary Estimand] 
1039  9.2.3  Handling of Missing Data 
1040  This section should describe how missing data will be dealt with. Refer to the E9(R1) addendum 
1041  when estimand framework is used. 
1042  The protocol should describe how missing data will be handled (for example, type of imputation 
1043  technique, if any, and provide justification)   
1044  In cases where the Primary Objective is related to safety, this section should also be completed. 
1045  It may also be helpful to include additional statements regarding handling of missing data in 
1046  general for other important efficacy or safety endpoints or this information can be included in 
1047  the analysis of secondary endpoint section below. 
1048  [Handling of Missing Data] 
1049  9.2.4  Sensitivity Analysis 
1050  Sensitivity analyses are a series of analyses conducted with the intent to explore the robustness 
1051  of inferences from the main estimator to deviations from its underlying modelling assumptions 
1052  and limitations in the data.  
1053   [Sensitivity Analysis] 
1054  9.2.5  Supplementary Analysis 
1055  Describe any supplementary analysis if applicable. 
1056  [Supplementary Analysis] 
1057  9.3  Analysis Supporting Secondary Objective(s) 
1058  This section should focus on estimands for Secondary Objectives. 
1059  In this section describe the statistical analysis, handling of intercurrent events, handling of 
1060  missing data, and if applicable, sensitivity analysis corresponding to each secondary estimand.  
1061  [Analyses Supporting Secondary Objectives] 
1062  9.4  Analysis of Exploratory Objective(s) 
1063  [Analyses Supporting Tertiary/Exploratory Objective(s)] 
1064  9.5  Safety Analyses 
1065  If safety is a primary and/or secondary objective, describe the corresponding safety analyses in 
1066  the appropriate section above (Section 9.2 or Section 9.3). 
1067  [Safety Analyses] 
46 
   
1068  9.6  Other Analyses 
1069  Describe Other Analyses such as Subgroup analyses, Adjusted analysis if needed. 
1070  [Other Analyses] 
1071  9.7  Interim Analyses 
1072  Describe any interim analysis and criteria for stopping or adapting the trial. 
1073  The description should include, but is not limited to, the following: 
1074    Any interim analysis plan, even if it is only to be performed at the request of an 
1075  oversight body (for example, DMC). 
1076    Describe (briefly and concisely) and reference the applied statistical method, for 
1077  example, group sequential test and spending function (for example, OBrien-Fleming), as 
1078  applicable. 
1079    Who will perform the analyses. 
1080    When they will be conducted (timing and/or triggers). 
1081    The decision criteriastatistical or otherthat will be adopted to judge the interim 
1082  results as part of a guideline for early stopping or other adaptations.  
1083    Who will see the outcome data while the trial is ongoing. 
1084    Whether these individuals will remain blinded to trial groups. 
1085    How the integrity of the trial implementation will be protected (for example, 
1086  maintaining blinding) when any adaptations to the trial are made. 
1087    Who has the ultimate authority to stop or modify the trial, for example, investigator, 
1088  principal investigator, Data Monitoring Committee, or sponsor. 
1089    The stopping guidelines.  
1090    If pre-specified interim analyses are to be used for other trial adaptations such as 
1091  sample size re-estimation, alteration to the proportion of participants allocated to each 
1092  trial group, and changes to eligibility criteria. 
1093  [Interim Analyses] 
1094  9.8  Sample Size Determination  
1095  This section should detail the methods used for the determination of the sample size and a 
1096  reference to tables or statistical software used to carry out the calculation. Sufficient information 
1097  should be provided so that the sample size calculation can be reproduced or described. 
1098  If the planned sample size is not derived statistically, then this should be explicitly stated along 
1099  with a rationale for the intended sample size (for example, exploratory nature of pilot trials; 
1100  pragmatic considerations for trials in rare diseases). 
1101   [Sample Size Determination] 
1102 
47 
   
1103  9.9  Protocol Deviations 
1104  Plans for detecting, reviewing, and reporting any deviations from the protocol should be 
1105  described. 
1106  [Protocol Deviations Plans] 
1107  10  GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND 
1108  TRIAL OVERSIGHT 
1109  No text is intended here (header only).  
1110  10.1  Regulatory and Ethical Considerations 
1111  List the prevailing ethical, legal, and regulatory guidelines that will be applied throughout the 
1112  trial. 
1113  This trial will be conducted in accordance with the protocol and with the following: 
1114    Consensus ethical principles derived from international guidelines including the 
1115  Declaration of Helsinki and Council for International Organisations of Medical 
1116  Sciences (CIOMS) International Ethical Guidelines  
1117    ICH Good Clinical Practice (GCP) Guidelines  
1118    Applicable laws and regulations  
1119  List the investigators and sponsors responsibilities in this regard.   
1120  Investigator Responsibilities 
1121  [Investigator Responsibilities] 
1122  Sponsor Responsibilities 
1123  [Sponsor Responsibilities] 
1124  10.2  Committees  
1125  Briefly describe the administrative structure of committees that will be reviewing data while 
1126  the trial is ongoing, and the type of committee (for example, Dose Escalation Committee, Data 
1127  Monitoring Committee or Data Safety Monitoring Board). Note that specific details may be 
1128  required depending on local law or regulation.  If applicable, Committee Charters may be cross-
1129  referenced. 
1130  [Committees Structure] 
1131  10.3  Informed Consent Process 
1132  Specify the key elements of the informed consent process, including any special needs and how 
1133  these are addressed (for example, assent, capacity, legally acceptable representative). 
1134  [Informed Consent Process] 
1135  If enrollment in the trial may occur during an emergency in which the participant or their legally 
1136  authorised representative is not able or available to give consent, describe the consent process.   
48 
   
1137  [Emergency Consent Process] 
1138  Rescreening 
1139  If participants can be rescreened, add the text to state whether the participant needs to 
1140  complete a new consent.  Screen failure and rescreening should be clearly defined in the 
1141  protocol, with cross-reference to those definitions. 
1142  [Consent Requirements for Rescreening] 
1143  [Additional ICF text for Use of Remaining Samples in Optional Exploratory 
1144  Research] 
1145  10.4  Data Protection 
1146  Describe how personal data will be protected and any measures that should be taken in case of 
1147  a data security breach. 
1148  [Data Protection] 
1149  10.5  Early Site Closure or Trial Termination 
1150  List the decision rights of sponsor or designee to close a site or terminate the trial.  Likewise, list 
1151  the investigators right to initiate site closure. 
1152  [Decision Rights for Site Closure and Trial Termination] 
1153  List the criteria for early closure of a site by the sponsor or investigator. 
1154  [Criteria for Early Closure] 
1155  List the responsibilities of the sponsor and investigator following termination or suspension, 
1156  such as informing the ethics committee(s), and prompt notification of the participant and 
1157  transition to appropriate therapy and/or follow-up. 
1158  [Responsibilities following Termination or Suspension] 
1159   
1160     
49 
   
1161  11  GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
1162  QUALITY ASSURANCE 
1163  No text is intended here (header only).  
1164  11.1  Quality Tolerance Limits 
1165  Indicate where Quality Tolerance Limits will be predefined, how they will be monitored during 
1166  the trial, and expected discussion in the clinical trial report. 
1167  [QTL] 
1168  11.2  Data Quality Assurance 
1169  Delineate the responsibilities of the Sponsor with respect to data quality assurance.   
1170  [Sponsor or Designee Responsibilities for Data Quality Assurance] 
1171  [Investigator Responsibilities for Data Quality Assurance] 
1172  11.3  Source Data 
1173  Establish the importance of source data and expectation for traceability of transcribed 
1174  information back to source.  Delineate expectations for investigators (for example, maintain 
1175  source data at the site, ensure availability of current records) and trial monitors (for example, 
1176  verify CRF data relative to source, safety of participants is being protected, conduct is in 
1177  accordance with GCP).  Define what constitutes source data and its origin or provide a 
1178  reference to the location of these definitions, if contained in a separate document, such as a 
1179  monitoring guideline or source data acknowledgement). 
1180  [Source Data Introduction] 
1181  [Investigator Expectations for Source Data] 
1182  [Trial Monitor Expectations for Source Data] 
1183  [Definition of Source Data]   
50 
   
1184  12  APPENDIX:  ADVERSE EVENTS AND SERIOUS ADVERSE 
1185  EVENTS  DEFINITIONS, SEVERITY, AND CAUSALITY 
1186  No text is intended here (header only).  
1187  12.1  Further Details and Clarifications on the AE Definition 
1188  Specify: 
1189    Any relevant regional AE requirements. 
1190    Any events that meet and do not meet the AE definition. 
1191    Any trial-specific AE clarifications. 
1192    The trial-specific definition for an overdose. 
1193    If applicable, any clarifications on the AE and SAE definitions for efficacy trials (for example, 
1194  lack of efficacy or failure of pharmacological actions reporting). 
1195  12.2  Further Details and Clarifications on the SAE Definition 
1196  Specify: 
1197    Any relevant regional SAE requirements. 
1198    Any events that meet and do not meet the SAE definition. 
1199    Any trial-specific SAE clarifications. 
1200  12.3  Severity 
1201  Specify the severity rating categories/scale. 
1202  [Severity] 
1203  12.4  Causality 
1204  Specify: 
1205    The causality categories/scale. 
1206    Procedures for assessing causality. 
1207  [Causality] 
1208     
51 
   
1209  13  APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
1210  DETAILS 
1211  No text is intended here (header only).  
1212  13.1  Contraception and Pregnancy Testing  
1213  No text is intended here (header only).  
1214  13.1.1  Definitions Related to Childbearing Potential 
1215  Optional section to specify the definitions of: 
1216    Participant of childbearing potential 
1217    Participant of non-childbearing potential 
1218  [Definitions Related to Childbearing Potential] 
1219  13.1.2  Contraception 
1220  Optional section to specify the:  
1221    Contraceptive methods required   
1222    Duration of use 
1223  [Contraception] 
1224  13.1.3  Pregnancy Testing 
1225  Optional section to specify pregnancy testing requirements. 
1226  [Pregnancy Testing] 
1227  13.2  Clinical Laboratory Tests 
1228  Provide additional information, if needed, about clinical laboratory tests, such as  
1229    whether they will be performed by a central or local laboratory (if important to 
1230  distinguish)  
1231    specific analytes or parameters included in a panel  
1232    equations and references for locally calculated labs  
1233    acceptability of additional tests deemed necessary by the investigator or local 
1234  regulations 
1235    instructions for situations in which central laboratory results are not available in time for 
1236  trial intervention and/or response evaluation, or in the event of a severe disruption (for 
1237  example, a pandemic or natural disaster) 
1238    treatment algorithms for results out of normal range. 
1239  A tabular presentation for such information is common. 
1240  [Clinical Laboratory Tests] 
52 
   
1241   
1242  13.3  Country/Region-Specific Differences 
1243  Although global clinical trial practices are increasingly harmonised, some country/ region-
1244  specific differences in requirements do exist (for example, document retention periods, 
1245  contraception requirements).  Where differences in requirements cannot be reconciled, 
1246  sponsors should explain how they will document and communicate country/region-specific 
1247  differences (for example, by country/region-specific amendments or addenda).   
1248  An alternative to country/region-specific amendments is to list the specific differences by 
1249  country or countries in this section, including a reference to the relevant section of the protocol 
1250  where the differing requirement applies.   
1251  [Country/Region-specific Differences] 
1252  13.4  Prior Protocol Amendments 
1253  Choose the appropriate text. 
1254  {This protocol has not been amended.} 
1255  or 
1256  {The Protocol Amendment Summary of Changes for the current amendment is located directly 
1257  before the Table of Contents.  Details of prior amendments are presented below, beginning with 
1258  the most recent}. 
1259  See the instructions in the Protocol Amendment Summary of Changes located before the Table 
1260  of Contents. Move all Protocol Amendment Summaries of Changes for previous amendments to 
1261  this section in reverse chronological order (most recent first). 
1262  Amendment {amendment number}: ({date}) 
1263  {Amendment details from this amendment} 
1264  Add additional amendments/details as protocol amendments accrue. 
1265  Amendment {amendment number}: ({date}) 
1266  {Amendment details from this amendment}  
1267     
53 
   
1268  14  APPENDIX:  GLOSSARY OF TERMS 
1269  Define abbreviations and other terms used in the protocol.  Abbreviations do not need to be 
1270  defined at first mention within the protocol, and definition of abbreviations in common usage is 
1271  not necessary (for example, DNA).  A tabular presentation is common.   
1272  Ensure the following terms are clearly defined within the protocol unless not applicable to the 
1273  trial:  
1274    Pre-screening 
1275    Screening 
1276    Enrollment 
1277    Product Complaint 
1278  [Abbreviations and Definitions] 
1279  15  APPENDIX:  REFERENCES 
1280  References should be listed in a common format that includes all relevant information to 
1281  identify the source and date published.  If not published, this should be clearly indicated.  
1282  [References] 
54