Protocol template
Introduction
The guidance contained within the European GCP Directive, the Medicines for Human Use (Clinical
Trials) Regulations and in relation to the medical devices trials have been used to inform the content
of this protocol template. In addition, recommendations from the SPIRIT guidelines (Standard Protocol
Items: Recommendations for Interventional Trials) have been considered and included where
considered appropriate.
The guidance contained within this document is based on the requirements for national trials. The
protocol template must be adapted as appropriate for international trials.
How to use this template
 Read SOP UoB-CLN-ESD-SOP-001: Essential Documents development and maintenance
prior to using this template to develop the protocol
 Use this template to develop your protocol for any research project. For the purpose of this
document, a research project or study will be referred to as a trial.
Development of Protocol
 Save a copy of this template, for example in your trial folder
 Use the version number 0.1 for first draft. Subsequent draft versions should be updated using
the same format e.g. 0.2, 0.3 etc. until a final version is approved. Final versions should be
given the next whole number in the sequence, e.g. final draft 0.3 should become Final version
1.0.
 Update the version number and version date in the protocol template footer. Add the trial
name to the protocol template footer.
 Update header with the trial acronym.
 Work through each page of the protocol, once you have familiarised yourself with the
following:
o
The main headers are set up to reflect GCP and regulatory requirements, and are
therefore expected to be included in the protocol. These are preceded by a whole
number e.g. 1, 2, 3, etc. and given in brick red font colour. The exception is the header
‘Amendments’ which should not be included in the first version of the protocol, and is not
preceded by a whole number. If you choose to remove/amend a header, you have to
ensure that the requirements for protocol contents as listed in ICH GCP and any
regulations are still adhered to.
o
Sub-headings may be deleted / amended as required. These are also given in brick red
font colour but are numbered as a decimal place value.
o
All tables with the heading “Note: regulatory requirements” list the relevant ICH GCP and
EU CTD regulations and offers guidance on the type of information that may be included
in that section.
o
Red italic text:
 Instructions and guidance notes are given in red italic text
 Suggested text which may only be relevant to some trials is written in red italic text
contained within “ ”. Should it be relevant for you to include this text in your protocol,
change the font colour to black and remove italics, otherwise delete.
 Wherever red italic text is contained within red brackets < >, insert the relevant information
into the text, delete the brackets and change the font colour to black and remove italics,
otherwise delete if not relevant.
o
All passages in black ink are suggested text for inclusion in the protocol and changes
should be kept to a minimum.
Document1
Page 1 of 39
Protocol template
 Where the protocol is not being developed for a clinical trial the word ‘trial’ may be substituted,
e.g. with ‘study’ or ‘research project’ and the word ‘drug’, ‘IMP’ or ‘intervention’ may be
substituted as appropriate.
 Ensure any instructions in red italic text and/or text boxes headed with NOTE: Regulatory
requirements are removed prior to finalising the protocol.
 Ensure the use of abbreviations and terminology is consistent throughout the protocol and
updated in the abbreviations and definitions table.
Amendments to the protocol
 Update relevant sections in the protocol when an amendment is required. A version
containing the tracked changes should be maintained for the audit trail.
 Ensure that the protocol version number and the date are amended.
 For substantial amendments ensure appropriate approvals are obtained.
 Include a summary of protocol amendments within the introductory pages of the protocol.
 Ensure sites are informed of the changes.
 Ensure sponsors are informed of the changes.
Related documents
 UoB-CLN-ESD-SOP-001 - Essential Documents development and maintenance
Acknowledgements
The first version of this template has been based on the equivalent Cancer Research UK Clinical
Trials Unit template, and aspects of the Primary Care Clinical Research & Trials Unit template. We
would like to thank all staff members within the CTUs who have been involved in developing these
templates for their time and efforts.
Document1
Page 2 of 39
TRIAL PROTOCOL
<consider
including trial
logo(s) on this
page>
< trial acronym >
< full trial title >
Reference numbers for the trial can be included in the table below. Examples of the reference
numbers that could be included are given. Add/delete as appropriate. Note that for CTIMPs the
Sponsor reference number must be listed in the protocol.
EudraCT number (CTIMP only)
Sponsor reference number
ISRCTN number
REC reference number
PROTOCOL
<Insert trial acronym>
Protocol development and sign off
NOTE: Regulatory requirements:
As per EC guidance (ENTR/CT 2) the protocol should be signed by the CI and by the Sponsor to
confirm approval of the protocol.
NOTE: For UoB sponsored trials, the sponsor will confirm approval of the protocol by signing the
IRAS form and therefore a signature on the protocol is not required. The sponsor must be notified of
all amendments to the protocol, both substantial and non-substantial. Review of amendments by the
sponsor will act as the confirmation that the sponsor confirms approval of the amended protocol.
Protocol Contributors
The SPIRIT guidelines suggest for key protocol contributors to be listed. For this, please detail the
names, affiliations, and roles of protocol contributors, e.g. medical expert, statistician, trial
management expert using the table below. Add /delete rows as required.
The following people have contributed to the writing of this protocol:
Name:
Affiliation and role:
Protocol Amendments
The following amendments and/or administrative changes have been made to this protocol since the
implementation of the first approved version
For UoB (co-) Sponsored trials, the Research Governance Team must be notified of any amendment,
and asked for their agreement with the substantiality assessment. For external Sponsors ensure to
follow their local procedures with regards to being informed of amendments to allow for Sponsor
approval.
All amendments need to be notified to the appropriate regulators, REC and all R&D departments that
have given permission for the trial. Note that substantial amendments will need to be submitted for
approval. Where appropriate include a summary of protocol amendments e.g.:
Amendment
number
Date of
amendment
Protocol
version
number
Type of amendment
Summary of amendment
AM01
28th Oct 2005
2.0
Substantial
amendment
Change in eligibility criteria
NS01
15th Sep 2006
3.0
Non-substantial
Change in trial contact details
Trial name:
Protocol version number:
<inset trial name here>
<insert version
number>
version date:
<insert date here>
Page:
1 of 45
PROTOCOL
<Insert trial acronym>
amendment
AM02
16th Oct 2007
4.0
Substantial
amendment
Change in max. number of
chemotherapy cycles a
participant may receive from 6
to 10
The table below should be signed by the CI to confirm approval of the protocol.
CI Signature Page
This protocol has been approved by:
Trial Name:
Protocol Version Number:
Version: __ __
Protocol Version Date:
__ __ / __ __ / __ __ __ __
CI Name:
Trial Role:
Chief Investigator
Signature and date:
_________________________
__ __ / __ __ / __ __ __ __
Sponsor statement:
Where the University of Birmingham takes on the sponsor role for protocol development oversight, the
signing of the IRAS form by the sponsor will serve as confirmation of approval of this protocol.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
2 of 36
PROTOCOL
<Insert trial acronym>
Administrative Information
Use this page to document the key contact personnel for the trial.
Sponsor
< Name of sponsor >
< Telephone Number >
<Institution >
< City >
< email address >
Where the University of Birmingham acts as a (co-)Sponsor, details would be as listed below:
Sponsor
University of Birmingham
Sponsor contact: Dr Sean Jennings
Research Governance Team
University of Birmingham
Birmingham, B15 2TT
0121 414 7618
researchgovernance@contacts.bham.ac.uk
Chief investigator
< Name of Chief investigator >
< Job title >
<Institution >
< City >
< Telephone Number >
< email address >
Sponsor’s Medical Expert for the Trial
< Name of Medical Expert >
< Job title >
<Institution >
<City >
< Telephone Number >
< email address >
This would typically be the CI, if so, only provide name and job title in the table above, deleting cells
that hold the contact details to avoid repeating.
Co-investigator (s)
< Name of Co-investigator >
< Job title >
<Institution >
< City>
< Telephone Number >
< email address >
If the trial does not have a Co-Investigator, please delete the above table. if there is more than one
Co-Investigator, and you choose to list additional names, please copy and paste the 2nd and 3rd rows
from the table above as may times as required, adding to the Co-investigator table.
Trial Office Contact Details
< Name of Trial Co-ordinator >
Trial name:
Protocol version number:
< Job title >
<trial name>
1.0
version date:
22-Mar-16
Page:
3 of 36
PROTOCOL
<Insert trial acronym>
< Institution >
< City >
< Telephone Number >
< email address >
TRIAL SUMMARY
As a guide this should be no longer than 2 sides of A4
The following sub-headings should be included:
Title
Trial Design
E.g. prospective, phase III, international, 2 arm, multicentre, randomised, double-blinded clinical trial.
Objectives
Participant Population and Sample Size
Outcome Measures
Key Eligibility Criteria
Intervention
Trial Schema
This should include a representation, which could be diagrammatic, summarising the visits from
screening through to follow up.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
4 of 36
PROTOCOL
<Insert trial acronym>
TABLE OF CONTENTS
Please note this table will need updating each time a change is made to the protocol. This can be
done automatically by clicking anywhere on the table of contents and pressing the ‘update table’
button. The pages before the table of contents will automatically update to the table of contents.
Delete these rows from the table of contents.
TABLE OF CONTENTS ....................................................................................................................... 5
1.
Background and Rationale .......................................................................................................... 8
1.1.
Background ............................................................................................................................. 8
1.2.
Trial Rationale ......................................................................................................................... 8
1.2.1.
Justification for participant population ............................................................................. 8
1.2.2.
Justification for design ..................................................................................................... 8
1.2.3.
Choice of treatment ......................................................................................................... 8
1.2.4.
Sub-studies ..................................................................................................................... 8
2.
Aims, Objectives and Outcome Measures .................................................................................. 9
2.1.
Aims and Objectives ............................................................................................................... 9
2.2.
Outcome Measures ................................................................................................................. 9
3.
Trial Design AND SETTING ...................................................................................................... 10
3.1.
Trial Design ........................................................................................................................... 10
3.2.
Trial Setting ........................................................................................................................... 10
4.
Eligibility .................................................................................................................................... 10
4.1.
Inclusion Criteria ................................................................................................................... 10
4.2.
Exclusion Criteria .................................................................................................................. 10
5.
Consent ..................................................................................................................................... 10
6.
Enrolment and Randomisation .................................................................................................. 12
6.1.
Enrolment/Registration .......................................................................................................... 12
6.2.
Randomisation ...................................................................................................................... 12
6.3.
Blinding.................................................................................................................................. 12
7.
Trial treatment / intervention ..................................................................................................... 12
7.1.
Treatment .............................................................................................................................. 13
7.2.
Treatment Supply and Storage ............................................................................................. 13
7.2.1.
Treatment Supplies ....................................................................................................... 13
7.2.2.
Packaging and Labelling ............................................................................................... 13
7.2.3.
Drug Storage ................................................................................................................. 13
7.3.
Dosing Schedule ................................................................................................................... 13
7.4.
Drug Interaction or Contraindications ................................................................................... 13
7.5.
Accountability Procedures ..................................................................................................... 14
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
5 of 36
PROTOCOL
7.6.
8.
<Insert trial acronym>
Treatment Modification .......................................................................................................... 14
Trial procedures and assessments ........................................................................................... 15
8.1.
Summary of assessments ..................................................................................................... 15
8.2.
Schedule of Assessments ..................................................................................................... 15
8.3.
Trial Procedures .................................................................................................................... 16
8.3.1.
9.
Sub studies .................................................................................................................... 16
Adverse Event Reporting .......................................................................................................... 16
9.1.
Reporting Requirements ....................................................................................................... 16
9.2.
Adverse Events ..................................................................................................................... 17
9.3.
Serious Adverse Events ........................................................................................................ 17
9.3.1.
Events that do not require expedited (immediate) reporting ......................................... 17
9.3.2.
Events that do not require reporting on a Serious Adverse Event Form ...................... 18
9.3.3.
Monitoring pregnancies for potential Serious Adverse Events ..................................... 18
9.4.
Reporting period .................................................................................................................... 19
9.5.
Reporting Procedure – At Site .............................................................................................. 20
9.5.1.
Adverse Events ............................................................................................................. 20
9.5.2.
Serious Adverse Events ................................................................................................ 20
9.5.3.
Provision of follow-up information ................................................................................. 20
9.6.
Reporting Procedure – Trials Office ...................................................................................... 20
9.7.
Reporting to the Competent Authority and Research Ethics Committee .............................. 21
9.7.1.
Suspected Unexpected Serious Adverse Reactions .................................................... 21
9.7.2.
Serious Adverse Reactions ........................................................................................... 21
9.7.3.
Unexpected and Related Serious Adverse Events ....................................................... 21
9.7.4.
Adverse Events ............................................................................................................. 22
9.7.5.
Other safety issues identified during the course of the trial .......................................... 22
9.8.
Investigators .......................................................................................................................... 22
9.9.
Data Monitoring Committee .................................................................................................. 22
9.10.
Reporting to third parties ....................................................................................................... 22
10.
Data Handling and Record Keeping ..................................................................................... 22
10.1.
Source Data .......................................................................................................................... 23
10.2.
CRF Completion .................................................................................................................... 23
10.3.
Data Management ................................................................................................................. 24
10.4.
Archiving................................................................................................................................ 24
11.
Quality control and quality assurance ................................................................................... 24
11.1.
Site Set-up and Initiation ....................................................................................................... 24
11.2.
Monitoring.............................................................................................................................. 24
11.2.1.
On-site Monitoring ......................................................................................................... 25
11.2.2.
Central Monitoring ......................................................................................................... 25
11.3.
Audit and Inspection .............................................................................................................. 25
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
6 of 36
PROTOCOL
<Insert trial acronym>
11.4.
Notification of Serious Breaches ........................................................................................... 25
12.
End of Trial Definition ............................................................................................................ 26
13.
Statistical Considerations ...................................................................................................... 27
13.1.
Definition of Outcome Measures ........................................................................................... 27
13.1.1.
Primary outcome measures .......................................................................................... 27
13.1.2.
Secondary outcome measures/exploratory endpoints .................................................. 27
13.2.
Analysis of Outcome Measures ............................................................................................ 28
13.2.1.
Planned Randomisation Methodology .......................................................................... 28
13.2.2.
Planned Sub Group Analyses ....................................................................................... 28
13.2.3.
Planned Interim Analysis ............................................................................................... 28
13.2.4.
Planned Final Analyses ................................................................................................. 28
13.2.5.
Power Calculations........................................................................................................ 28
14.
Trial Organisational Structure ............................................................................................... 28
14.1.
Sponsor ................................................................................................................................. 29
14.2.
Trials Office ........................................................................................................................... 29
14.3.
Trial Management Group ...................................................................................................... 29
14.4.
Trial Steering Committee ...................................................................................................... 29
14.5.
Data Monitoring Committee .................................................................................................. 29
14.6.
Finance .................................................................................................................................. 30
15.
Ethical Considerations .......................................................................................................... 30
16.
Confidentiality and Data Protection ....................................................................................... 30
17.
Insurance and Indemnity ....................................................................................................... 31
18.
Publication Policy .................................................................................................................. 31
19.
Reference List ....................................................................................................................... 32
Abbreviations and Definitions: ........................................................................................................... 32
Appendices ........................................................................................................................................ 35
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
7 of 36
PROTOCOL
<Insert trial acronym>
1. Background and Rationale
ICH GCP and the EU CTD specify that the following regulatory requirements should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.2.1: name and description of the investigational product(s)
ICH GCP section 6.2.2: A summary of findings from nonclinical studies that potentially
have clinical significance and from clinical trials that are relevant to the trial.
ICH GCP section 6.2.3: Summary of the known and potential risks and benefits, if any, to
human subjects.
ICH GCP section 6.2.4: Description of and justification for the route of administration,
dosage, dosage regimen, and treatment period(s).
ICH GCP section 6.2.6: Description of the population to be studied.
ICH GCP section 6.2.7: References to literature and data that are relevant to the trial, and
that provide background for the trial.
EU CTD requirement: A discussion of the relevance of the clinical trial and its design
EU CTD requirement: An evaluation of the anticipated benefits and risks
EU CTD requirement: A justification for including subjects who are incapable of giving
informed consent or other special populations;
The background and trial rationale should include a description of the research question and
justification for undertaking the trial, including summary of relevant studies (published and
unpublished), examining benefits and harms for reach intervention. Where relevant please provide an
explanation for choice of comparators.
Example sub-headers include:
1.1. Background
1.2. Trial Rationale
1.2.1. Justification for participant population
1.2.2. Justification for design
1.2.3. Choice of treatment
1.2.4. Sub-studies
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
8 of 36
PROTOCOL
<Insert trial acronym>
2. Aims, Objectives and Outcome Measures
ICH GCP specifies that the following regulatory requirements should be included:
NOTE: Regulatory requirements:
ICH GCP Section 6.3: A detailed description of the objectives and the purpose of the trial.
ICH GCP section 6.4.1: A specific statement of the primary endpoints and the secondary
endpoints, if any, to be measured during the trial.
Sub--headers include:
2.1. Aims and Objectives
Specify aims or hypotheses. Note that ‘aims’ can be replaced with ‘hypothesis’ where appropriate.
2.2. Outcome Measures
Include primary, secondary, and other outcomes, including the specific measurement variable (e.g.,
systolic blood pressure), analysis metric (e.g. change from baseline, final value, time to event),
method of aggregation (e.g., median, proportion), and time point for each outcome. Provide an
explanation of the clinical relevance of chosen efficacy and harm outcomes.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
9 of 36
PROTOCOL
<Insert trial acronym>
3. Trial Design and Setting
NOTE: Regulatory requirements:
ICH GCP section 6.4 states that the scientific integrity of the trial and the credibility of the
data from the trial depend substantially on the trial design. A description of the trial design
should include (if not covered in other sections)
ICH GCP section 6.4.2: A description of the type/design of trial to be conducted (e.g.
double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design,
procedures and stages.
ICH GCP section 6.4.5: The expected duration of subject participation, and a description of
the sequence and duration of all trial periods, including follow-up, if any.
3.1. Trial Design
Description of trial design including type of trial (e.g. parallel group, crossover, factorial, single group),
allocation ratio, and framework (e.g., superiority, equivalence, noninferiority, exploratory) Give the
estimated number of participants needed to achieve trial objectives.
3.2. Trial Setting
Description of trial settings (e.g. community clinic, hospital) Include a description of where / how
recruitment will take place, including strategies for achieving adequate participant enrolment to reach
target sample size. If applicable, include the criteria that trial sites and individuals performing the
interventions (e.g. surgeons, psychotherapists) need to meet.
4. Eligibility
ICH GCP specifies that the following should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.5.1: Subject inclusion criteria.
ICH GCP section 6.5.2: Subject exclusion criteria.
Inclusion and exclusion criteria for participants. Only criteria essential to patient safety and/or trial
outcome should be listed as eligibility criteria
4.1. Inclusion Criteria
4.2. Exclusion Criteria
5. Consent
EU CTD indicates that the following should be included:
NOTE: Regulatory requirements:
EU CTD requirement: a description of the recruitment and informed consent procedures,
especially when subjects who are (temporarily or permanently) incapable of giving
informed consent are included or when a procedure with witnessed consent is to be used
Describe who will obtain informed consent or assent from potential trial participants or authorised
surrogates. Where a trial is enrolling vulnerable participants (e.g. adults who lack capacity or minors),
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
10 of 36
PROTOCOL
<Insert trial acronym>
the arrangements for consent e.g. use of legal representatives / witness must be described and the
text should be amended to reflect these arrangements. If there are multiple Participant Information
Sheets and Informed Consent Forms the text should be amended to reflect this fact. In addition a
paragraph explaining the purpose of the different Participant Information Sheets and Informed
Consent Forms may be required. Also include any additional consent provisions for collection and
use of participant data and biological specimens in ancillary studies, if applicable.
It will be the responsibility of the Investigator to obtain written informed consent for each participant
prior to performing any trial related procedure. Specify any others allowed to take consent (e.g.
Research Nurse if local practice allows and this responsibility has been delegated by the Principal
Investigator as captured on the Site Signature and Delegation Log). A Participant Information Sheet
(PIS) will be provided to facilitate this process. Investigators “or delegate(s)” will ensure that they
adequately explain the aim, trial treatment, anticipated benefits and potential hazards of taking part in
the trial to the participant. They will also stress that participation is voluntary and that the participant is
free to refuse to take part and may withdraw from the trial at any time. The participant will be given <
specify trial specific timeline> to read the PIS and to discuss their participation with others outside of
the site research team. The participant will be given the opportunity to ask questions.
If the participant expresses an interest in participating in the trial they will be asked to sign and date
the latest version of the Informed Consent Form (ICF). For CTIMP trials: “The participant must give
explicit consent for the regulatory authorities, members of the research team and representatives of
the sponsor to be given direct access to the participant’s medical records”. NOTE: this must be
reflected in the consent documentation.
The Investigator “or delegate(s)” will then sign and date the form. A copy of the ICF will be given to
the participant, a copy will be filed in the medical notes, and the original placed in the Investigator Site
File (ISF). Once the participant is entered into the trial, the participant’s unique trial identification
number will be entered on the Informed Consent Form maintained in the ISF. If internal review of
ICFs is being performed, the following text should also be included: “In addition, if the participant has
given explicit consent a copy of the signed Informed Consent Form will be sent to the Trials Office for
review”. Trials Office
Details of the informed consent discussions will be recorded in the participant’s medical notes. This
will include date of discussion, the name of the trial, summary of discussion, version number of the
PIS given to participant and version number of ICF signed and date consent received. Where consent
is obtained on the same day that the trial related assessments are due to start, a note will be made in
the medical notes as to what time the consent was obtained and what time the procedures started.
At each visit the participant’s willingness to continue in the trial will be ascertained and documented in
the medical notes. Throughout the trial the participant will have the opportunity to ask questions about
the trial. Any new information that may be relevant to the participant’s continued participation will be
provided. Where new information becomes available which may affect the participants’ decision to
continue, participants will be given time to consider and if happy to continue will be re-consented. Reconsent will be documented in the medical notes. The participant’s right to withdraw from the trial will
remain.
Electronic copies of the PIS and ICF will be available from the Trials Office and for UK trials will be
printed or photocopied onto the headed paper of the local institution. Details of all participants
approached about the trial will be recorded on the Participant Screening/Enrolment Log and with the
participant’s prior consent, their General Practitioner (GP) will also be informed that they are taking
part in the trial.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
11 of 36
PROTOCOL
<Insert trial acronym>
6. Enrolment and Randomisation
NOTE: Regulatory requirements:
ICH GCP section 6.4.3: A description of the measures taken to minimise/avoid bias, including:
o Randomisation
o Blinding
ICH GCP section 6.4.8: Maintenance of trial treatment randomisation codes and procedures for
breaking codes.
6.1. Enrolment/Registration
In this section, include the schedule of enrolment and detail all procedures and interventions
(including any run-ins and washouts) that must be completed prior to the participant being
enrolled/randomised.
Include plans to promote participant retention and complete follow-up.
6.2. Randomisation
Describe the randomisation procedures specific to the protocol and provide enough detail to allow
replication. Include the method of randomisation e.g. telephone randomisation service; sequentially
numbered, opaque, sealed envelopes, computer generated programme etc. Specify who will enrol
participants, and who will assign participants to interventions.
6.3. Blinding
For all blinded trials, describe who will be blinded to interventions (e.g., trial participants, care
providers, outcome assessors, data analysts) and describe any steps to conceal the sequence until
interventions are assigned. You should also detail the circumstances under which unblinding is
permissible (e.g. emergency unblinding for medical reasons, and for suspected SUSARs), and
procedure for revealing a participant’s allocated intervention during the trial (who to contact – Trials
Office, local pharmacy, out of hours service,...). Include what will happen with unblinded participants –
will they continue treatment or will they stop the trial?
7. Trial treatment / intervention
ICH GCP and the EU CTD specify that the following should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.6.1: The treatment(s) to be administered, including the name(s) of all the
product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and
the treatment period(s), including the follow-up period(s) for subjects for each
investigational product treatment/trial treatment group/arm of the trial.
ICH GCP section 6.6.2: Medication(s)/treatment(s) permitted (including rescue medication)
and not permitted before and/or during the trial.
ICH GCP section 6.6.3: Procedures for monitoring subject compliance.
ICH GCP section 6.4.4: A description of the trial treatment(s) and the dosage and dosage
regimen of the investigational product(s). Also include a description of the dosage form,
packaging, and labelling of the investigational product(s).
ICH GCP section 6.4.7: Accountability procedures for the investigational product(s),
including the placebo(s) and comparator(s), if any.
EU CTD requirement: a description of the plan for the provision of any additional care of
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
12 of 36
PROTOCOL
<Insert trial acronym>
the subjects once their participation in the trial has ended, where it differs from what is
normally expected according to the subject’s medical condition.
ICH GCP section 6.7.1: Specification of the efficacy parameters.
ICH GCP section 6.7.2: Methods and timing for assessing, recording, and analysing of
efficacy parameters.
ICH GCP section 6.8.1: Specification of safety parameters.
ICH GCP section 6.8.2: The methods and timing for assessing, recording, and analysing
safety parameters.
ICH GCP section 6.5.3: Subject withdrawal criteria (i.e. terminating investigational product
treatment/trial treatment) and procedures specifying:

When and how to withdraw subjects from the trial/ investigational product treatment.

The type and timing of the data to be collected for withdrawn subjects.

Whether and how subjects are to be replaced.

The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
Example sub-headers include:
7.1. Treatment
List the IMPs and NIMPs and state their licenced status
7.2. Treatment Supply and Storage
7.2.1.Treatment Supplies
Detail who will be supplying the treatment, include details of shipping and handling.
7.2.2.Packaging and Labelling
Detail who will be responsible for packaging and labelling of the treatment. A sample label may be
included here.
7.2.3.Drug Storage
Include where the drug will be stored and any special considerations e.g. temperature.
7.3. Dosing Schedule
You must include details of the following:
For trials using an IMP:
Name of the treatment(s) to be administered, giving the dose(s), the dosing schedule(s), the
route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for
subjects for each investigational product treatment/trial treatment group/arm of the trial. Where
applicable, you should also include details of NIMPs.
For trials using a device/intervention
Provide details of the device/intervention to be used for the trial.
7.4. Drug Interaction or Contraindications
This should include the following consideration before and/or during the trial:
 permitted medication(s)/treatment(s (including rescue medication)
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
13 of 36
PROTOCOL


<Insert trial acronym>
prohibited medication(s)/treatment(s (including highlighting those that are known to be related
to standard participant care for this participant population group)
concomitant medication(s)/treatment(s)
7.5. Accountability Procedures
Detail the procedures for monitoring subject compliance with treatment and include any strategies to
improve adherence (e.g. drug tablet return, laboratory tests).
7.6. Treatment Modification
In this section, include the criteria for discontinuing or modifying allocated interventions for a given trial
participant (e.g. drug dose change in response to harms, participant request, or improving/worsening
disease). Where applicable, specify safety parameters.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
14 of 36
PROTOCOL
<Insert trial acronym>
8. Trial procedures and assessments
8.1. Summary of assessments
Please include a table of assessment detailing the timeline of study procedures alongside the
assessments that will be carried out at each stage.
The template below provides an example of a schedule for interventions and assessments.*
Figure <update number and add name>.
TRIAL PERIOD
Enrolment
Allocation
-t1
0
TIMEPOINT**
Post-allocation
t1
t2
t3
Close-out
t4
etc.
tx
X
etc.
X
X
etc.
X
ENROLMENT:
Eligibility screen
X
Informed consent
X
[List other
procedures]
X
Allocation
X
INTERVENTIONS:
[Intervention A]
[Intervention B]
X
X
[List other trial
groups]
ASSESSMENTS:
[List baseline
variables]
X
X
[List outcome
variables]
X
[List other data
variables]
X
X
X
*Recommended content can be displayed using various schematic formats. See SPIRIT 2013
Explanation and Elaboration for examples from protocols.
**List specific time points in this row.
8.2. Schedule of Assessments
Expand on the summary of assessment table in section 8.1 and provide details on each participant
visit, including the plans for assessments and collection of outcome, baseline, and other trial data.
This section should include headers for each visit, e.g.
Screening
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
15 of 36
PROTOCOL
<Insert trial acronym>
visit 1,
visit 2 etc.
Ensure all procedures that will take place at each subject visit e.g. screening, baseline etc. are listed.
Under each visit heading e.g. the type of questionnaires to be completed; detailed description of the
samples to be taken (e.g. ALT/AST, WBC); procedures to be performed; dispensing of IMP etc. Under
each visit heading, ensure detail is provided on what will specifically happen at that visit. Reference to
where data collection forms can be found.
Ensure that any acceptable time windows for visits are appropriately documented. For example, if it is
acceptable for a visit to be scheduled with a window of + or – a certain number of days, then ensure
that this is documented in the protocol.
8.3. Trial Procedures
Detail any trial procedures that should be followed to ensure standardisation. For each procedure,
include a description of any equipment or trial instrument(s) (e.g. type of questionnaires, type of
laboratory tests, e.g. AST/ALT, WBC) to be used along with their reliability and validity (if known).
Include any related processes to promote data quality e.g. duplicate measurements; training of
assessors; calibration. If applicable, other procedures specific to the trial, e.g. laboratory, imaging
etc. should be included.
Consider the logistics of planning any assessments that need to be performed and any time delays
that may occur e.g. planning an MRI scan 1 week after screening and the logistics of being able to
plan this with the NHS provider within the specified timeframe
8.3.1.Sub studies
If the trial includes any additional optional procedures e.g. sample collection; questionnaires, then this
will need to be detailed. The sub study may involve a separate protocol which will need approval by
the relevant authorities. If the sub study forms a part of the same protocol for the main trial then
details of the features of the sub study must be detailed here. The PIS and ICF must be developed in
adherence with the specifications of the protocol. Specific protocol requirements must translate to the
information given to participants. If tissue is being collected, information must be provided to the
participant on where it will be stored.
If the trial includes optional elements, the specific consent for these elements must be obtained.
Ensure the ICF is designed to capture this information
9. Adverse Event Reporting
ICH GCP specifies that the following should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.8.3: Procedures for eliciting reports of and for recording and reporting
adverse event and intercurrent illnesses.
ICH GCP section 6.8.4: The type and duration of the follow-up of subjects after adverse
events
9.1. Reporting Requirements
This section should include information about the types of AEs for which data will be collected and
any exclusion to the reporting process.
The decision on the nature of the adverse events to be recorded, notified and reported depends both
on the how much is known of the risk/benefit profile of the Investigational Medicinal Products
(IMPs)/intervention under study, particularly in the population to be studied in the trial, and on the
aims of the trial. For medicines where there is already a significant amount of safety data available,
such as many marketed medicines, it is possible to state in the protocol that certain adverse events
do not need to be reported by the investigator to the sponsor in the normal way. This proposal in the
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
16 of 36
PROTOCOL
<Insert trial acronym>
protocol will be assessed at the time of the CTA assessment by the MHRA, as either acceptable or
not. This applies to Type A trials and potentially to some Type B trials
In order to make these decisions, the CI should carry out and document a risk assessment of the risks
associated with the clinical trial. It is anticipated that all early phase trials will collect all AEs however
phase III trials utilising well characterised IMPs may choose to collect data on selected Adverse
Reactions or SAEs only.
The protocol should document how the approach taken is compatible with the safety and aims of the
trial. Standard sub-headers are shown below with examples of text which can be utilised in different
scenarios.
Indicated which sections of the product information e.g. (compendium of) Summary of Product
Characteristics, Investigator Brochure, protocol (non-IMP) will form the Reference Safety Information,
the information against which SAEs will be categorised
Refer to table of abbreviations and definitions for definitions of all types of Adverse Events
CTIMPs
The collection and reporting of Adverse Events (AEs) will be in accordance with the Medicines for
Human Use Clinical Trials Regulations 2004 and its subsequent amendments. The Investigator will
assess the seriousness and causality (relatedness) of all AEs experienced by the participant with
reference to the Reference Safety Information, This should be documented in the source data.
Non-CTIMPs
The collection and reporting of Adverse Events (AEs) will be in accordance with the Research
Governance Framework for Health and Social Care and the requirements of the National Research
Ethics Service (NRES). Definitions of different types of AEs are listed in the table of abbreviations and
definitions. The Investigator should assess the seriousness and causality (relatedness) of all AEs
experienced by the trial participant this should be documented in the source data with reference to the
protocol.
9.2. Adverse Events
Example of text for trials collecting all AEs
All medical occurrences, including out of range laboratory values, which meet the definition of an AE
should be reported.
Example of text for trials collecting selected AEs
AEs are commonly encountered in participants receiving <insert treatment name>. As the safety
profiles of the IMPs used in this trial are well characterised, only Adverse Reactions (ARs)
experienced during treatment will be reported.
9.3. Serious Adverse Events
SAEs must be collected for all trials. However, it is possible in certain cases for SAEs not to be
reported in an expedited (immediate) fashion. This section describes both options.
Investigators will report AEs that meet the definition of an SAE. If there are certain SAEs which will be
collected but excluded from the expedited reporting process, the following statement can be added
“other than the SAEs listed in section 9.3.1”.
9.3.1.Events that do not require expedited (immediate) reporting
It is possible to exclude SAEs from expedited (immediate) reporting by sites. SAEs which are to be
excluded from expedited reporting process must be clearly defined in the protocol and the type of
event that is excluded should be restricted to those events which generate large volumes of SAEs or
such events that are an outcome measure and thus will be collected on the routine CRFs. An
example is given below:
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
17 of 36
PROTOCOL
<Insert trial acronym>
Participants receiving adjuvant chemotherapy may require admission to hospital for appropriate
medical intervention following development of some of the more severe known side effects of
treatment. For this reason the following SAEs do not require expedited (immediate) reporting by site
and are not regarded as unexpected for the purpose of this trial:

Admissions to control symptoms of vomiting unless the condition is life threatening or proves
fatal

Admissions for supportive treatment during an episode of myelosuppression unless this
proves fatal or requires admission to a high dependency or intensive care facility
An SAE Form should still be completed for these events but can be faxed to the Trials Office at any
time prior to completion of chemotherapy treatment. This would not apply to category A trials where
there are SAEs identified in the protocol that are not required to be reported.
If this section applies to the protocol, then details of any SAEs which do not require expedited
reporting must be included here with justification for the decision provided.
9.3.2.Events that do not require reporting on a Serious Adverse Event Form
This is an optional section. This section should be used to list SAEs which will not be captured using
an SAE form.
For example: SAEs that are related and expected (in CTIMPs referred to as Expected Serious
Adverse Reactions (SARs))
These can be captured another way, for example via an expected and related SAE/expected SAR
form rather than an SAE Form. The data collected for this type of event is significantly less than that
collected for an SAE. Such events do not require expedited reporting by site and do not require
clinical evaluation (as they are by definition expected). The intent is to cut down on workload for both
sites and the Trials Office. Again the number of expected and related SAEs/expected SARs should be
restricted to 2-3 high volume events.
The following are regarded as expected SAEs for the purpose of trial and should not be reported on
an SAE form. These events should be reported on <insert name of the trial specific form that will
capture this information, e.g. an expected SAR form or expected and related SAE form>) form
instead.
Examples are:
Admissions to control symptoms of vomiting unless the condition is life threatening or proves fatal
Admissions for supportive treatment during an episode of myelosuppression unless this proves fatal
or requires admission to a high dependency or intensive care facility
SAEs that are related to a pre-existing condition
SAEs that are related to symptoms or progression of the participant’s disease
Death from disease under trial, as a result of the participant’s standard treatment or from a preexisting medical condition
Events that that are outcome measures and thus will be collected on the routine CRFs e.g.
hospitalisations for protocol defined treatment or treatment for progression of the participant’s
condition under study
This is not an exclusive list and Investigators should only report SAEs which are attributable to the
trial protocol.
<Insert name of trial specific form> forms should be completed and returned <insert method and
timeline for return e.g. posted as soon as possible>.
9.3.3.Monitoring pregnancies for potential Serious Adverse Events
This section should be included for all trials where there is a risk of congenital anomalies or birth
defects in the offspring of participants as a result of their participation in the trial. For female
participants consent to collect this information may be addressed in the main trial Participant
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
18 of 36
PROTOCOL
<Insert trial acronym>
Information Sheet or a separate pregnancy release of information form for pregnant trial participants
and/or partners of trial participants may be used. Note a pregnancy notification form may need to be
set up.
There is an identified risk of congenital anomalies or birth defects in the offspring of participants as a
result of their participation in the trial. The outcome of pregnancies of participants will therefore be
monitored in order to provide SAE data on congenital anomalies or birth defects.
For trials involving females only (and where pregnancy is addressed in the main trial Participant
Information Sheet) include:
In the event that a participant becomes pregnant during the SAE reporting period a pregnancy
notification form will be completed and returned to the Trials Office. Details of the outcome of the
pregnancy will be provided on a follow-up pregnancy notification form and “an SAE Form will be
completed”. A pregnancy notification form must be set up.
For trials involving males only include:
In the event that a participant’s partner becomes pregnant during the SAE reporting period a
pregnancy notification form will be completed (providing the participant’s details) and returned to the
Trials Office. The participant should be given a <insert pregnancy release of information form or
appropriate form name> to give to their partner. If the partner is happy to provide information on the
outcome of their pregnancy they should sign the <insert pregnancy release of information form or
appropriate form name>. Once consent has been obtained details will be provided of the outcome of
the pregnancy on a follow-up pregnancy notification form and “an SAE Form will be completed.”
For trials involving both genders (and where pregnancy is addressed in the main trial Participant
Information Sheet) include:
In the event that a participant or their partner becomes pregnant during the SAE reporting period a
pregnancy notification form will be completed (providing the participant’s details) and returned to the
Trials Office.
 If it is the participant who is pregnant, outcome data will be provided on a follow-up pregnancy
notification form.
 Where the participant’s partner is pregnant consent must first be obtained and the participant
should be given a <insert pregnancy release of information form or appropriate form name> to
give to their partner. If the partner is happy to provide information on the outcome of their
pregnancy they should sign the <insert pregnancy release of information form or appropriate
form name>.
Once consent has been obtained details of the outcome of the pregnancy will be provided on a followup pregnancy notification form and “an SAE Form will be completed.”
9.4. Reporting period
This section is mandatory and should include information on the length of the AE reporting period.
This should be defined on a trial specific basis.
For most trials the reporting period will commence when the participant begins trial treatment or on
entry into the trial. However for trials where the screening period includes trial specific tests which
may impact on the safety of participants the start date can be the date of informed consent.
The reporting period will cease after an appropriate washout period following the participant’s last
protocol defined treatment, unless there are trial specific assessments that may impact on participant
safety scheduled to take place after this washout period. If the latter is the case, consider setting the
end date in such a way that it allows for reporting of any AEs that may be related to this trial specific
assessment. The washout period will be dependent on the treatment under study.
For example:
Details of all AEs (except those listed above) will be documented and reported from the date of
commencement of protocol defined treatment until 30 days after the administration of the last
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
19 of 36
PROTOCOL
<Insert trial acronym>
treatment. SAEs that are judged to be at least possibly related to the IMP must still be reported in an
expedited manner irrespective of how long after IMP administration the reaction occurred.
9.5. Reporting Procedure – At Site
9.5.1.Adverse Events
Ensure the medical coding dictionary e.g. MEDRA, CTCAE that will be used for the coding of adverse
events is documented in the protocol.
Example of text for trials collecting all AEs:
AEs should be collected on an AE Form (and where applicable on an SAE Form). An AE Form should
be completed and returned <insert method and timeline for return e.g. posted as soon as possible>.
Example of text for trials collecting selected AEs
AEs are commonly encountered in participants receiving <insert treatment name>. As the safety
profiles of the IMPs used in this trial are well characterised, only Adverse Reactions (ARs)
experienced during treatment will be reported.
9.5.2.Serious Adverse Events
This section is used to describe the SAE reporting process.
AEs defined as serious and which require reporting as an SAE should be reported on an SAE Form.
When completing the form, the Investigator will be asked to define the causality and the severity of
the AE.
On becoming aware that a participant has experienced an SAE, the Investigator (or delegate) must
complete, date and sign an SAE Form. The form should arrive at the trials office state method e.g.
<faxed to the Trials Office using one of the numbers listed below> as soon as possible and no later
than 24 hours after first becoming aware of the event: if method to be used is by fax, provide 2 fax
numbers below
To report an SAE, fax the SAE Form to:
<Insert fax number> or <Insert fax number>>
On receipt the Trials Office will allocate each SAE a unique reference number which will be forwarded
to the site as proof of receipt. If confirmation of receipt is not received within 1 working day please
contact the Trials Office. The SAE reference number should be quoted on all correspondence and
follow-up reports regarding the SAE and filed with the actual SAE in the Site File.
For SAE Forms completed by someone other than the Investigator the Investigator will be required to
countersign the original SAE Form to confirm agreement with the causality and severity assessments.
The form should then be returned to the Trials Office and a copy kept in the Site File.
Investigators should also report SAEs to their own Trust in accordance with local practice.
9.5.3.Provision of follow-up information
Participants should be followed up until resolution or stabilisation of the event. Follow-up information
should ideally be provided on a new SAE Form.
9.6. Reporting Procedure – Trials Office
For CTIMPs
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
20 of 36
PROTOCOL
<Insert trial acronym>
On receipt the Trials Office will allocate each SAE a unique reference number which will be forwarded
to the site as proof of receipt within 1 working day. The SAE reference number will be quoted on all
correspondence and follow-up reports regarding the SAE and filed with the actual SAE in the TMF.
On receipt of an SAE Form seriousness and causality will be reviewed independently by a <insert title
of the medical person responsible for determining causality assessments>. An SAE judged by the
investigator or <insert title of the medical person responsible for determining causality assessments>
to have a reasonable causal relationship with the trial medication will be regarded as a Serious
Adverse Reaction (SAR). The <insert title of the medical person responsible for determining
expectedness assessments> this will usually be the CI will also assess all SARs for expectedness.
If the event meets the definition of a SAR that is unexpected (i.e. is not defined in the <insert
Reference Safety Information (RSI)>) it will be classified as a Suspected Unexpected Serious
Adverse Reaction (SUSAR).
For non-CTIMPs
On receipt the Trials Office will allocate each SAE a unique reference number which will be forwarded
to the site as proof of receipt within 1 working day. The SAE reference number will be quoted on all
correspondence and follow-up reports regarding the SAE and filed with the actual SAE in the TMF.
On receipt of an SAE Form seriousness and causality will be determined independently by a Clinical
Coordinator. An SAE judged by the Investigator or Clinical Coordinator to have a reasonable causal
relationship with the trial treatment will be regarded as a related SAE. The Clinical Coordinator will
also assess all related SAEs for expectedness. If the event is unexpected (i.e. is not defined in the
protocol as an expected event) it will be classified as an unexpected and related SAE.
9.7. Reporting to the Competent Authority and Research Ethics Committee
9.7.1.Suspected Unexpected Serious Adverse Reactions
Required for CTIMPs only
The Trials Office will report a minimal data set of all individual events categorised as a fatal or life
threatening SUSAR to the Medicines and Healthcare products Regulatory Agency (MHRA) and
Research Ethics Committee (REC) within 7 days. Detailed follow-up information will be provided
within an additional 8 days.
All other events categorised as SUSARs will be reported within 15 days.
*Note that for trials where the UoB takes on sponsor responsibility for pharmacovigilance, reports of
any SUSARs need to be forwarded to the Research Governance Team at the time it is reported to the
MHRA/REC, with a note of the CI explaining how this SUSAR impacts the safety profile of the study.
Where this is the case, the following needs to be included:
A copy is also sent to the University of Birmingham Research Governance Team
(researchgovernance@contacts.bham.ac.uk, subject line should read: SUSAR RG_xx-xxx) at the
time of sending the SUSAR report.
9.7.2.Serious Adverse Reactions
Required for CTIMPs only
The Trials Office will report details of all SAEs and SARs (including SUSARs) to the MHRA and REC
annually from the date of the Clinical Trial Authorisation, in the form of a Development Safety Update
Report (DSUR).
For trials where the UoB takes on sponsor responsibility for pharmacovigilance include the following:
A copy is also sent to the University of Birmingham Research Governance Team at the time of
sending out the DSUR.
9.7.3.Unexpected and Related Serious Adverse Events
Required for non-CTIMPS only
The Trials Office will report all events categorised as Unexpected and Related SAEs to the within 15
days.
For trials where the UoB takes on sponsor responsibility for pharmacovigilance include the following:
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
21 of 36
PROTOCOL
<Insert trial acronym>
A copy is also sent to the University of Birmingham Research Governance Team at the time of
sending out the Unexpected and Related Serious Adverse Event.
9.7.4.Adverse Events
Required for CTIMPs only
Details of all AEs will be reported to the MHRA on request.
9.7.5.Other safety issues identified during the course of the trial
Required for CTIMPs only
The MHRA and REC will be notified immediately if a significant safety issue is identified during the
course of the trial.
For trials where the UoB takes on sponsor responsibility for pharmacovigilance include the following:
The University of Birmingham Research Governance Team will also be informed at the time that the
REC and MHRA is informed.
Required for non-CTIMPS only
The REC will be notified immediately if a significant safety issue is identified during the course of the
trial.
For trials where the UoB takes on sponsor responsibility for pharmacovigilance include the following:
The University of Birmingham Research Governance Team will also be informed at the time that the
REC is informed.
9.8. Investigators
Required for CTIMPs only
Details of all SUSARs and any other safety issue which arises during the course of the trial will be
reported to Principal Investigators. A copy of any such correspondence should be filed in the
Investigator Site File.
Required for non-CTIMPS only
Details of all Unexpected and Related SAEs and any other safety issue which arises during the
course of the trial will be reported to Principal Investigators. A copy of any such correspondence
should be filed in the Site File.
9.9. Data Monitoring Committee
May be required for both CTIMPS and non-CTIMPS – if there is no Data Monitoring Committee for the
trial, then delete this section
The independent Data Monitoring Committee (DMC) will review all SAEs.
9.10.
Reporting to third parties
(Pharmaceutical) Companies providing funding for the trial and/or supplying an Investigational
Medicinal Product for CTIMPs may wish to be notified of safety information resulting from the trial.
Any such requirements must be defined contractually and the arrangements made explicit in the PIS.
Document in this section what exactly needs to be forwarded to the third party (SAEs, SARS,
SUSARs and/or Unexpected and Related SAEs), the process for reporting (if not documented
elsewhere, e.g. in trial specific instructions), and the timelines for reporting.
10.
Data Handling and Record Keeping
ICH GCP also specifies that the following should be included
NOTE: Regulatory requirements:
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
22 of 36
PROTOCOL
<Insert trial acronym>
ICH GCP section 6.4.9 The identification of any data to be recorded directly on the CRFs
(i.e. no prior written or electronic record of data), and to be considered to be source data.
ICH GCP section 6.4.9 requires the protocol to detail data handling and record keeping
10.1.
Source Data
In order to allow for the accurate reconstruction of the trial and clinical management of the subject,
source data will be accessible and maintained.
If the CRF is the source document for any data e.g. questionnaires or physical examination, you must
list these variables either in the protocol or in a separate agreement. Select one of the following as
appropriate (a) “Some data may be entered directly onto the CRF these are clearly identified and
detailed below” or (b) “Some data may be entered directly onto the CRF these are clearly identified
and detailed in the source data agreement” or (c) “The CRF will not be source for any data”.
For clinical trials the source data is generally speaking kept at the site in the participants’’ medical
notes. However, source data may be kept elsewhere, e.g. if MRI scans are done at the UoB. Where
this is the case, clarify here where source data is kept. For example:
Source data is kept as part of the participants’ medical notes generated and maintained at site. In
addition, for this trial <include a test> is performed; the source data will be kept at <insert location>.
10.2.
CRF Completion
Normal practices are for CRFs to be set up, however for some trials analysis is directly performed on
source data, especially where the source data are complex reports such as MRI scans,
histopathology reports Where this is the case, a CRF is still expected to be used for clinical data as
captured in the participants’ medical notes. The protocol should however define what data will not be
found in the CRF, and either refer to trial specific guidelines or detail here as to how this data is
obtained and processed to allow for final analysis.
Data reported on each Case Report Form will be consistent with the source data and any
discrepancies will be explained. Staff delegated to complete CRFs will be trained to adhere to state
the guidance that will be followed. CRF completion guidelines typically include advice on:











Date format and partial dates
Time format and unknown times
Rounding conventions
Trial-specific interpretation of data fields
Entry requirements for concomitant medications.(generic or brand names)
Which forms to complete and when
What to do in certain scenarios, for example when a subject withdraws from the trial
Missing/incomplete data
Completing SAE forms and reporting SAEs
Repeat laboratory tests
Protocol and GCP non-compliances
In all cases it remains the responsibility of the site’s Principal Investigator to ensure that the CRF has
been completed correctly and that the data are accurate. Where applicable for the trial this will be
evidenced by the signature of the site’s Principal Investigator on the CRF.
For paper CRFs, describe what will happen to the documentation, e.g. “The completed originals will
be submitted to the Trials Office and a copy filed in the Investigator Site File”
For electronic CRFs describe the design and how they will be implemented and used and where
applicable how the data will be uploaded.
Any questionnaires used for the trial must be specified in the protocol. Only CRFs specified in the
protocol must be used
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
23 of 36
PROTOCOL
10.3.
<Insert trial acronym>
Data Management
In this section describe the plans for data entry, coding, security, and storage, including any related
processes to promote data quality (e.g., double data entry; range checks for data values). Where
appropriate, include reference to where details of data management procedures can be found, if not
in the protocol. Include here that all missing and ambiguous data will be queried.
This section also needs to include details of how queries will be raised on trial data e.g. by using data
clarification forms and expected turnaround times for queries. CRF in the Trials Office must be
verifiable at site. Detail should therefore be provided on how changes will be made to the CRF at site
and to the copy of the CRF held in the Trials Office. Include what obvious changes can be made by
the trials office staff.
10.4.
Archiving
All records created by following trial procedures and all documents listed in guidance relating to the
conduct of the trial must be retained and archived for the specified period.
It is the responsibility of the Principal Investigator to ensure all essential trial documentation and
source documents (e.g. signed Informed Consent Forms, Investigator Site Files, Pharmacy Files,
participants’ hospital notes, copies of CRFs etc.) at their site are securely retained for at least 25
years.
Documents are archived following any regulatory requirements (e.g. for CTIMPs) and any local
procedures (e.g. for UoB sponsored trials, refer to the UoB Code of Practice for Research). In some
trials it may be necessary to consider the archiving period extending until the processing of all
biological material collected for research has completed. This must be established with the sponsor
and details of archiving relating the protocol must be detailed in this section. No documents will be
destroyed without prior approval from the Trials Office.
11.
Quality control and quality assurance
ICH GCP also specifies that the following should be included
NOTE: Regulatory requirements:
ICH GCP section 6.10 The sponsor should ensure that it is specified in the protocol or
other written agreement that the investigator(s)/institution(s) will permit trial-related
monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to
source data/documents.
ICH GCP section 6.11 requires the protocol to detail Quality Control and Quality Control
processes
11.1.
Site Set-up and Initiation
All participating Principal Investigators will be asked to sign the necessary agreements <specify other
documents as appropriate for the trial e.g. registration forms> and supply a current CV to the Trials
Office. All members of the site research team will also be required to sign a site signature and
delegation log. Prior to commencing recruitment all sites will undergo a process of initiation and will
have completed GCP training. Key members of the site research team will be required to attend either
a meeting or a teleconference <if required amend to specify only “meeting” or only “teleconference”>
covering aspects of the trial design, protocol procedures, Adverse Event reporting, collection and
reporting of data and record keeping. Sites will be provided with an Investigator Site File <where
applicable insert “and a Pharmacy File”> containing essential documentation, instructions, and other
documentation required for the conduct of the trial. The Trials Office must be informed immediately of
any change in the site research team.
11.2.
Monitoring
There is always a need for monitoring to ensure safety of participants and the credibility of the data.
Monitoring can be performed by visiting the trial site(s) (‘on-site monitoring’) which gives the benefit of
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access to source documents. However, centralised monitoring techniques can also be employed.
The risk assessment should be performed to identify the risks and how these can be mitigated
through either on-site or centralised monitoring, or a combination of the two. Findings generated from
monitoring should be shared with local R&D departments who may have plans to perform quality
checks on the same trial.
11.2.1. On-site Monitoring
On-site monitoring should be provided by the Trials Office. However, if there is not the expertise
within the trials team to perform this, then this service may be provided by an external provider, e.g. a
UKCRN registered CTU or the UoB CRCT. These discussions would need to take place at the time
of grant submission and detailed in the protocol.
Monitoring will be carried out as required following a risk assessment and as documented in the
monitoring plan. Any monitoring activities will be reported to the trials team and any issues noted will
be followed up to resolution. Additional on-site monitoring visits may be triggered, for example by
poor CRF return, poor data quality, low SAE reporting rates, excessive number of participant
withdrawals or deviations. If a monitoring visit is required the Trials Office will contact the site to
arrange a date for the proposed visit and will provide the site with written confirmation. Investigators
will allow the <insert trial name> trial staff access to source documents as requested.
11.2.2. Central Monitoring
Where applicable include the following paragraph:
The Trials Office will be in regular contact with the site research team to check on progress and
address any queries that they may have. The Trials Office will check incoming Case Report Forms
for compliance with the protocol, data consistency, missing data and timing. Sites will be asked for
missing data or clarification of inconsistencies or discrepancies. If consent forms are being collected
for in-house review, explicit consent will need to be obtained from the participant and the following
statement should be included “Sites will be requested to send in copies of signed Informed Consent
Forms and other documentation for in-house review for all participants providing explicit consent.
This will be detailed in the monitoring plan”. If source data is requested for central monitoring (e.g. for
checking eligibility or endpoints), this should be captured in the protocol so that sites are aware of
this. Such source data should be redacted and labelled with the participant’s trial specific ID number.
11.3.
Audit and Inspection
The Principal Investigator will permit trial-related monitoring, quality checks, audits, ethical reviews,
and regulatory inspection(s) at their site, providing direct access to source data/documents. The
Principal Investigator will comply with these visits and any required follow up. Sites are also requested
to notify the Trials Office of any MHRA inspections.
11.4.
Notification of Serious Breaches
For CTIMPs being run in the UK include the following:
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004
and its amendments the Sponsor of the trial is responsible for notifying the licensing authority in
writing of any serious breach of the conditions and principles of GCP in connection with that trial or
the protocol relating to that trial, within 7 days of becoming aware of that breach.
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a
significant degree the safety or physical or mental integrity of the subjects of the trial; or the scientific
value of the trial. Sites are therefore requested to notify the Trials office of any suspected trial-related
serious breach of GCP and/or the trial protocol. Where the Trials Office is investigating whether or not
a serious breach has occurred sites are also requested to cooperate with the Trials Office in providing
sufficient information to report the breach to the MHRA where required and in undertaking any
corrective and/or preventive action. Sites may be suspended from further recruitment in the event of
serious and persistent non-compliance with the protocol and/or GCP, and/or poor recruitment. Any
major problems identified during monitoring may be reported to <specify trial specific committees
and/or stakeholders e.g. Trial Management Group, Trial Steering Committee>, the REC and the
relevant regulatory bodies. This includes reporting serious breaches of GCP and/or the trial protocol
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to the REC and MHRA. Where the UoB takes on the sponsor responsibility for Serious Breach
reporting include the following: A copy is sent to the University of Birmingham Clinical Research
Compliance Team at the time of reporting to the REC and/or relevant regulatory bodies.
For non-CTIMPs being run in the UK include the following:
The sponsor is responsible for notifying the REC of any serious breach of the conditions and
principles of GCP in connection with that trial or the protocol relating to that trial. Sites are therefore
requested to notify the Trials Office of any suspected trial-related serious breach of GCP and/or the
trial protocol. Where the Trials Office is investigating whether or not a serious breach has occurred
sites are also requested to cooperate with the Trials Office in providing sufficient information to report
the breach to the REC where required and in undertaking any corrective and/or preventive action.
Sites may be suspended from further recruitment in the event of serious and persistent noncompliance with the protocol and/or GCP, and/or poor recruitment. Any major problems identified
during monitoring may be reported to <specify trial specific committees and/or stakeholders e.g. Trial
Management Group, Trial Steering Committee>, and the REC. This includes reporting serious
breaches of GCP and/or the trial protocol to the REC and MHRA. Where the UoB takes on the
sponsor responsibility for Serious Breach reporting include the following: A copy is sent to the
University of Birmingham Clinical Research Compliance Team at the time of reporting to the REC.
12.
End of Trial Definition
NOTE: Regulatory requirements:
EU CTD requires the protocol to detail a definition for the end of trial
The definition of end of a trial must be clearly defined in the protocol. Definitions of end of trial will
differ according to whether the trial is an Investigational Medicinal Product (IMP) or non-IMP trial and
whether the trial involves long-term follow-up. The end of trial is normally defined as the date of the
last visit of the last participant. Describe the arrangements for how the results of the trial will be
shared with the sites and patients where applicable.
For all types of trial, where ethical approval for a sub-study (e.g. sample collection) has been (or will
be) granted as part of the main protocol, the date of last data capture must also include the final
processing / testing of all samples, as specified in the protocol. Note: where analysis is not expected
to be completed in an acceptable timeframe (e.g. sub-study does not form part of primary or
secondary endpoints) it is preferable to have a separate protocol and ethics approval for the substudy.
The following text should be used according to the type of trial and modified as appropriate:
Non- CTIMP
The end of trial will be <the date of or x months after> the last data capture. The Trials Office will
notify the REC the trial has ended and a summary of the clinical trial report will be provided within 12
months of the end of trial.
For trials where the UoB takes on sponsor responsibility for end of trial notification and summary
report submission include the following:
A copy of the end of trial notification as well as the summary report is also sent to the University of
Birmingham Research Governance Team at the time of sending these are sent to the REC.
CTIMP
When calculating the end of trial date for CTIMPs without long-term follow-up the end of trial date
should be the defined as the same date for both the MHRA and REC. Allow sufficient time following
the last participant visit for all relevant trial data to be received and entered onto the trial database.
Consider the size of the trial and anticipated rate of data return.
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The end of trial will be <the date of or x months after > the last data capture. This will allow sufficient
time for the completion of protocol procedures, data collection and data input. The Trials Office will
notify the MHRA and REC that the trial has ended within 90 days of the end of trial. Where the trial
has terminated early, the Trials Office will inform the MHRA and REC within 15 days of the end of
trial. The Trials Office will provide them with a summary of the clinical trial report within 12 months of
the end of trial.
For trials where the UoB takes on sponsor responsibility for end of trial notification and summary
report submission include the following:
A copy of the end of trial notification as well as the summary report is also sent to the University of
Birmingham Research Governance Team at the time of sending these are sent to the MHRA and
REC.
13.
Statistical Considerations
ICH GCP specifies that the following should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.4.6 A description of the "stopping rules" or "discontinuation criteria" for
individual subjects, parts of trial and entire trial.
ICH GCP section 6.9.1 A description of the statistical methods to be employed, including
timing of any planned interim analysis(ses).
ICH GCP section 6.9.2 The number of subjects planned to be enrolled. In multicentre trials,
the numbers of enrolled subjects projected for each trial site should be specified. Reason
for choice of sample size, including reflections on (or calculations of) the power of the trial
and clinical justification.
ICH GCP section 6.9.3 The level of significance to be used.
ICH GCP section 6.9.4 Criteria for the termination of the trial.
ICH GCP section 6.9.5 Procedure for accounting for missing, unused, and spurious data.
ICH GCP section 6.9.6 Procedures for reporting any deviation(s) from the original
statistical plan (any deviation(s) from the original statistical plan should be described and
justified in protocol and/or in the final report, as appropriate).
ICH GCP section 6.9.7 The selection of subjects to be included in the analyses (e.g. all
randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).
Example sub-headers include:
13.1.
Definition of Outcome Measures
Detail the statistical methods for analysing primary and secondary outcomes. Reference to where
other details of the statistical analysis plan can be found, if not in the protocol.
13.1.1. Primary outcome measures
See section 2.2.
13.1.2. Secondary outcome measures/exploratory endpoints
See section 2.2.
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13.2.
<Insert trial acronym>
Analysis of Outcome Measures
Full details may be specified in a Statistical Analysis Plan; where this is the case an outline of the plan
will be given here with a reference to the Statistical Analysis Plan. .
Give details on the following:

The statistical analysis by describing the comparisons that are planned between treatment arms
and any adjustments being made for multiple comparisons and by describing the methods that
may be used to compare each outcome measure, i.e. summary measures and hypothesis tests

Selection of participants to be used in the analyses (if not intention to treat)

definition of analysis population relating to protocol non-adherence (e.g., as randomised analysis),
and any statistical methods to handle missing data (e.g., multiple imputation)

Rationale for the analysis of stratification factors

If applicable, give the criteria for the termination (“stopping rules”) of the trial and cross reference
the DMC and TSC
Note that if no Statistical Analysis Plan is set up for the trial, this section must have sufficient
information to refer to in lieu of a Statistical Analysis Plan.
13.2.1. Planned Randomisation Methodology
In this section summarise the randomisation methodology and mechanism for generating and
implementing the allocation sequence e.g. computer-generated random numbers, randomisation list)
and 3rd party providers/persons responsible. List any factors for stratification.
To reduce predictability of a random sequence, details of any planned restriction (e.g., blocking)
should be provided in a separate document that is unavailable to those who enrol participants or
assign interventions.
13.2.2. Planned Sub Group Analyses
Give details of any subgroup and adjusted analyses by describing in which subgroups the treatment
effects will be investigated and the statistical methods which will be used.
13.2.3. Planned Interim Analysis
Describe the type of interim analyses that will be performed including who will have access to these
interim results and make the final decision to terminate the trial. Give the criteria for the termination
(“stopping rules”) of the trial and cross reference the DMC and TSC. Include any trial milestones with
the number of participating sites (approximate) and the timing of interim analyses.
13.2.4. Planned Final Analyses
Give the timing of final analysis (there may be several final analyses that relate to different outcome
measures or to different lengths of follow-up).
13.2.5. Power Calculations
Detail how the sample size was determined and provide a rationale i.e. a statement of the size of
difference and significance level and power that contributed to the sample size calculations for the
primary outcome measure(s) and any other measures (secondary or subgroups). Include any
clinical and statistical assumptions supporting any sample size calculations.
Specify any adjustments that have been made for drop-outs (e.g. inflation by X%) or interim analyses
(e.g. adjustment of p-values).
14.
Trial Organisational Structure
You should consider including the composition, roles, and responsibilities of the coordinating centre,
steering committee, endpoint adjudication committee, data management team, and other individuals
or groups overseeing the trial, if applicable.
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14.1.
<Insert trial acronym>
Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation,
management, and/or financing of a clinical trial.
14.2.
Trials Office
14.3.
Trial Management Group
The Trial Management Group should include those individuals responsible for the day-to-day
management of the trial, such as the Chief Investigator, statistician, trial manager, research nurse,
data manager. The role of the group is to monitor all aspects of the conduct and progress of the trial,
ensure that the protocol is adhered to and take appropriate action to safeguard participants and the
quality of the trial itself.
14.4.
Trial Steering Committee
The role of the Trial Steering Committee (TSC) is to provide the overall supervision of the trial. Ideally,
the TSC should include members who are independent of the investigators, their employing
organisations, funders and sponsors. The TSC should monitor trial progress and conduct and advise
on scientific credibility. The TSC will consider and act, as appropriate, upon the recommendations of
the Data Monitoring Committee (DMC) or equivalent and ultimately carries the responsibility for
deciding whether a trial needs to be stopped on grounds of safety or efficacy.
14.5.
Data Monitoring Committee
An independent data-monitoring committee established for the sponsor to assess at intervals the
progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the
sponsor whether to continue, modify, or stop a trial.
Detail the composition of data monitoring committee (DMC); summary of its role and reporting
structure; statement of whether it is independent from the sponsor and competing interests; and
reference to where further details about its charter can be found, if not in the protocol. Alternatively,
an explanation of why a DMC is not needed.
Data analyses will be supplied in confidence to an independent Data Monitoring Committee (DMC),
which will be asked to give advice on whether the accumulated data from the trial, together with the
results from other relevant research, justifies the continuing recruitment of further participants. The
DMC will operate in accordance with a trial specific charter based upon the template created by the
Damocles Group. The DMC will meet <insert details of when the DMC will meet> unless there is a
specific reason (e.g. safety phase) to amend the schedule. Avoid stating that the DMC will meet
following the recruitment of XX participants, because if the recruitment rate is not as predicted the
DMC may meet too early or too late which may affect their ability to effectively monitor the trial.
Instead consider a time-based schedule.
Consider adding: “During the recruitment phase of the trial the DMC is scheduled to meet <insert
timeline> e.g. six months after the recruitment of the first participant and annually thereafter”.
Additional meetings may be called if recruitment is much faster than anticipated and the DMC may, at
their discretion, request to meet more frequently or continue to meet following completion of
recruitment. An emergency meeting may also be convened if a safety issue is identified. The DMC will
report directly to the <insert Trial Management Group (TMG) or Trial Steering Committee as
applicable> who will convey the findings of the DMC to <specify to whom the report will be sent e.g.
Trial Steering Committee, MHRA, funders, and/or sponsors as applicable. For independent UoB
Sponsored studies report should be sent to RGT.
The DMC may consider recommending the discontinuation of the trial if the recruitment rate or data
quality are unacceptable or if any issues are identified which may compromise participant safety. The
trial would also stop early if the interim analyses showed differences between treatments that were
deemed to be convincing to the clinical community. If the trial includes stopping rules indicate here
and reference the relevant section of the protocol.
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14.6.
<Insert trial acronym>
Finance
Provide details of the sources and types of financial, material, and other support granted to the trial,
including where payments are made e.g. pathology payments, amend accordingly. Where applicable
include statement re (NIHR CRN) Portfolio adoption and/or endorsements.
This is an investigator-initiated and investigator-led trial funded by <insert all relevant funders, and
acknowledge companies that provide free drug>.
15.
Ethical Considerations
ICH GCP specifies that the following should be included:
NOTE: Regulatory requirements:
ICH GCP section 6.2.5 A statement that the trial will be conducted in compliance with the
protocol, GCP and the applicable regulatory requirement(s).
ICH GCP section 6.12 Description of ethical considerations relating to the trial.
The trial will be performed in accordance with the recommendations guiding physicians in biomedical
research involving human subjects, adopted by the 18th World Medical Association General
Assembly, Helsinki, Finland, June 1964, amended at the 48th World Medical Association General
Assembly, Somerset West, Republic of South Africa, October 1996 (website:
http://www.wma.net/en/30publications/10policies/b3/index.html).
The trial will be conducted in accordance with the Research Governance Framework for Health and
Social Care, the applicable UK Statutory Instruments, (which include the Medicines for Human Use
Clinical Trials 2004 and subsequent amendments and the Data Protection Act 1998 <add “and
Human Tissue Act 2008” and Human Tissue (Scotland) Act 2006 (if applicable)”
“EU Clinical Trials Directive”; “Medical Devices Regulations and amendment Regulations” as
appropriate>) and Guidelines for Good Clinical Practice (GCP). This trial will be carried out under a
Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical Trials
regulations. The protocol will be submitted to and approved by the REC prior to circulation.
Before any participants are enrolled into the trial, the Principal Investigator at each site is required to
obtain local R&D approval. Sites will not be permitted to enrol participants until written confirmation of
R&D approval is received by the Principal Investigator.
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain the
necessary local approval. This does not affect the individual clinicians’ responsibility to take
immediate action if thought necessary to protect the health and interest of individual participants.
16.
Confidentiality and Data Protection
In this section, consider what personal data will be collected, whether it will be moved and where it will
be stored. Provide justification. Arrangements detailed in this section must transfer to the information
provided to participants in the PIS and ICF.
For large multicentre trials as well as a unique trial identification number, additional identifiers could
be collected. This must be stated and justified. Refer to guideline for participant identifiers on UoB
CRCT web page.
Personal data recorded on all documents will be regarded as strictly confidential and will be handled
and stored in accordance with the Data Protection Act 1998.
Participants will always be identified using only their unique trial identification number, <add any
additional identifiers> on the Case Report Form and correspondence between the Trials Office and
the participating site. Where a trial is collecting consent forms for in house review, explicit consent
regarding the movement of the consent forms will be required from the participants, and the following
section should be included.“ Participants will give their explicit consent for the movement of their
consent form, giving permission for the Trials Office to be sent a copy. This will be used to perform inhouse monitoring of the consent process”.
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The Investigator must maintain documents not for submission to the Trials Office (e.g. Participant
Identification Logs) in strict confidence. In the case of specific issues and/or queries from the
regulatory authorities, it will be necessary to have access to the complete trial records, provided that
participant confidentiality is protected.
The Trials Office will maintain the confidentiality of all participant’s data and will not disclose
information by which participants may be identified to any third party <include exceptions to this e.g.
“other than those directly involved in the treatment of the participant and organisations for which the
participant has given explicit consent for data transfer (e.g. Cancer Registries, laboratory staff,
competent authority, sponsor)”>. Representatives of the <insert trial name> Trials Office and sponsor
may be required to have access to participant’s notes for quality assurance purposes but participants
should be reassured that their confidentiality will be respected at all times.
17.
Insurance and Indemnity
This is the standard text for a University of Birmingham only sponsored clinical trial
The University of Birmingham has in place Clinical Trials indemnity coverage for this trial which
provides cover to the University for harm which comes about through the University’s, or its staff’s,
negligence in relation to the design or management of the trial and may alternatively, and at the
University’s discretion provide cover for non-negligent harm to participants.
With respect to the conduct of the trial at Site and other clinical care of the patient, responsibility for
the care of the patients remains with the NHS organisation responsible for the Clinical Site and is
therefore indemnified through the NHS Litigation Authority.
The University of Birmingham is independent of any pharmaceutical company, and as such it is not
covered by the Association of the British Pharmaceutical Industry (ABPI) guidelines for participant
compensation.
18.
Publication Policy
NOTE: Regulatory requirements:
ICH GCP section 6.15 requires the protocol to detail the publication policy
Include plans for investigators and sponsor to communicate trial results to participants, healthcare
professionals, the public, and other relevant groups (e.g., via publication, reporting in results
databases, or other data sharing arrangements), including any publication restrictions
Include authorship eligibility guidelines and any intended use of professional writers. Detail plans, if
any, for granting public access to the full protocol, participant-level dataset, and statistical code
Results of this trial will be submitted for publication in a peer reviewed journal. The manuscript will be
prepared by the <insert name> and authorship will be determined by mutual agreement.
Any secondary publications and presentations prepared by Investigators must be reviewed by the
<insert name>. Manuscripts must be submitted to the <insert name> in a timely fashion and in
advance of being submitted for publication, to allow time for review and resolution of any outstanding
issues. Authors must acknowledge that the trial was performed with the support of <specify name of
Sponsor>.
<For international trials taking place in more than one country and coordinated at a national level the
following text may also be inserted, “Individual countries will be allowed to publish their efficacy
results, however the publication of efficacy results from the pooled analysis will take precedence over
efficacy result publications of individual countries, unless the TMG decides otherwise.”>
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19.
<Insert trial acronym>
Reference List
Abbreviations and Definitions:
Include a list of all abbreviations used in the main text
Term
Description
For CTIMPs
Adverse Event (AE) Any untoward medical occurrence in a participant or clinical trial subject
administered a medicinal product and which does not necessarily have a
causal relationship with this treatment.
Comment:
An AE can therefore be any unfavourable and unintended sign (including
abnormal laboratory findings), symptom or disease temporally associated with
the use of an investigational medicinal product, whether or not related to the
investigational medicinal product.
Adverse Reaction
(AR)
All untoward and unintended responses to an IMP related to any dose
administered.
Comment:
An AE judged by either the reporting Investigator or Sponsor as having causal
relationship to the IMP qualifies as an AR. The expression reasonable causal
relationship means to convey in general that there is evidence or argument to
suggest a causal relationship.
Serious Adverse
Event (SAE)
Any untoward medical occurrence or effect that:

Results in death <for phase III trials with long term follow-up where
survival is an endpoint consider adding text “(unrelated to original
disease)”>

Is life-threatening*

Requires hospitalisation or prolongation of existing inparticipants’
hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect
 Or is otherwise considered medically significant by the Investigator**
Comments:
The term severe is often used to describe the intensity (severity) of a specific
event. This is not the same as serious, which is based on participants/event
outcome or action criteria.
* Life threatening in the definition of an SAE refers to an event in which the
participant was at risk of death at the time of the event; it does not refer to an
event that hypothetically might have caused death if it were more severe.
** Medical judgment should be exercised in deciding whether an AE is serious
in other situations. Important AEs that are not immediately life threatening or do
not result in death or hospitalisation but may jeopardise the subject or may
require intervention to prevent one of the other outcomes listed in the definition
above, should be considered serious.
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Serious Adverse
Reaction (SAR)
An Adverse Reaction which also meets the definition of a Serious Adverse
Event
Unexpected
Adverse Reaction
(UAR)
An AR, the nature or severity of which is not consistent with the applicable
product information (e.g. Investigator Brochure for an unapproved IMP or
(compendium of) Summary of Product Characteristics (SPC) for a licensed
product).
When the outcome of an AR is not consistent with the applicable product
information the AR should be considered unexpected.
Source data
All information in original records and certified copies of original records of
clinical findings, observations, or other activities in a clinical trial necessary for
the reconstruction and evaluation of the trial
Suspected
A SAR that is unexpected i.e. the nature, or severity of the event is not
Unexpected Serious consistent with the applicable product information.
Adverse Reaction
A SUSAR should meet the definition of an AR, UAR and SAR.
(SUSAR)
Trials Office
The team of people, including the Chief Investigator, responsible for the overall
management and coordination of the trial.
For non-CTIMPs
Adverse Event (AE) Any untoward medical occurrence in a participant or clinical trial subject
participating in the trial which does not necessarily have a causal relationship
with the treatment received.
Comment:
An AE can therefore be any unfavourable and unintended sign (including
abnormal laboratory findings), symptom or disease temporally associated with
the use of a medicinal product, whether or not related to the medicinal product.
Related Event
Serious Adverse
Event (SAE)
An event which resulted from the administration of any of the research
procedures.
An untoward occurrence that:

Results in death

Is life-threatening*

Requires hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Consists of a congenital anomaly/ birth defect
 Or is otherwise considered medically significant by the Investigator**
Comments:
The term severe is often used to describe the intensity (severity) of a specific
event. This is not the same as serious, which is based on participants/event
outcome or action criteria.
* Life threatening in the definition of an SAE refers to an event in which the
participant was at risk of death at the time of the event; it does not refer to an
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<Insert trial acronym>
event that hypothetically might have caused death if it were more severe.
** Medical judgment should be exercised in deciding whether an AE is serious
in other situations. Important AEs that are not immediately life threatening or do
not result in death or hospitalisation but may jeopardise the subject or may
require intervention to prevent one of the other outcomes listed in the definition
above, should be considered serious
Unexpected and
Related Event
An event which meets the definition of both an Unexpected Event and a
Related Event
Unexpected Event
The type of event that is not listed in the protocol as an expected occurrence.
Source data
All information in original records and certified copies of original records of
clinical findings, observations, or other activities in a clinical trial necessary for
the reconstruction and evaluation of the trial
Trials Office
The team of people, including the Chief Investigator, responsible for the overall
management and coordination of the trial.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
34 of 36
PROTOCOL
<Insert trial acronym>
Appendices
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
35 of 36
PROTOCOL
<Insert trial acronym>
Consider adding Trials Office contact details to the back page of the protocol.
Trial name:
Protocol version number:
<trial name>
1.0
version date:
22-Mar-16
Page:
36 of 36