Date and version No: insert

Information on Clinical Trial Protocol Template – please read before starting

This protocol template has been designed primarily for Clinical Trials which are subject to the Medicines
for Human use (Clinical Trials) Regulations 2004, and Amendments. It has been specifically adapted for
non-commercially sponsored studies.

An algorithm is available to help you decide whether or not your trial is a Clinical Trial under the
regulations. This is usually, but not always, sufficiently helpful, especially regarding studies involving
Healthy Volunteers.
See https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/317952/
Algothrim.pdf If you remain unsure about your trial, CTRG or R&D staff will be
happy to advise you.

The template is available for use by all investigators who are carrying out clinical trials sponsored by the
University of Oxford or Oxford University Hospital (OUH) NHS Foundation Trust if they so wish. However,
there is no requirement to do so, provided that an alternative GCP-compliant protocol is used. Other
templates are available, for example, the SPIRIT (Standard Protocol Items: Recommendations for
Interventional Trials) protocol guidelines for minimum protocol content at http://www.spirit-
statement.org/spirit-statement/ or guidance available via the HRA protocol development tool at
https://www.hra.nhs.uk/planning-and-improving-research/research-planning/protocol/

All advisory text and quotations from GCP are highlighted in yellow. These should all be deleted before
finalising the document. All sample text is in ‘basic text’ style. This text of course will be altered or
deleted as required while you produce the draft. Where advisory text regarding <relevant possible
options> is inserted into sample text, delete as needed.

Where a section is not relevant, this should be stated clearly and the section header retained. There may
be instances where rearrangement of the subsections within section 9 is appropriate, in order to match
with the order of trial processes. Instructional text for deletion/rearrangement is highlighted in blue.

Repetition of information throughout the protocol is not necessary; it may be useful to cross-reference
other sections of the protocol to avoid repetition.

Should you require any assistance, contact either CTRG (University) or R&D (NHS) as early as possible in
the planning stage:

https://researchsupport.admin.ox.ac.uk/ctrg

https://www.ouh.nhs.uk/researchers/default.aspx

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Trial Title: insert full title including brief reference to the design, disease or condition being studied,
and primary objective

Internal Reference Number / Short title: This should be assigned by the Investigator/department (may
be deleted if not required)

Ethics Ref: Insert

IRAS Project ID: Insert

EudraCT Number: Insert

Date and Version No: Insert

Chief Investigator: Insert name and contact details, including institutional affiliations

Investigators: Insert names of key collaborators, including institutional affiliations

Sponsor: Oxford University Hospitals NHS Foundation Trust/University of Oxford

Delete as appropriate

(Address of Sponsor)

Funder: Insert details of organisation providing funding

Chief Investigator Signature: The approved protocol should be signed by author(s) and/or person(s)
authorised to sign the protocol

Statistician Signature:

Please declare any/no potential conflicts of interest

Confidentiality Statement

This document contains confidential information that must not be disclosed to anyone other than the
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee
and Regulatory Authorities unless authorised to do so.

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Optional page: Protocol signatures continued

For multi-site trials, the Principal Investigator at each site should sign below to document that the
protocol has been read and understood before the protocol is filed in the site ISF. If the same PI covers
more than 1 site both sites might appear here, but otherwise there is no requirement for signatures of
multiple (or all) PI signatures to appear here together.

Example (amend as appropriate):

Trial Title: insert full title

EudraCT Number: insert
Protocol Date and Version No: insert

Protocol signature page

The undersigned has read and understood the trial protocol detailed above and agrees to conduct the
trial in compliance with the protocol.

Principal Investigator Signature Site name or ID number Date

(Please print name)

Following any amendments to the protocol, this page must be updated with the new protocol version number and
date and re-signed by the site PI.

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TABLE OF CONTENTS
To update table of contents, hover cursor over the table and ‘right click’. Choose ‘update field’, then
‘update entire table’.

1. KEY TRIAL CONTACTS............................................................................................................................6

2. LAY SUMMARY.....................................................................................................................................7
3. SYNOPSIS..............................................................................................................................................7
4. ABBREVIATIONS....................................................................................................................................8
5. BACKGROUND AND RATIONALE...........................................................................................................9
6. OBJECTIVES AND OUTCOME MEASURES............................................................................................10
7. TRIAL DESIGN......................................................................................................................................11
8. PARTICIPANT IDENTIFICATION............................................................................................................11
8.1. Trial Participants.........................................................................................................................11
8.2. Inclusion Criteria.........................................................................................................................12
8.3. Exclusion Criteria........................................................................................................................12
9. TRIAL PROCEDURES............................................................................................................................13
9.1. Recruitment................................................................................................................................13
9.2. Screening and Eligibility Assessment..........................................................................................13
9.3. Informed Consent.......................................................................................................................13
9.4. Randomisation............................................................................................................................14
9.5. Blinding and code-breaking........................................................................................................14
9.6. Baseline Assessments.................................................................................................................15
9.7. Subsequent Visits........................................................................................................................15
9.8. Sample Handling.........................................................................................................................16
9.8.1 Sample handling for trial purposes............................................................................................16
9.8.2 Sample handling for tissue bank................................................................................................16
9.8.3 Sample handling for standard of care........................................................................................16
9.9. Early Discontinuation/Withdrawal of Participants......................................................................16
9.10. Definition of End of Trial.........................................................................................................18
10. TRIAL INTERVENTIONS....................................................................................................................18
10.1. Investigational Medicinal Product(s) (IMP) Description..........................................................18
10.1.1. Blinding of IMPs......................................................................................................................19
10.1.2. Storage of IMP........................................................................................................................19
10.1.3. Compliance with Trial Treatment...........................................................................................19
10.1.4. Accountability of the Trial Treatment.....................................................................................19
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10.1.5. Concomitant Medication........................................................................................................19

10.1.6. Post-trial Treatment...............................................................................................................19
10.2. Other Treatments (non-IMPS)................................................................................................19
10.3. Other Interventions................................................................................................................20
11. SAFETY REPORTING........................................................................................................................20
11.1. Adverse Event Definitions.......................................................................................................20
11.2. Assessment results outside of normal parameters as AEs and SAEs.......................................22
11.3. Assessment of Causality..........................................................................................................22
11.4. Procedures for Reporting Adverse Events..............................................................................22
11.5. Reporting Procedures for Serious Adverse Events..................................................................23
11.5.1. Events exempt from immediate reporting as SAEs.................................................................23
11.5.2. Procedure for immediate reporting of Serious Adverse Events..............................................23
11.6. Expectedness..........................................................................................................................24
11.7. SUSAR Reporting.....................................................................................................................25
11.8. Development Safety Update Reports.....................................................................................25
12. STATISTICS......................................................................................................................................25
12.1. Statistical Analysis Plan (SAP)..................................................................................................25
12.2. Description of Statistical Methods..........................................................................................26
12.3. Sample Size Determination.....................................................................................................26
12.4. Analysis Populations...............................................................................................................26
12.5. Decision Points.......................................................................................................................26
12.6. Stopping Rules........................................................................................................................26
12.7. The Level of Statistical Significance.........................................................................................26
12.8. Procedure for Accounting for Missing, Unused, and Spurious Data.......................................26
12.9. Procedures for Reporting any Deviation(s) from the Original Statistical Plan.........................27
12.10. Health Economics Analysis......................................................................................................27
13. DATA MANAGEMENT.....................................................................................................................27
13.1. Source Data............................................................................................................................27
13.2. Access to Data........................................................................................................................28
13.3. Data Recording and Record Keeping.......................................................................................28
14. QUALITY ASSURANCE PROCEDURES...............................................................................................28
14.1. Risk assessment......................................................................................................................28
14.2. Monitoring..............................................................................................................................29
14.3. Trial committees.....................................................................................................................29

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14.3.1 Safety Monitoring Committee.................................................................................................29

15. PROTOCOL DEVIATIONS.................................................................................................................30
16. SERIOUS BREACHES........................................................................................................................30
17. ETHICAL AND REGULATORY CONSIDERATIONS..............................................................................30
17.1. Declaration of Helsinki............................................................................................................30
17.2. Guidelines for Good Clinical Practice......................................................................................30
17.3. Approvals................................................................................................................................30
17.4. Other Ethical Considerations..................................................................................................31
17.5. Reporting................................................................................................................................31
17.6. Participant Confidentiality......................................................................................................31
17.7. Expenses and Benefits............................................................................................................31
18. FINANCE AND INSURANCE..............................................................................................................31
18.1. Funding...................................................................................................................................31
18.2. Insurance................................................................................................................................32
18.3. Contractual arrangements......................................................................................................32
19. PUBLICATION POLICY......................................................................................................................32
20. DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL
PROPERTY...................................................................................................................................................32
21. ARCHIVING.....................................................................................................................................33
22. REFERENCES...................................................................................................................................33
23. APPENDIX A: TRIAL FLOW CHART..................................................................................................34
24. APPENDIX B: SCHEDULE OF PROCEDURES.....................................................................................35
25. APPENDIX C: SAE REPORTING FLOW CHART..................................................................................36
26. APPENDIX D: AMENDMENT HISTORY............................................................................................37

1. KEY TRIAL CONTACTS

Insert full details of the key trial contacts including the following; please add/remove headings as
necessary.

Chief Investigator Full contact details including phone, email and fax numbers

Sponsor Oxford University Hospitals NHS Foundation Trust/University of Oxford

Delete as appropriate

Full contact details including phone and email.

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Funder(s) Names and contact details of all the organisations providing funding
and /or support in kind for this trial.

Clinical Trials Unit Full contact details including phone, email and fax numbers (If
applicable)

Statistician Full contact details including phone, email and fax numbers

Committees Head of committee

Full contact details including phone, email and fax numbers

2. LAY SUMMARY
It may be useful to include a copy of the lay summary from the IRAS form here. Suggested length, as per
IRAS form A6-1 is 300 words.

3. SYNOPSIS
It may be useful to include a brief synopsis of the trial for quick reference and/or to use as a standalone
document. Complete information and, if required, add additional rows.

Trial Title Please ensure this is in accordance with the title page and the IRAS
form
Internal ref. no. (or Please ensure this is in accordance with the title page and the IRAS
short title) form
Trial registration Trial identifier, registry name, registration number and date of
registration. If not yet registered, name of intended registry.
Sponsor Oxford University Hospitals NHS Foundation Trust/University of Oxford
Delete as appropriate
(Address of Sponsor)
Funder Names and contact details of all the organisations providing funding
and /or support in kind for this trial.
Clinical Phase
Trial Design
Trial Participants

Sample Size

Planned Trial Period Include both the total length of the project and the duration of an
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individual participant’s involvement (intervention phase and all follow

up – including any long term follow up via medical records and
registries etc.).
Planned Recruitment Indicate start and end dates for recruitment
period
Objectives Outcome Measures Timepoint(s)
Primary

Secondary

Intervention(s)

 IMP(s) Provide Formulation, Dose, Route of Administration for each named

Investigational Medicinal Product(s)
 nIMP(s)
Where applicable, provide details of non- Investigational Medicinal
Product(s) used in the trial.
 Other
intervention(s) If there is an additional investigational intervention such as
radiotherapy, surgery or device use provide the relevant details here in
addition to the IMP details above.
Comparator Provide Formulation, Dose, Route of Administration for each named
comparator

4. ABBREVIATIONS
Define all unusual or ‘technical’ terms related to the trial. Add or delete line items as appropriate to your
trial. Maintain alphabetical order for ease of reference.

AE Adverse event
AR Adverse reaction
CI Chief Investigator
CRA Clinical Research Associate (Monitor)
CRF Case Report Form
CRO Contract Research Organisation
CT Clinical Trials
CTA Clinical Trials Authorisation
CTRG Clinical Trials and Research Governance
DMC/DMSC Data Monitoring Committee / Data Monitoring and Safety Committee
DSUR Development Safety Update Report
GCP Good Clinical Practice
GP General Practitioner

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GTAC Gene Therapy Advisory Committee

HRA Health Research Authority
IB Investigators Brochure
ICF Informed Consent Form
ICH International Conference on Harmonisation
IMP Investigational Medicinal Product
IRB Independent Review Board
MHRA Medicines and Healthcare products Regulatory Agency
NHS National Health Service
RES Research Ethics Service
OXTREC Oxford Tropical Research Ethics Committee
PI Principal Investigator
PIL Participant/ Patient Information Leaflet
R&D NHS Trust R&D Department
REC Research Ethics Committee
RSI Reference Safety Information
SAE Serious Adverse Event
SAR Serious Adverse Reaction
SDV Source Data Verification
SMPC Summary of Medicinal Product Characteristics
SOP Standard Operating Procedure
SUSAR Suspected Unexpected Serious Adverse Reactions
TMF Trial Master File
Oxford University Hospitals NHS Foundation Trust / University of Oxford Trials Safety
TSG
Group

5. BACKGROUND AND RATIONALE

Include the following adding sub headings if needed:

Summarise briefly the main characteristics of the disease being studied and any possible opportunity for
better treatment. Include information on the current standard therapy with indication as to why a trial of
a new intervention is needed.

Description of the population to be studied.

Name, description and characteristics of the investigational medicinal product(s) (may include
mechanism of action). For CTIMPS, indicate if the IMP has or has not a marketing authorisation in the
UK /or in other EU member.

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Provide a brief summary of findings from non-clinical studies (if relevant) that potentially have clinical
significance and from other clinical trials relevant to this trial.

Summary of the known and potential risks and benefits, if any, to human participants with a cross
reference to the fuller detail provided in the safety reporting section if required.

Brief description of the rationale for undertaking the trial with justification for the choice of the trial
intervention/IMP(s), and the route of administration, dosage, dosage regimen, and treatment period. If
applicable, include explanation for the choice of comparators also.

References to literature and data that are relevant to the trial and that provide background for the trial.

For early phase studies, clearly state the number of patients who have already received the IMP(s).

6. OBJECTIVES AND OUTCOME MEASURES

There is usually only one primary objective, the rest are secondary objectives.

The wording of the objectives and outcomes provided below should be clear, unambiguous and as
specific as possible – the trial will be judged on how, and how well, the objectives were satisfied. The
definitions should include specific measurement variables (e.g., systolic blood pressure or Incidence and
severity of adverse events or Disability Rating Index etc.,) analysis metrics (e.g., change from baseline
measurement or time to event etc.,) and, where relevant, the time point for each outcome measure.
Additional more detailed descriptions and definitions of outcomes for all primary and secondary
outcomes may also be provided elsewhere in the protocol (e.g., in the statistics section) with a cross
reference to the summary information here.

Complete table below with all relevant information.

Please ensure these are in accordance with those stated in the synopsis above and on the IRAS form.

Objectives Outcome Measures Timepoint(s) of

evaluation of this
outcome measure
(if applicable)

Primary Objective Describe the outcome measures and Example: Blood

Example: To compare the effect of how/when they will be measured during sampling at day 0
treatment A versus treatment B on the trial. and day 28 post-
the levels of protein X in the blood treatment
Outcome measures should reflect the
objectives. It is important that only one
primary outcome measure is selected as
it will be used to decide the overall
results or ‘success’ of the trial. The
primary outcome measure should be
measurable, clinically relevant to
participants and widely accepted by the

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scientific and medical community.

Assessments of outcome measures

should be described in detail in section 9.

Example: Concentration of protein X in

blood samples from participants on each
treatment arm.

Secondary Objectives As above

Example: To assess the safety of
treatment A in <insert
condition/population>

Exploratory Objectives As Above

Please add if applicable, otherwise
delete this row

7. TRIAL DESIGN
Briefly summarise the overall trial design by type of trial (e.g., double-blind, placebo-controlled, parallel
design, open labelled, observational) and framework (e.g., superiority, equivalence, non-inferiority,
exploratory). Avoid repetition as full details will be given in later sections.

Briefly summarise the trial setting (e.g., hospitals, GP surgeries, care homes, academic centres etc.)
indicating number of trial sites, types of site (e.g., recruiting, providing intervention, continuing care
etc.,) and, where there are non-UK sites naming the countries where trial data will be collected.

Give the expected duration of participant involvement providing concise details of the number of visits,
including description of the sequence and duration of all trial periods e.g. screening, treatment, and
post-treatment follow-up. Include a chart of the flow of the participant through the study (here, or as an
appendix), if appropriate.

Briefly describe processes for collecting data, and why this method will be used (e.g. type of equipment,
questionnaire, interview schedule, observation schedule). Avoid repetition as full details will be given in
later sections.

Include a flowchart for the project as a whole (here, or as an appendix), if appropriate.

8. PARTICIPANT IDENTIFICATION

8.1. Trial Participants

Give an overall description of the trial participants.

Example:

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Participants with <medical condition> of <xyz> severity and <other symptoms/disease specific criteria>
and/or healthy volunteers aged <insert age>.

8.2. Inclusion Criteria

Example criteria only (amend as appropriate):

 Participant is willing and able to give informed consent for participation in the trial.
 Male or Female, aged 18 years or above.
 Diagnosed with required disease/severity/symptoms, any specific assessment criteria for these,
or, if healthy volunteer trial: be in good health.
 (alter as required) Stable dose of current regular medication (specify type if needed) for at least
4 weeks prior to trial entry. If healthy volunteer trial: have had no course of medication, whether
prescribed or over-the-counter, in the four weeks before first trial dose and no individual doses
in the final two weeks other than mild analgesia, vitamins and mineral supplements or, for
females, oral contraceptives.
 Female participants of child bearing potential and male participants whose partner is of child
bearing potential must be willing to ensure that they or their partner use effective contraception
during the trial and for 3 months thereafter*.
 Participant has clinically acceptable laboratory and ECG results (specify any other additional
assessments) within <insert duration> of enrolment.
 In the Investigator’s opinion, is able and willing to comply with all trial requirements.
 Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of
participation in the trial.
 Additional trial specific criteria as required.

* NOTE where the use of effective contraception is a protocol requirement a section on Contraception
and Pregnancy should be added to the safety reporting section with corresponding information in the
Participant Information Sheet.

8.3. Exclusion Criteria

Example criteria only (amend as appropriate):

The participant may not enter the trial if ANY of the following apply:

 Female participant who is pregnant, lactating or planning pregnancy during the course of the
trial.
 Significant renal or hepatic impairment.
 Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.

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 Participant with life expectancy of less than 6 months, or is inappropriate for placebo
medication.
 Any other significant disease or disorder which, in the opinion of the Investigator, may either put
the participants at risk because of participation in the trial, or may influence the result of the
trial, or the participant’s ability to participate in the trial.
 Participants who have participated in another research trial involving an investigational product
in the past 12 weeks.
 Additional trial specific criteria as required.

Note: ensure each criterion is stated as either an inclusion or an exclusion criterion, but not as both. For
example, it is not necessary to include ‘Male or female aged under 18’ among the example exclusion
criteria above as this is already covered by the inclusion criterion ‘Male or female, aged 18 or above’.

9. TRIAL PROCEDURES
Add a schedule of procedures either here or as an appendix.

9.1. Recruitment
Describe how recruitment centres will be selected.

Describe how potential participants will be identified, approached, screened, and recruited (registered
and /or randomised).

9.2. Screening and Eligibility Assessment

Specify the maximum duration allowed between screening and registration and/or randomisation (if
applicable).

State that protocol waivers are not permitted.

Describe the screening procedures in detail, such as demographics, medical history, concomitant
medication, physical examination, ECG, laboratory tests, biopsies and samples, scans.

Specify if rescreening will be permitted and any conditions or restrictions on this.

If any screening procedures (such as blood sampling) require prior informed consent, then this section
should be moved to between ‘Informed Consent’ and ‘Randomisation’. If participants are first consented
and then registered to the trial for screening purposes before being later randomised to a trial arm, then
place the screening and eligibility section between ‘Informed Consent’ and ‘Registration’. If applicable,
provide details of how the registration procedure relates to the randomisation procedure.

9.3. Informed Consent

You need to specify who will take Informed Consent, how, and when it will be taken. Informed Consent
must be obtained prior to any trial related procedures being undertaken. In the example below

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participant* can be substituted by parent/guardian or legally authorised representative, as appropriate,

make sure that the term is consistent throughout the document.

For further details on the ethical considerations of including persons who cannot consent for themselves
see the guidance on the HRA website.

Example:

The participant* must personally sign and date the latest approved version of the Informed Consent
form before any trial specific procedures are performed.

Written and verbal versions of the Participant Information and Informed Consent will be presented to
the participants detailing no less than: the exact nature of the trial; what it will involve for the
participant; the implications and constraints of the protocol; the known side effects and any risks
involved in taking part. It will be clearly stated that the participant is free to withdraw from the trial at
any time for any reason without prejudice to future care, without affecting their legal rights and with no
obligation to give the reason for withdrawal.

The participant will be allowed as much time as wished to consider the information, and the opportunity
to question the Investigator, their GP or other independent parties to decide whether they will
participate in the trial. Written Informed Consent will then be obtained by means of participant dated
signature and dated signature of the person who presented and obtained the Informed Consent. The
person who obtained the consent must be suitably qualified and experienced, and have been authorised
to do so by the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the
participant. The original signed form will be retained at the trial site.

9.4. Randomisation
If the trial is not randomised include a clear statement to that effect and change the section header to
Registration or Enrolment as appropriate. Provide details of the trial registration procedure here (e.g.,
web-based registration system), notification system and instructions for sites if required.

If applicable, describe how randomisation is going to be carried out for the trial. Specify the method for
generating the randomisation schedule / allocation sequence (e.g., block allocation, simple computer
generated random numbers, stratified randomisation) and include details of how this will be
implemented for the trial (sequentially numbered list, sealed envelopes, telephone or web-based
randomisation system). Where computerised systems are used, will there be need for a paper-based
back up randomisation procedure for use in emergencies?

Specify who will design the randomisation schedule (e.g., statistician, CRO) and who will hold the
allocation code (e.g., pharmacy, independent organisation). Provide details on the timing for
randomisation in terms of the participant’s study schedule. Will randomisation be done at the same visit
as the baseline visit for example, or must participants return for a randomisation visit? Will there be a
run in period? State who will receive notification of a new participant/new randomisation, (e.g., trial
pharmacist at site, site PI, central trial manager) and provide details as to how this will be communicated
to them.

9.5. Blinding and code-breaking

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If there is no blinding in the trial, and/or no code breaking procedure, please state that clearly and retain
the section header.

In a blinded trial, specify who it is that is blinded to the allocation; e.g., the participant and/or the
treating clinician; the central research team; the (independent) outcome assessors. Describe the steps
taken to conceal the treatment/intervention allocation from the blinded parties. For example, it may be
necessary that the full details of the method of randomisation not appear in the protocol document, that
such information be held separately and confidentially.

If the clinical condition of a participant necessitates breaking the allocation code, describe the
procedures for this (who will do this, and how). For example, will individual envelopes per participant per
period be supplied so that the code may be broken for a single participant without unblinding the whole
trial? Or will the pharmacist access the randomisation schedule if required by the Investigator and supply
the needed information? Cross reference to the ‘Safety Reporting’ section on SUSAR reporting and
address steps to be taken to conceal the wider randomisation schedule after code-breaking for specific
participants.

Note “it is the opinion of the EMA GCP Inspectors Working Group (GCP IWG) and the Clinical
Trial Facilitation Group (CTFG) that the responsibility to break the treatment code in emergency
situations resides solely with the investigator. Consequently the sponsor <or sponsor delegate> can’t
require or insist on being involved in the decision to unblind, stall or delay in any way the unblinding of
trial subject treatment in emergency situations.”

Please see number 6 on the following link for further information:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/
q_and_a_detail_000016.jsp&mid=WC0b01ac05800296c5

If out of hours code-breaking will not be required due to the risk level of the IMP, state this and justify
the decision.

9.6. Baseline Assessments

Specify and describe all baseline assessments. They must reflect the objectives and outcome measures.

If there will only be one visit, this section should be renamed ‘Trial Visit’ and full details of this visit be
included. The next section ‘Subsequent Visits’ can be marked not applicable and the section header
retained.

9.7. Subsequent Visits

Specify when participants will attend for visits/follow-up, and what assessments will be conducted.
Specify if they are clinic visits, telephone assessments, or home visits by the trial staff. Add visit numbers
and window periods if applicable. Clearly number these visits.

For each visit, list appropriate assessment, and consider inclusion of the following, where appropriate.
Refer to the trial schedule of procedures (appendix):

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 eligibility check
 assessment of outcome measures
 assessments of safety including general (e.g. physical examination), specific safety assessments
(e.g. specific laboratory tests according to the applicable product information and/or population)
and adverse event collection
 dispensing of trial drug (and of standard of care drugs, if applicable)
 assessment of compliance with trial intervention /trial drugs
 recording of concomitant medications

9.8. Sample Handling

If not detailed previously, describe the samples that will be taken from each participant (e.g. blood,
urine, tissue, etc.), the volume of sample, and the frequency of sampling. Clarify in this section whether
the samples referred to in the protocol are taken as part of a standard of care pathway with the results
accessed by the research team or are research samples for analysis under this protocol and/or ancillary
studies or are taken for future research. Consider using separate sections such as:

9.8.1 Sample handling for trial purposes (delete subsection header if not required)

9.8.2 Sample handling for tissue bank (delete subsection header if not required)

9.8.3 Sample handling for standard of care (delete subsection header if not required)

In each applicable subsection provide brief details as to how the sample will be processed and stored
once taken; who for example will have access to the samples (i.e. Trial team only for this project, or will it
be stored long-term for use in future ethically approved studies), and duration of storage (destroyed
following local (NHS) analysis; stored for 12 months following end of the study etc.). If the samples will
be transferred to another organisation, state this clearly providing the name of the receiving institution
and the country in which that organisation is situated. Provide an overview of the laboratory analyses
that will be performed. Ensure that the appropriate information is included in the participant
information sheet with corresponding clause(s) on the consent sheet(s). Note, if samples are being
biobanked a separate information sheet and consent form for the biobank is required.

If no samples will be taken, please state that clearly and retain the main section header.

9.9. Early Discontinuation/Withdrawal of Participants

Example:

During the course of the trial a participant may choose to withdraw early from the trial treatment at any
time. This may happen for a number of reasons, including but not limited to:

 The occurrence of what the participant perceives as an intolerable AE.

 Inability to comply with trial procedures
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 Participant decision

Participants may choose to stop treatment and/or study assessments but may remain on study follow -up.

Participants may also withdraw their consent, meaning that they wish to withdraw from the study
completely. In the case of withdrawal from both treatment and active follow up consider the following
options for a tiered withdrawal from the study. Not all the options may be relevant to your study. The
options elected for use in the study must be covered in the participant information sheet.

According to the design of the trial, participants may have the following three options for withdrawal;
1) Participants may withdraw from active follow-up and further communication but allow the trial
team to continue to access their medical records and any relevant hospital data that is recorded
as part of routine standard of care; i.e., CT-Scans, blood results and disease progression data etc.

2) Participants can withdraw from the study but permit data and samples obtained up until the
point of withdrawal to be retained for use in the study analysis. No further data or samples
would be collected after withdrawal.

3) Participants can withdraw completely from the study and withdraw the data and samples
collected up until the point of withdrawal. The data and samples already collected would not be
used in the final study analysis. (Any limits to this type of withdrawal where, for example analysis
of their data or samples has already been integrated into interim results or dose escalation
decisions etc. should be explained in the participant information sheet).

In addition, the Investigator may discontinue a participant from the trial treatment at any time if the
Investigator considers it necessary for any reason including, but not limited to:

Example only (amend as appropriate):

 Pregnancy
 Ineligibility (either arising during the trial or retrospectively having been overlooked at screening)
 Significant protocol deviation
 Significant non-compliance with treatment regimen or trial requirements
 An adverse event which requires discontinuation of the trial medication or results in inability to
continue to comply with trial procedures
 Disease progression which requires discontinuation of the trial medication or results in inability
to continue to comply with trial procedures

Specify what follow up of participants that have withdrawn from treatment will consist of.

Provide justification for any procedures and observations that will be required following a complete
withdrawal (e.g., clinic visits during a safety wash out period) or that will continue to be required of all
participants until the end of the trial; for example, would investigators be required to follow up SAEs
until resolution or end of trial? Ensure that the appropriate information on these arrangements is
included in the participant information sheet.

Wherever possible the data of randomised participants (or registered participants in the case of non-
randomised trials) should be analysed. State whether withdrawal from the trial treatment will result in

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exclusion of the data for that participant from certain trial analyses. (Note that intention-to-treat
analyses and analysis of all participants receiving the trial medication (e.g., most safety analyses) may
require admission of data to analysis for participants that are withdrawn from treatment)

State whether or not withdrawn participants will be replaced and describe the conditions and limitations
for this.

The type of withdrawal and reason for withdrawal will be recorded in the CRF.

If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up visits
or telephone calls until the adverse event has resolved or stabilised.

If a participant is withdrawn from treatment due to pregnancy the pregnancy will be followed-up to
outcome. See the Safety Reporting section below.

9.10. Definition of End of Trial

The definition of end of trial must be provided. In most cases the end of trial will be the date of the last
visit of the last participant. Where long term follow up of participants is planned, the end of trial must
include that follow-up period.

Example:

The end of trial is the point at which all the data has been entered and queries resolved.

10. TRIAL INTERVENTIONS

The following sections may be adapted based on your trial classification. Please refer to the MHRA risk-
adapted approach document for guidance
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/343677/Risk-
adapted_approaches_to_the_management_of_clinical_trials_of_investigational_medicinal_products.pdf

An investigational medicinal product (IMP) is a pharmaceutical form of an active substance or placebo

being tested or used as a reference in a clinical trial, including products already with a marketing
authorisation, but used or assembled (formulated or packaged) in a way different from the authorised
form, or when used at an unapproved dose or for an unauthorised indication, or when used to gain
further information about the authorised form. (EU clinical trial directive 2001/20/EC).

10.1. Investigational Medicinal Product(s) (IMP) Description

Name and describe the trial treatment(s) including comparator or placebo if used.

Confirm the marketing authorisation status of the IMP (and comparator(s) if applicable).

Briefly describe the comparator and indicate whether it is standard of care and describe how it will be
administered.

Briefly describe the dosage, treatment duration and administration of trial medications.

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Briefly describe the dosage form, packaging, and labelling of the trial medication(s) including Qualified
Person (QP) release if applicable.

For labelling requirements, refer to Volume 4. Good Manufacturing Practices, Annex 13. Manufacture of
investigational medicinal products, July 2010.

Where a medication is to be used in its normal indication and standard therapeutic dose, labelling
exemptions may apply. Contact Sponsor for advice.

10.1.1. Blinding of IMPs

If not detailed elsewhere then describe how the IMP(s) and placebo will be packaged to achieve and
maintain effective blinding. (Cross reference to section 9.5 Blinding and code-breaking above, if
appropriate).

If there is no blinding of IMPs in the trial, please state that clearly and retain the section header.

10.1.2. Storage of IMP

Describe the storage arrangements and required storage conditions of the trial treatment. Will it be
stored in the pharmacy? If not using the pharmacy, describe the conditions for storage and any
procedures for checking that appropriate temperatures are maintained etc.

10.1.3. Compliance with Trial Treatment

You need to describe how compliance is assessed, and how it will be defined for the trial (e.g. 80% doses
taken). Will you ask the participants to keep a diary, bring all unused or part-used medication/vials and
packaging from used medication at each visit? You may want to define significant non-compliance and
what procedures will be taken if there is significant non-compliance.

10.1.4. Accountability of the Trial Treatment

Describe how medication including placebo will be accounted for (Is full accountability required or will a
risk adapted approach be employed?)

10.1.5. Concomitant Medication

List any contraindicated medications and check that they correspond with the exclusion and withdrawal
criteria.

10.1.6. Post-trial Treatment

State if there will or will not be provision of the IMP beyond the trial period.

10.2. Other Treatments (non-IMPS)

A non-investigational medicinal product is a product which is not the object of investigation (i.e., is not
the tested product, the placebo or the active comparator) and is supplied to participants in a trial and
used in accordance with the protocol. For classification of NIMPS see

https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-10/imp_03-2011.pdf

Name and describe each Non-IMP (NIMP) supplied to trial participants.

Briefly describe the dosage, treatment duration and administration of the NIMP trial medications.

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As for IMPs, confirm the risk adapted arrangements for storage, tracking of compliance and
accountability or contraindicated medications

If there are no non-IMPs in the trial design, please state that clearly and retain the section header.

10.3. Other Interventions

If there is an additional investigational intervention such as radiotherapy, surgery or device use provide
the relevant details here in addition to the IMP details above.

If there are no additional interventions in the trial design, please state that clearly and retain the section
header.

11. SAFETY REPORTING

Please refer to the risk-adapted approach document as some of the following sections may be adapted
based on your trial classification
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/343677/Risk-
adapted_approaches_to_the_management_of_clinical_trials_of_investigational_medicinal_products.pdf

Define the safety reporting window for the trial with a clearly stated starting point (e.g., from time of
consent, from first administration of intervention etc.) and clearly stated end point (e.g.30 days after last
administration of the IMP, point that the participant completes the trial, end of trial). Note the end point
will depend on the nature of the IMP. Advanced Therapy Medicinal Products, for example, have specific
requirements over and above those for most trials and the MHRA and EMA websites should be consulted
for their evolving guidance on ATMPs.

Confirm the limit of investigator follow up of AEs (e.g., follow up until event resolution or stabilisation, to
participant completion of the trial, to trial end etc.). Confirm if the follow up requirement is the same for
all AEs or differs for some events (e.g., follow up until event resolution required for related events only).

11.1. Adverse Event Definitions

Adverse Event (AE) Any untoward medical occurrence in a participant to whom a medicinal
product has been administered, including occurrences which are not
necessarily caused by or related to that product.

Adverse Reaction (AR) An untoward and unintended response in a participant to an

investigational medicinal product which is related to any dose
administered to that participant.
The phrase "response to an investigational medicinal product" means
that a causal relationship between a trial medication and an AE is at

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least a reasonable possibility, i.e. the relationship cannot be ruled out.

All cases judged by either the reporting medically qualified professional
or the Sponsor as having a reasonable suspected causal relationship to
the trial medication qualify as adverse reactions.

Serious Adverse Event A serious adverse event is any untoward medical occurrence that:
(SAE)
 results in death
 is life-threatening
 requires inpatient hospitalisation or prolongation of existing
hospitalisation
 results in persistent or significant disability/incapacity
 consists of a congenital anomaly or birth defect*.
Other ‘important medical events’ may also be considered a serious
adverse event when, based upon appropriate medical judgement, the
event may jeopardise the participant and may require medical or
surgical intervention to prevent one of the outcomes listed above.
NOTE: The term "life-threatening" in the definition of "serious" 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 which hypothetically might
have caused death if it were more severe.
*NOTE: Pregnancy is not, in itself an SAE. In the event that a
participant or his/her partner becomes pregnant whilst taking part in a
clinical trial or during a stage where the foetus could have been
exposed to the medicinal product (in the case of the active substance
or one of its metabolites having a long half-life) the pregnancy should
be followed up by the investigator until delivery for congenital
abnormality or birth defect, at which point it would fall within the
definition of “serious”.

Serious Adverse Reaction An adverse event that is both serious and, in the opinion of the
(SAR) reporting Investigator, believed with reasonable probability to be due
to one of the trial treatments, based on the information provided.

Suspected Unexpected A serious adverse reaction, the nature and severity of which is not
Serious Adverse Reaction consistent with the Reference Safety Information for
(SUSAR) the medicinal product in question set out:
 in the case of a product with a marketing authorisation, in the
approved summary of product characteristics (SmPC) for that
product
 in the case of any other investigational medicinal product, in the
approved investigator’s brochure (IB) relating to the trial in
question.

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NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”,
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific
event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition
supplied above.

* NOTE if use of effective contraception is a protocol requirement a section on Contraception and

Pregnancy should be added to the Safety Reporting Section of the protocol. See the MHRA website for
Clinical Trial Facilitation Group’s guidance document on what constitutes effective contraception and
pregnancy testing recommendations.

https://www.gov.uk/government/publications/common-issues-identified-during-clinical-trial-
applications/useful-resources

11.2. Assessment results outside of normal parameters as AEs and SAEs

Confirm which trial assessments are relevant (e.g., only laboratory results or also others such as ECGs,
chest x-rays or other scans). Specify any predefined criteria for ‘abnormality’ that signify that an out of
range result is to be reported as serious (e.g., Grade ≥3 elevation of ALT or AST lasting 8 days or more).
Consider providing tables of adverse event grading criteria for the relevant trial assessments (e.g., a
Laboratory AE Grading Chart indicating the limits at which ‘out of range’ laboratory results are Grade 1,
Grade 2, Grade 3, and the point they are reportable as SAEs etc.). Where relevant, confirm if the clinical
significance of an abnormal result will be determined on a case by case basis by the medically qualified
investigator.

11.3. Assessment of Causality

The relationship of each adverse event to the trial medication must be determined by a medically
qualified individual according to the following definitions:

Example:

Related: The adverse event follows a reasonable temporal sequence from trial medication
administration. It cannot reasonably be attributed to any other cause.

Not Related: The adverse event is probably produced by the participant’s clinical state or by other
modes of therapy administered to the participant.

Note: where the SAE form used for the trial employs additional options for expressing the probability of
the causal relationship (e.g., definitely related, probably related, possibly related, probably not related
and definitely not related) the binary definitions above may need to be supplemented and/or modified.
If the SAE form includes the option ‘possibly related’ there should be a clear statement of whether
events reported as ‘possibly related’ will be managed as not related or as related i.e., may be assessed as
a SUSAR.

11.4. Procedures for Reporting Adverse Events

Note it may be possible to adopt a risk adapted approach here; consider whether all non-serious AE’s
need to be reported on the trial CRF, taking into account the safety profile of the IMP i.e. if the safety
profile of the IMP is very well known then you may not need to report all or any non-serious AEs. If you
decide not to report all non-serious AEs then state this and provide justification for not doing so.
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If all (or, all related) non-serious AEs are to be reported on the trial CRF, consider adapting text below as
appropriate:

<All/all related> AEs occurring during the safety window for the trial as defined above that are observed
by the Investigator or reported by the participant, will be reported on the trial CRF, <whether or not
attributed to trial medication>.

The following information will be reported on the CRF: description, date of onset and end date, severity,
assessment of relatedness to trial medication, other suspect drug or device and action taken. Follow-up
information should be provided as necessary.

The severity of events will be assessed on the following scale: 1 = mild, 2 = moderate, 3 = severe.

Non-serious AEs considered related to the trial medication as judged by a medically qualified investigator
or the Sponsor will be followed up <either until resolution, or the event is considered stable>.

It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity
to require the participant’s removal from treatment. A participant may also voluntarily withdraw from
treatment due to what he or she perceives as an intolerable AE. If either of these occurs, the participant
must <Insert statement of requirements/conditions here (e.g., undergo an end of trial assessment and
be given appropriate care under medical supervision until symptoms cease, or the condition becomes
stable)>. The statement should be consistent with information specified in section 9.9: Early
Discontinuation/Withdrawal of Participants above, and outlined in the Participant Information Sheet.

11.5. Reporting Procedures for Serious Adverse Events

Note it may be possible to adopt a risk adapted approach here taking into account the nature of the
disease under study and the safety profile of the IMP; consider whether all adverse events meeting the
criteria for seriousness above will be subject to immediate reporting. Note certain foreseeable and
predefined SAEs do not need to be reported immediately, these should be clearly specified and the
decision(s) justified.

All SAEs <other than those defined in this protocol as not requiring reporting> must be reported on the
SAE Reporting Form to the Sponsor or delegate immediately or within 24 hours of Site Study Team
becoming aware of the event being defined as serious.

11.5.1. Events exempt from immediate reporting as SAEs

If relevant: specify if types of hospitalisation are not classed as SAEs: e.g., Hospitalisation for a pre-
existing condition, including elective procedures planned prior to study entry, which has not worsened,
does not constitute a serious adverse event; e.g., Hospitalisation for procedures and treatments
specified within the protocol, and standard supportive care for the disease under study are not SAEs, and
do not require SAE reporting.

If relevant: specify if deaths due to the disease under study are exempt from reporting as SAEs (with
instruction as to where in the trial CRF the information about this is captured).

If relevant: specify if disease progression/ relapse/ recurrence are exempt from reporting as SAEs (with
instruction as to where in the trial CRF the information about this is captured).

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If this section is not relevant to the trial, please state that clearly and retain the section header.

11.5.2. Procedure for immediate reporting of Serious Adverse Events

If the trial is multicentre, or if the single research site and the sponsor delegate office are separate, you
need to consider the coordination of SAE reporting for the whole trial and outline the plan for that here.

Example (amend as needed):

 Site study team will complete an SAE report form for all reportable SAEs.
 Where the SAE requires immediate reporting, the SAE report form will be scanned and emailed
to <insert the relevant name and contact details for the sponsor delegate i.e., for the
coordinating centre/CRO/CTU/CI team> immediately i.e., within 24 hours of site study team
becoming aware of the event.
 Site study team will provide additional, missing or follow up information in a timely fashion.

The processes for receipt, acknowledgement, and review of reported SAEs at the sponsor delegate’s
office should also be outlined.

Specify who will review the SAE once reported to the sponsor delegate and the timelines for this. (e.g.,
pharmacovigilance officer, a local safety committee, nominated clinician, the trial DMC/DMSC). Review
of SAEs must be timely, taking into account the reporting timeline for a potential SUSAR. The SAE review
will include an assessment of expectedness using the Reference Safety Information (RSI) current at the
time of the event.

It must be clear if the assessment of expectedness is completed at the reporting site by the local
investigator or is made centrally by the sponsor delegate (e.g., PV officer, SAE Panel, Local safety
Committee etc.). The design of the trial’s SAE form and any completion guidelines provided to site(s)
should reflect this.

If needed please contact your Sponsor (CTRG/R&D reviewer) for further assistance.

If the trial will be using the University of Oxford /OUH Trial Safety Group, for independent review of
SAEs (if this use is required by or agreed with the trial Sponsor) use the following wording (otherwise
delete):

All SAEs <other than those defined in the protocol as not requiring reporting> must be reported on the
SAE reporting form to <CTRG/R&D> within 24 hours of the Central Study Team becoming aware of the
event. SAEs that are reported late must be accompanied by an explanation for this. <CTRG/R&D> will
perform an initial check of the report and request any additional information from the Central Study
Team. <CTRG/R&D> will ensure the SAE is reviewed by the TSG Medical Monitor on a weekly basis,
(note events reported as related are subject to expedited review procedures). The SAE will also be
reviewed at the next quarterly Trial Safety Group meeting. All SAE information must be recorded on an
SAE form and scanned and emailed, to the Central study team at <insert appropriate email address>. The
central study team are responsible for ensuring that the SAE is reported to <R&D/CTRG> within 24 hours
of awareness of an SAE report. Additional and further requested information (follow-up or corrections to
the original case) will be detailed on a new SAE Report Form and emailed to <CTRG/R&D>.

Delete CTRG or R&D from instances of <CTRG/R&D> in the paragraph above to retain the Sponsor of the
trial. Where Oxford University Hospital NHS Foundation Trust is the Sponsor retain ‘R&D’; for University
of Oxford sponsored trials retain ‘CTRG’.

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Note: the template SAE form for use by trials using the University of Oxford /OUH Trial Safety Group,
allows for local completion of the assessment of causality AND of expectedness prior to review by the TSG
Medical Monitor.

11.6. Expectedness
Expectedness will be determined according to the approved RSI e.g. in the Investigators’
Brochure/Summary of Product Characteristics. (delete as appropriate, please note some trials may have
both)

11.7. SUSAR Reporting

All SUSARs will be reported by the sponsor delegate to the relevant Competent Authority and to the REC
and other parties as applicable. For fatal and life-threatening SUSARS, this will be done no later than 7
calendar days after the Sponsor or delegate is first aware of the reaction. Any additional relevant
information will be reported within 8 calendar days of the initial report. All other SUSARs will be reported
within 15 calendar days.

Treatment codes will be un-blinded for specific participants.

Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same
Sponsor, whether or not the event occurred in the current trial.

11.8. Development Safety Update Reports

Where appropriate, the IMP manufacturer may be encouraged to submit Development Safety Update
Reports (DSURs). In such cases, this must be clearly covered by the relevant agreement.

Either

<Name of Company> will submit DSURs once a year throughout the clinical trial, or on request to the
Competent Authority (MHRA in the UK), Ethics Committee, HRA (where required), Host NHS Trust and
Sponsor.

Or

The CI will submit (in addition to the expedited reporting above) DSURs once a year throughout the
clinical trial, or on request, to the Competent Authority (MHRA in the UK), Ethics Committee, HRA (where
required), Host NHS Trust and Sponsor.

12. STATISTICS
This section should be written by the study statistician.

State whether a Statistical Analysis Plan (SAP) is to be produced separately, and if it is then condense the
most relevant information from the SAP sub sections at 12.1 below; otherwise provide full details below
of the planned analyses. The sub-headings given below are suggestions. Sub-headings that are not
applicable may be deleted entirely.

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12.1. Statistical Analysis Plan (SAP)

Example: Either

The statistical aspects of the study are summarised here with details fully described in a statistical
analysis plan that will be available from the time <that the first participant is recruited>. The SAP will be
finalised before <any analysis> takes place.

Or

The plan for the statistical analysis of the trial are outlined below. There is not a separate SAP document
in use for the trial.

(delete as appropriate)

12.2. Description of Statistical Methods

Describe the statistical methods to be employed for analysing primary and secondary outcomes. If not
provided elsewhere detailed descriptions and definitions of outcomes for all primary and secondary
outcomes should be provided here including specific measurement variables, analysis metrics and,
where relevant, the time point for each outcome measure. If already described elsewhere, provide cross
reference to the relevant protocol section.

12.3. Sample Size Determination

State the estimated number of participants required to demonstrate the study objectives. (Note it is the
primary outcome that determines the sample size needed).

Justify choice of sample size, i.e., how was it determined including reflections on (or calculations of) the
power of the trial, any statistical assumptions or clinical justifications (where for e.g., the sample size was
not arrived at statistically, due to rarity of the disease etc.).

Take into account any potential withdrawals.

12.4. Analysis Populations

Describe the selection of participants to be included in the analyses e.g. all participants as randomised /
registered / enrolled (intention to treat); all dosed participants (adverse event analysis); all eligible
participants (per protocol analysis); all ‘evaluable’ participants (define ‘evaluability’) etc. Will you include
data from participants who have been unblinded?

12.5. Decision Points

Provide details of any interim analysis, including schedule and description of why the interim analyses
are to be performed at those time points (as the basis for specified dose escalating decisions or stopping
decisions for example). Confirm who will have access to the results and who will make any decisions
based on the results.

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12.6. Stopping Rules

Describe any formal stopping rules for futility, efficacy or lack of power. Confirm who would make the
final decision to terminate the trial.

12.7. The Level of Statistical Significance

State the level of significance to be used.

12.8. Procedure for Accounting for Missing, Unused, and Spurious Data.
Briefly describe the procedure(s) to be used for handling of spurious or missing or unused data (e.g. use
of multiple imputation, random effects models or complete case analyses). Describe any possible biases
these techniques may introduce. Cross refer to the Data Management Plan (if applicable).

12.9. Procedures for Reporting any Deviation(s) from the Original Statistical Plan
Detail 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).

12.10. Health Economics Analysis

If a health economics analysis is to be undertaken, include the rationale for inclusion of the economic
investigation and means of assessment here. (To be written by the health economist).

13. DATA MANAGEMENT

A detailed Data Management Plan should be developed in tandem with the protocol. A template DMP is
available from the MRC @ https://mrc.ukri.org/documents/doc/data-management-plan-template/

The data management aspects of the study are summarised here with details fully described in the Data
Management Plan.

Or,

The plan for the data management of the study are outlined below. There is not a separate Data
Management document in use for the trial. A justification for not developing a separate detailed DMP
must be provided here. This will be considered by your sponsor during the sponsor review process.

(delete as appropriate)

13.1. Source Data

Define what will comprise source documents

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Example:

Source documents are where data are first recorded, and from which participants’ CRF data are
obtained. These include, but are not limited to, hospital records (from which medical history and
previous and concurrent medication may be summarised into the CRF), clinical and office charts,
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence.

CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no
other written or electronic record of data). All documents will be stored safely in confidential conditions.
On all trial-specific documents, other than the signed consent, the participant will be referred to by the
trial participant number/code, not by name.

13.2. Access to Data

Direct access will be granted to authorised representatives from the Sponsor, host institution and the
regulatory authorities to permit trial-related monitoring, audits and inspections.

13.3. Data Recording and Record Keeping

Describe method(s) of data collection, entry and management, including details of data management
tools, for example CRF software, etc.

Example:

All trial data will be entered on <to paper CRFs and/or a <<quote software and validation procedure>>.
Note that ICH GCP (Section 5.5) requires that electronic data entry systems are validated and that
Standard Operating Procedures are maintained.

The participants will be identified by a unique trial specific number and/or code in any database. The
name and any other identifying detail will NOT be included in any trial data electronic file.

Describe where, and for how long, data will be retained

If no identifiable, personal data will be retained centrally (i.e. by the sponsoring organisation), but rather
this will be held at individual sites only, please state this explicitly.

If your study will collect samples and intends to make further use of these beyond the study, please be
aware that the consent form will need to be retained for the life of the sample to meet HTA traceability
requirements.

If participants are given the option to be approached for future research, please be aware that under
GDPR, it is necessary to retain the consent form as the basis for retention of details and future approach.
Those contact details should be held securely, separately from the research data, and kept updated.

Ensure compliance with the relevant Sponsor organisation’s data policy. For University of Oxford
sponsored trials please refer in particular to the University of Oxford’s

Data Protection Checklist https://researchsupport.admin.ox.ac.uk/policy/data/checklist

Practical Considerations https://researchsupport.admin.ox.ac.uk/policy/data/practical

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Cross refer to the Data Management Plan (if applicable).

14. QUALITY ASSURANCE PROCEDURES

14.1. Risk assessment

Provide details of how data monitoring and other quality control measures will be performed in the light
of risk adaptive approach based on the formal risk assessment.

Example:

The trial will be conducted in accordance with the current approved protocol, GCP, relevant regulations
and standard operating procedures. A risk assessment and monitoring plan will be prepared before the
study opens and will be reviewed as necessary over the course of the trial to reflect significant changes
to the protocol or outcomes of monitoring activities.

14.2. Monitoring
Describe arrangements for GCP monitoring

Example:

Regular monitoring will be performed according to the trial specific Monitoring Plan. Data will be
evaluated for compliance with the protocol and accuracy in relation to source documents as these are
defined in the trial specific Monitoring Plan. Following written standard operating procedures, the
monitors will verify that the clinical trial is conducted and data are generated, documented and reported
in compliance with the protocol, GCP and the applicable regulatory requirements. Cross refer to the trial
Risk Assessment and Monitoring Plan documents

14.3. Trial committees

Provide a separate subsection below for each committee in place for the trial (e.g., Trial Management
Group, Trial Steering Committee (or equivalent), Independent Data (Safety) Monitoring Committee, (or
the University of Oxford /OUH Trial Safety Group if being used), and describe the role(s), frequency of
meetings and composition of the committee here. Where applicable, cross refer to the charter document
governing the relevant committee for further details.

14.3.1 Safety Monitoring Committee

If a trial specific safety monitoring committee / DSMC is to be used, describe arrangements here.

Or

If you are using the Oxford University Hospitals NHS Foundation Trust / University of Oxford Trials Safety
Group to centrally review SAEs then the following text should be adapted as appropriate.

The Oxford University Hospitals NHS Foundation Trust / University of Oxford Trials Safety Group (TSG)
will conduct a review of all SAEs for the trial reported during the quarter and cumulatively. The aims of
this committee include:

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 To pick up any trends, such as increases in un/expected events, and take appropriate action
 To seek additional advice or information from investigators where required
 To evaluate the risk of the trial continuing and take appropriate action where necessary

15. PROTOCOL DEVIATIONS

A trial related deviation is a departure from the ethically approved trial protocol or other trial document
or process (e.g. consent process or IMP administration) or from Good Clinical Practice (GCP) or any
applicable regulatory requirements. Any deviations from the protocol will be documented in a
protocol deviation form and filed in the trial master file.

A standard operating procedure should be in place describing the procedure for identifying non-
compliances, escalation to the central team and assessment of whether a non-compliance /deviation
may be a potential Serious Breach

16. SERIOUS BREACHES

The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the notification of
"serious breaches" to the MHRA within 7 days of the Sponsor becoming aware of the breach.

A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a
significant degree –

(a) the safety or physical or mental integrity of the subjects of the trial; or

(b) the scientific value of the trial”.

In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In
collaboration with the CI the serious breach will be reviewed by the Sponsor and, if appropriate, the
Sponsor will report it to the REC committee, Regulatory authority and the relevant NHS host organisation
within seven calendar days.

17. ETHICAL AND REGULATORY CONSIDERATIONS

17.1. Declaration of Helsinki

The Investigator will ensure that this trial is conducted in accordance with the principles of the
Declaration of Helsinki. NB. The 2008 Declaration of Helsinki provides detail on what must be included in
a protocol: funding, sponsorship, affiliations and potential conflicts of interest, incentives to participate,
compensation for harm and post-trial access to drugs and care.

17.2. Guidelines for Good Clinical Practice

The Investigator will ensure that this trial is conducted in accordance with relevant regulations and with
Good Clinical Practice.

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17.3. Approvals
Consider the following example text:

Following Sponsor approval the protocol, informed consent form, participant information sheet <and any
proposed advertising material> will be submitted to an appropriate Research Ethics Committee (REC),
HRA (where required), regulatory authorities (MHRA in the UK), and host institution(s) for written
approval.

The Investigator will submit and, where necessary, obtain approval from the above parties for all
substantial amendments to the original approved documents.

17.4. Other Ethical Considerations

Include any other general or trial-specific ethical considerations, e.g. use of placebo, involvement of
vulnerable participants

17.5. Reporting
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report to
the REC, HRA (where required), host organisation, funder (where required) and Sponsor. In addition, an
End of Trial notification and final report will be submitted to the MHRA, the REC, host organisation and
Sponsor.

17.6. Participant Confidentiality

Example:

The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 2018,
which require data to be de-identified as soon as it is practical to do so. The processing of the personal
data of participants will be minimised by making use of a unique participant study number only on all
study documents and any electronic database(s), <with the exception of the CRF, where participant
initials may be added>. All documents will be stored securely and only accessible by study staff and
authorised personnel. The study staff will safeguard the privacy of participants’ personal data.

For University of Oxford sponsored trials please refer in particular to the University of Oxford’s :
Data Protection Checklist https://researchsupport.admin.ox.ac.uk/policy/data/checklist
Practical Considerations: https://researchsupport.admin.ox.ac.uk/policy/data/practical

OUH researchers see https://www.ouh.nhs.uk/privacy/default.aspx

17.7. Expenses and Benefits

Detail all intended payments to participants and any other benefits (Declaration of Helsinki
requirement).

Example:

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Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of
receipts, or a mileage allowance provided as appropriate.

18. FINANCE AND INSURANCE

18.1. Funding
Describe financing arrangements, including all the organisations providing finance and /or support in
kind for this trial.

18.2. Insurance
Describe insurance arrangements.

Either for OUH sponsored studies:

NHS bodies are legally liable for the negligent acts and omissions of their employees. If participants are
harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of the trial
team this liability cover would apply.

Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Foundation
Trust, therefore, cannot agree in advance to pay compensation in these circumstances.

In exceptional circumstances an ex-gratia payment may be offered.

Or for University of Oxford sponsored studies:

The University has a specialist insurance policy in place which would operate in the event of any
participant suffering harm as a result of their involvement in the research (Newline Underwriting
Management Ltd, at Lloyd’s of London). NHS indemnity operates in respect of the clinical treatment that
is provided.

The section in red is only to be included if there is a clinical procedure taking place during the trial.

18.3. Contractual arrangements

Add to the template text below to describe what the appropriate arrangements for the study are, e.g. it
may require multiple separate site agreement(s), collaboration agreements and/or service level
agreement(s).

Appropriate contractual arrangements will be put in place with all third parties.

19. PUBLICATION POLICY

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The publication policy should cover authorship, acknowledgements, and review procedures for scientific
publications. If there is a department or institution policy, or agreement, the protocol can refer to it.
Consider describing how trial results may be disseminated to trial participants.

Ensure that the publication policy stated here is consistent with any contract applicable to the trial.

20. DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL

PROPERTY

Describe what arrangements the sponsor has in place to protect intellectual property rights.

Either for University of Oxford sponsored studies:

Ownership of IP generated by employees of the University vests in the University. The protection and
exploitation of any new IP is managed by the University’s technology transfer office, Oxford University
Innovations.

Or for OUH sponsored studies:

Ownership of IP generated by employees of the OUH vests in OUH. The protection and exploitation of
any new IP is managed by the IP and Research Contracts Team at OUH unless it is generated in
collaboration with the University of Oxford in which case this is led by the University’s technology
transfer office, Oxford University Innovations.

If the section is not applicable state ‘not applicable’ and retain the section header.

21. ARCHIVING
Describe the arrangements for archiving the study including location and duration of storage. These
details should correspond with those provided in the participant information sheet.

22. REFERENCES
Insert references used in text (preferably numbered, or in alphabetical order of first author).

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23. APPENDIX A: TRIAL FLOW CHART

Optional

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24. APPENDIX B: SCHEDULE OF PROCEDURES

Alter as required, delete from here if the schedule appears in the procedures section above instead.

Procedures Visits (insert visit numbers as appropriate)

Visit timing
<e.g. Day 0> <e.g. Day 7>
Screening Baseline

Informed consent

Demographics

Medical history

Concomitant medications

Physical examination

ECG

Laboratory tests

Eligibility assessment

Randomisation

Dispensing of trial drugs

Compliance

<Assessment 1 (describe)>

<Assessment 2 (describe)>

<Assessment 3 (describe)>

<Assessment 4 (describe)>

Adverse event assessments

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25. APPENDIX C: SAE REPORTING FLOW CHART

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26. APPENDIX D: AMENDMENT HISTORY

Amendment Protocol Date issued Author(s) of Details of Changes made

No. Version changes
No.

List details of all protocol amendments here whenever a new version of the protocol is produced. This is
not necessary prior to initial REC / MHRA / HRA submission.

Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC
committee, HRA (where required) or MHRA.

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