uob-qms-qcd-001 - web viewuob-cln-esd-qcd-002 protocol template ... a version containing the tracked...

Protocol template

IntroductionThe 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.

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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.

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<consider including trial logo(s) on this

page>

Protocol template

< 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

Trial name: <trial name>Protocol version number: 0.1 version date: 05-May-23 Page: 3 of 45

TRIAL PROTOCOL

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 AmendmentsThe following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved versionFor 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: <inset trial name here>Protocol version number: <insert

version number>

version date: <insert date here> Page: 4 of 45


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.



Administrative InformationUse 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 JenningsResearch Governance TeamUniversity of BirminghamBirmingham, B15 2TT

0121 414 7618 [email protected]

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 >


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>


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 > < Job title >

< Institution >< City >


TRIAL SUMMARY

As a guide this should be no longer than 2 sides of A4The following sub-headings should be included:

Title

Trial DesignE.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 SchemaThis should include a representation, which could be diagrammatic, summarising the visits from screening through to follow up.



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



7.6. Treatment Modification.........................................................................................................14

8. 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. Sub studies.................................................................................................................. 16

9. 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



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



1. Background and Rationale ICH GCP and the EU CTD specify that the following regulatory requirements should be included:


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



2. Aims, Objectives and Outcome Measures ICH GCP specifies that the following regulatory requirements should be included:


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 MeasuresInclude 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.



3. Trial Design and Setting


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. EligibilityICH GCP specifies that the following should be included:


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:


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),



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. Re-consent 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.



6. Enrolment and RandomisationNOTE: Regulatory requirements:

ICH GCP section 6.4.3: A description of the measures taken to minimise/avoid bias, including:o Randomisationo Blinding

ICH GCP section 6.4.8: Maintenance of trial treatment randomisation codes and procedures for breaking codes.

6.1.Enrolment/RegistrationIn 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.RandomisationDescribe 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.BlindingFor 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 / interventionICH GCP and the EU CTD specify that the following should be included:


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



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.TreatmentList the IMPs and NIMPs and state their licenced status

7.2.Treatment Supply and Storage

7.2.1.Treatment SuppliesDetail who will be supplying the treatment, include details of shipping and handling.

7.2.2.Packaging and LabellingDetail who will be responsible for packaging and labelling of the treatment. A sample label may be included here.

7.2.3.Drug StorageInclude where the drug will be stored and any special considerations e.g. temperature.

7.3.Dosing ScheduleYou 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/interventionProvide details of the device/intervention to be used for the trial.

7.4.Drug Interaction or ContraindicationsThis should include the following consideration before and/or during the trial:

permitted medication(s)/treatment(s (including rescue medication)



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 ProceduresDetail 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 ModificationIn 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.



8. Trial procedures and assessments8.1.Summary of assessmentsPlease 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 Post-allocation Close-out

TIMEPOINT** -t1 0 t1 t2 t3 t4 etc. tx

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 X etc. X

[List other data variables] X X X X etc. 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



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 ProceduresDetail 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 studiesIf 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 ReportingICH GCP specifies that the following should be included:


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 RequirementsThis 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



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 trialsIn 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

CTIMPsThe 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-CTIMPsThe 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 EventsExample 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 AEsAEs 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 EventsSAEs 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: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 pre-existing 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 EventsThis 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 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 follow-up pregnancy notification form and “an SAE Form will be completed.”

9.4.Reporting periodThis 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



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 EventsEnsure 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 AEsAEs 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 EventsThis 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 informationParticipants 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 OfficeFor 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 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-CTIMPsOn 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 ReactionsRequired for CTIMPs onlyThe 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 ([email protected], subject line should read: SUSAR RG_xx-xxx) at the time of sending the SUSAR report.

9.7.2.Serious Adverse ReactionsRequired for CTIMPs onlyThe 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 EventsRequired for non-CTIMPS onlyThe 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:


mailto:[email protected]


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 EventsRequired for CTIMPs onlyDetails of all AEs will be reported to the MHRA on request.

9.7.5.Other safety issues identified during the course of the trialRequired for CTIMPs onlyThe 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 onlyThe 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.InvestigatorsRequired for CTIMPs onlyDetails 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 onlyDetails 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 CommitteeMay be required for both CTIMPS and non-CTIMPS – if there is no Data Monitoring Committee for the trial, then delete this sectionThe 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




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 DataIn 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 CompletionNormal 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



10.3. Data ManagementIn 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. ArchivingAll 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 assuranceICH GCP also specifies that the following should be included


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 InitiationAll 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



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 MonitoringOn-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 InspectionThe 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 BreachesFor 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



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 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>, 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 DefinitionNOTE: 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 sub-study.

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.



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:


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 MeasuresDetail 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 measuresSee section 2.2.

13.1.2. Secondary outcome measures/exploratory endpointsSee section 2.2.



13.2. 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 MethodologyIn 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 AnalysisDescribe 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 StructureYou 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.



14.1. SponsorAn 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 GroupThe 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.



14.6. FinanceProvide 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:


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 ProtectionIn 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 in-house monitoring of the consent process”.


http://www.wma.net/en/30publications/10policies/b3/index.html


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 trialThe 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.”>



19. 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.



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 Unexpected Serious Adverse Reaction (SUSAR)

A SAR that is unexpected i.e. the nature, or severity of the event is not consistent with the applicable product information.A SUSAR should meet the definition of an AR, UAR and SAR.

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 An event which resulted from the administration of any of the research procedures.

Serious Adverse Event (SAE)

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



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.



Appendices



Consider adding Trials Office contact details to the back page of the protocol.
