Ma Trial Court Brief Template - Download as DOC

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DRAFT V1, dated / / of Clinical Trial Protocol V1, dated
/ /2010
[Please check out that this template is the most
recent one by looking it up on: http://www.ucl.ac.uk/joint-rd-unit/
Throughout your trial you will need to verify that you are using the current document version
numbers by logging on to this website]

If you trial has been adopted by the CTC, you will need to comply with the CTC
requirements on protocol writing. Please contact the CTC.

Text in red is for instruction only and should be deleted.
Text in blue should be included if appropriate for the trial.
Please keep all headings to demonstrate to your GCP inspectors that you
have addressed all issues. Some headings will not be applicable for your
trial please write ‘Not applicable’.

Please request the CI self-monitoring report template from the TC prior to
completing this template. Your trial monitoring plan will need to be
outlined in this document and proportional to the level of risk associated to
the trial as defined by the monitoring template risk assessment.
This template is associated to SOP INV/S01


 Full title of trial                                   [Click here and type full descriptive trial title]
 Title to include phase, design (e.g.
 double-blind,     randomised,       placebo-
 controlled), single-site/multi-site, name of
 IMP, target disease, and subject
 population.

 Short title                                           [Click here and type short title]
 The full and short title must be the same
 on all trial documents e.g. patient
 information sheet.

 Version and date of protocol                          [Type 'Draft' here if applicable] Version [Insert version number],
                                                       [insert date]


                                                       [The protocol you send to the MHRA and REC should be V1]


 Sponsor:                                              University College London (UCL)


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 Sponsor protocol number                               [Type sponsor protocol number]


 Funder (s) :                                          [Names of ALL organisations providing funding for this trial]




 EudraCT no                                            [Type EudraCT No]


 ACTIVE IMP(s):                                        [Insert trial medication]


 PLACEBO IMP(s):                                       [Insert trial medication]


 Phase of trial                                        Phase [Insert phase of trial]


 Trial sites(s)                                        [Single site]/[Multi-site]




 Chief investigator:                                   Sponsor Representative:

                                                       Nadeem Khan, Divisional Manager,
 [Insert name, title, address and contact details]
                                                       Joint UCLH/UCL Biomedical Research Unit, 1st Floor Maple
                                                       House,
                                                       149 Tottenham Court Road,
                                                       London W1T 7NF.

                                                       Postal address:
                                                       Joint UCLH/UCL Biomedical Research and Development (R&D)
                                                       Unit,
                                                       (1st Floor, Maple House),
                                                       Ground Floor, Rosenheim Wing,
                                                       25 Grafton Way,
                                                       London WC1E 6DB.




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Signatures

The Chief Investigator and the JBRU have discussed this protocol. The
investigators agree to perform the investigations and to abide by this protocol
except in case of medical emergency (see SPON/S15 “SOP for the recording
and reporting of deviations, violations, potential serious breaches , serious
breaches and urgent safety measures” see section 10.3.6) or where departures
from it are mutually agreed in writing.
The investigator agrees to conduct the trial in compliance with the protocol, GCP
and UK Regulations for CTIMPs, the Data Protection Act (1998), the Trust
Information Governance Policy (or other local equivalent), the Research
Governance Framework (2005), the Sponsor‟s SOPs, and other regulatory
requirements as appropriate.




 Chief investigator
 [Insert name of CI]
 [Insert name of site]                     Signature                               Date


 Sponsor Representative

 Dr.     Nadeem                 Khan,
 Divisional Manager
 UCL                                       Signature                               Date


 Include following text if the trial is an international trial, and UCL is the
 sponsor for the UK sites only:
 This is an international trial led by [insert main international sponsor].UCL
 will sponsor the trial for UK sites only.




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Contents

Signatures ...................................................................................................................3
Contents ......................................................................................................................4
List of abbreviations.....................................................................................................7
1      Trial personnel .....................................................................................................9
2      Summary ...........................................................................................................10
3      Introduction ........................................................................................................10
    3.1      Background .......................................................................................... 10
    3.2      Investigational medicinal product(s) ..................................................... 11
    3.3      Preclinical data ..................................................................................... 11
    3.4      Clinical data .......................................................................................... 11
    3.5      Rationale and risks/benefits ................................................................. 11
    3.6      Assessment and management of risk .................................................. 11
4      Objectives ..........................................................................................................12
5      Trial design ........................................................................................................12
    5.1      Overall design ...................................................................................... 12
6      Selection of Subjects .........................................................................................13
    6.1      Inclusion criteria ................................................................................... 13
    6.2      Exclusion criteria .................................................................................. 13
    6.3      Concomitant medication ....................................................................... 14
7      Recruitment .......................................................................................................14
8      Study procedures and schedule of assessments ..............................................14
    8.1      Informed consent procedure ................................................................ 14
    8.2      Randomisation procedures .................................................................. 15
    8.3      Emergency unblinding .......................................................................... 16
    8.4      Screening assessments ....................................................................... 16
    8.5      Baseline assessments.......................................................................... 17
    8.6      Treatment procedures .......................................................................... 17
    8.7      Subsequent assessments .................................................................... 17
    8.8      Flowchart of study assessments .......................................................... 17
    8.9      Methods ............................................................................................... 17


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       8.9.1        Laboratory procedures .................................................................. 17
       8.9.2        Radiology or other procedures ...................................................... 18
    8.10     Definition of end of trial......................................................................... 18
    8.11     Discontinuation/withdrawal of participants and „stopping rules‟ ............ 18
9       Name and description of all drugs used in the trial ............................................19
    9.1      Name and description of each IMP ...................................................... 19
    9.2      Source of IMPs including placebo ........................................................ 19
    9.3   Accountability procedures for the investigation product(s), including the
    placebo(s) and comparator(s), if any. ............................................................. 20
    9.4    Route of administration, dosage, dosage regimen, and treatment
    period(s) of the IMPs. ...................................................................................... 20
    9.5      Dose modifications ............................................................................... 20
    9.6      Assessment of compliance................................................................... 20
    9.7      Post-trial IMP arrangements ................................................................. 21
    9.8      Name and description of each NIMP .................................................... 21
10      Recording and reporting of adverse events and reactions ................................21
    10.1     Definitions ............................................................................................ 21
    10.2     Recording adverse events.................................................................... 22
    10.3     Procedures for recording and reporting Serious Adverse Events ......... 24
       10.3.1       Notification of deaths..................................................................... 25
       10.3.2       Reporting SUSARs ....................................................................... 25
       10.3.3       Annual safety reports .................................................................... 26
       10.3.4       Annual progress reports ................................................................ 26
       10.3.5       Pregnancy ..................................................................................... 26
       10.3.6       Reporting Urgent Safety Measures (SPON/S15) .......................... 26
       10.3.7 Notification of Serious Breaches to GCP and/or the protocol
       (SPON/S15) ................................................................................................ 27
    10.4     The type and duration of the follow-up of subjects after adverse events.
             27
11      Data management and quality assurance .........................................................28
    11.1     Confidentiality ....................................................................................... 28
    11.2     Data collection tools and source document identification ..................... 28
    11.3     Data handling and analysis .................................................................. 29
12      Record keeping and archiving ...........................................................................29
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13    Statistical Considerations ..................................................................................30
   13.1     Endpoints ............................................................................................. 30
      13.1.1      Primary endpoints ......................................................................... 30
      13.1.2      Secondary endpoints .................................................................... 30
   13.2     Sample size and recruitment ................................................................ 30
      13.2.1      Sample size calculation ................................................................. 30
      13.2.2      Planned recruitment rate ............................................................... 31
   13.3     Statistical analysis plan ........................................................................ 31
      13.3.1      Summary of baseline data and flow of patients ............................. 31
      13.3.2      Primary endpoint analysis ............................................................. 31
      13.3.3      Secondary endpoint analysis ........................................................ 32
      13.3.4      Sensitivity and other planned analyses ......................................... 32
   13.4     Randomisation ..................................................................................... 32
   13.5     Interim analysis .................................................................................... 32
   13.6     Other statistical considerations ............................................................ 33
14    Name of Committees involved in trial ................................................................33
15    Direct Access to Source Data/Documents .........................................................33
16    Ethics and regulatory requirements ...................................................................33
17    Monitoring plan for the trial ................................................................................35
18    Finance..............................................................................................................36
19    Insurance ...........................................................................................................36
20    Publication policy ...............................................................................................36
21    Statement of compliance ...................................................................................36
22    References ........................................................................................................37




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List of abbreviations

Commonly used abbreviations – add or delete as applicable:
AE                                                 Adverse Event
AR                                                 Adverse Reaction
ASR                                                Annual Safety Report
CA                                                 Competent Authority
CI                                                 Chief Investigator
CRF                                                Case Report Form
CRO                                                Contract Research Organisation
CTA                                                Clinical Trial Authorisation
CTIMP                                              Clinical Trial of Investigational Medicinal
                                                   Product
DMC                                                Data Monitoring Committee
EC                                                 European Commission
EMEA                                               European Medicines Agency
EU                                                 European Union
EUCTD                                              European Clinical Trials Directive
EudraCT                                            European Clinical Trials Database
EudraVIGILANCE                                     European database for Pharmacovigilance
GAfREC                                             Governance    Arrangements              for     NHS
                                                   Research Ethics
GCP                                                Good Clinical Practice
GMP                                                Good Manufacturing Practice
IB                                                 Investigator Brochure
ICF                                                Informed Consent Form
IMP                                                Investigational Medicinal Product
IMPD                                               Investigational Medicinal Product Dossier
ISF                                                Investigator Site File
ISRCTN                                             International Standard Randomised
MA                                                 Marketing Authorisation
MHRA                                               Medicines    and  Healthcare                 products
                                                   Regulatory Agency

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MRC                                                Medical Research Council
MS                                                 Member State
Main REC                                           Main Research Ethics Committee
NHS R&D                                            National Health       Service      Research       &
                                                   Development
PI                                                 Principal Investigator
PIS                                                Participant Information Sheet
QA                                                 Quality Assurance
QC                                                 Quality Control
QP                                                 Qualified Person for release of trial drug
RCT                                                Randomised Control Trial
REC                                                Research Ethics Committee
SAR                                                Serious Adverse Reaction
SAE                                                Serious Adverse Event
SDV                                                Source Document Verification
SOP                                                Standard Operating Procedure
SmPC                                               Summary of Product Characteristics
SSA                                                Site Specific Assessment
SSAR                                               Suspected Serious Adverse Reaction
SUSAR                                              Suspected Unexpected Serious Adverse
                                                   Reaction
TMG                                                Trial Management Group
TSC                                                Trial Steering Committee




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1         Trial personnel

          [Please note: If this trial is a Phase I or Phase I/II trial you will need to
          employ a trial specific experienced Phase I monitor who will HAVE to be
          on site and carry out 100% source data verification while the first patient
          is being treated.]
                         Chief Investigator (CI)             [insert name and address]
                                                            e-mail: [add email address]
                                                              tel: [tel no.] fax: [fax no.]


                         Sponsor‟s representative [insert name and address]
                                                 e-mail: [add email address]
                                                   tel: [tel no.] fax: [fax no.]


                         Statistician                        [insert name and address]
                                                            e-mail: [add email address]
                                                              tel: [tel no.] fax: [fax no.]


                         Routine local laboratories [insert name and address]
                                                   e-mail: [add email address]
                                                     tel: [tel no.] fax: [fax no.]


                         Central laboratories                [insert name and address]
                                                            e-mail: [add email address]
                                                              tel: [tel no.] fax: [fax no.]


                         Pharmacies                          [insert name and address]
                                                            e-mail: [add email address]
                                                              tel: [tel no.] fax: [fax no.]
           Add appropriate name (eg Head of Department) and address of any
           local and central laboratories, medical and/or technical
           departments (e.g. imaging, radiology), and any external Contract
           Research Organisation (CRO) or Clinical Trials Unit (CTU) involved
           in the trial.
           Please ensure you include all relevant details here to
           help ensure the correct contracts are put in place for
           your trial.


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2            Summary

This summary should be 1–2 pages only. It should give the reader
sufficient information to understand the rationale for the trial, its objectives
and the methods that will be used to achieve these objectives.


 Title:

 Short title:

 Trial medication:                  List all IMPs to be used in the trial.

 Phase of trial:                    Insert development phase (I, II, II or IV).

 Objectives:                        Summarise primary and secondary objectives.

 Type of trial:                     Example: Phase [N], open/single-blind/double-blind, randomised, crossover/partial
                                    crossover/parallel group, single/multi-site trial in [insert patient population].

 Trial design and methods:          Give brief summary of trial design, including dosing regime and the assessments
                                    that will be made to achieve the primary and secondary objectives.

 Trial duration per participant:    ie. from consent to last trial assessment.

 Estimated total trial duration:    I.e. from when first patient enrolled to last patient follow-up.

 Planned trial sites:               Single-site or multi-site. If multi-site, include number of planned sites.

 Total number of participants       Include planned number to be enrolled for the whole trial.
 planned:

 Main inclusion criteria:           Include the main disease/area to be investigated and the key inclusion criteria.

 Statistical    methodology   and   Briefly describe the statistical methodology to be used in the study.
 analysis:




3            Introduction


3.1          Background

             This section should describe:
                       The disease to be studied in the trial, including its incidence.
                       The trial population.




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3.2       Investigational medicinal product(s)

          Name, description and characteristics of ALL the IMP(s)
          Brief description of, and justification, for the route of administration,
          dosage, dosage regimen, and treatment period(s).


3.3       Preclinical data


3.4       Clinical data


3.5       Rationale and risks/benefits

          Include the rationale or “problem statement” i.e. the research question
          (the hypothesis to be tested).
          The current available treatment(s) and their limitations, and why you
          think the IMP might be an improvement on those treatments.
          If the IMP is to be used outside its licence, you should include a
          risk/benefit analysis.
          Justification should be provided to support that the IMP could achieve
          clinical improvement over current practice (and indicate its relevance to
          healthcare practice). Include findings from non-clinical studies, other
          clinical trials, or previous clinical experience (insert cross references –
          reference list to be included in later section).
          This justification is particularly important if the trial proposes to use the
          IMP:
                   in children or in adults unable to consent for themselves;
                   in higher doses;
                   for longer duration;
                   in a subject population that might handle it differently (e.g. hepatic
                    or     renally     impaired      patients,      children,      elderly,
                    immunocompromised);
                   it is being used in combination with another medicinal product; or
                   the indication/ medical condition compromises the subject‟s
                    tolerance.


3.6       Assessment and management of risk

          Include a section on risk management especially for Phase I trials. What
          are the risks, how high is the risk, how will risk be minimised, and how
          will AEs be managed?
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          Consider the starting dose, dose increments, administration of doses,
          resources available particularly in terms of facilities and staff,
          procedures, type of patients, staff training required.
          More info available at:
          http://www.abpi.org.uk/publications/pdfs/phase1_guidelines.pdf


4         Objectives
          Primary:
          Secondary:


5         Trial design


5.1       Overall design

          This section of the protocol should include the following information:
               Purpose of research (e.g. non commercial trial, licensing).
               Clear description and justification of the type of design (e.g. open
                label, blind, parallel group, crossover, placebo-controlled, sequential,
                cluster randomised and equivalence).
               Include detail and justification for:
                        o level of blinding to be used – double-blind or single-blind
                        o how blinding of investigator team and participant will be
                          implemented (e.g. through use of identical active and
                          placebo treatment)
               For a trial with a crossover design, information about possible carry
                over effects, detail of orderings, washout (/in) periods.
               Schematic diagram(s) of overall trial design.
               Description and justification of the duration of treatment, subject
                participation and trial follow-up.
               Criteria for dose escalation if applicable.




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6         Selection of Subjects


6.1       Inclusion criteria


6.2       Exclusion criteria

          Please add criteria as appropriate (for example consider contra-
          indications to trial treatments, incompatible concurrent treatments, recent
          involvement in other research), and include points below if appropriate:
           1. Females of childbearing potential and males must be willing to use
              an effective method of contraception (hormonal or barrier method of
              birth control; abstinence) from the time consent is signed until 6
              weeks after treatment discontinuation. [If the SmPCs of the IMPs
              state that the IMPs are not teratogenic you might be able to state
              that this is NA for your trial]
           2. Females of childbearing potential must have a negative pregnancy
              test within 7 days prior to being registered for trial treatment. [If the
              SmPCs of the IMPs state that the IMPs are not teratogenic you might
              be able to state that this is NA for your trial]. NOTE: Subjects are
              considered not of child bearing potential if they are surgically sterile
              (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or
              bilateral oophorectomy) or they are postmenopausal.
           3. Females must not be breastfeeding.
           Consider contraindications to trial treatment (e.g. as listed in SmPc),
           incompatible concurrent treatments, recent involvement in other
           research.
           [Please consider each criterion carefully as there must be NO
           deviations from it during the trial. You are defining these criteria
           and you are expected to comply with them.
           These criteria need to be defined in such a way that a
           monitor/inspector can clearly identify from the CRF and medical
           notes that the CI is compliant with his eligibility criteria.
           It used to be the case that for “investigator led studies”, when
           blood results were slightly outside the inclusion criteria range, the
           CI was phoned and asked if it was ok to include the patient. THIS IS
           NO LONGER AN APPROPRIATE PRACTICE. Let‟s be crystal clear,
           Deviations from the inclusion/exclusion criteria will be reported to
           the MHRA as a serious breach and the dataset will not be usable.
           Please note: UCL as a sponsor has had in 2009 to report a serious
           breaches of inclusion criteria on a trial and put the trial on hold]

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6.3       Concomitant medication

          Medication(s)/treatment(s) permitted (including rescue medication) and
          not permitted before and/or during the trial (specify time restrictions).
          Consider possible interactions or effects that could confound the results
          and conclusions.


7         Recruitment
          Need to include:
          Patient recruitment at a site will only be done when the trial has
          1. documented REC, Regulatory and Local Trust R&D approval,
          2. a signed site agreement and
          3. the site has sent back to the TC the PI self-monitoring template and
          4. been initiated by the Sponsor.
          In this section you need to describe recruitment methods such as the
          use of adverts, websites and the involvement of different centres.


8         Study procedures and schedule of assessments


8.1       Informed consent procedure

          All staff taking consent will have to have signed section 23 of this
          protocol: 23. PROTOCOL TRAINING LOG:
          Specify who will take informed consent, how and when it will be taken.
          Informed consent must be obtained before any trial-related procedures
          are done.
          The person taking consent must be GCP trained, suitably qualified and
          experienced, and have been delegated this duty by the CI/PI on the
          delegation log.
          If Senior Research Nurses will be taking consent, please state it clearly
          in this section so that the MREC can approve that this is fine. State that
          the PI will countersign these consent forms prior to the IMP having been
          prescribed to these subjects.
          If the amount of time between the patient information leaflet being given
          and informed consent being taken is less than 24 h, you must explain the
          rationale for this.
          Please include if applicable:
          It is the responsibility of the Investigator, or a person delegated by the
          Investigator to obtain written informed consent from each subject prior to
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          participation in the trial, following adequate explanation of the aims,
          methods, anticipated benefits and potential hazards of the study.
          “Ample time” must be given for consideration by the patient before
          taking part. The PI must record when the patient information leaflet (PIL)
          has been given to the patient. [If the amount of time between the PIL
          being given and the date of consent is less than 24 hours, the PI needs
          to explain why this is the case in this study].
          The Investigator or designee will explain the patients are under no
          obligation to enter the trial and that they can withdraw at any time during
          the trial, without having to give a reason.
          A copy of the signed Informed Consent will be given to the participant.
          The original signed form will be retained at the study site.
          If new safety information results in significant changes in the risk/benefit
          assessment, the consent form should be reviewed and updated if
          necessary. All subjects, including those already being treated, should be
          informed of the new information, giving a copy of the revised form and
          give their consent to continue in the study.
          If the trial is in children or adults unable to consent for themselves please
          include       appropriate      procedure.     Refer   to     NRES     website
          (http://www.nres.npsa.nhs.uk/applications/guidance/).


8.2       Randomisation procedures

          We strongly advise that for double blind trials, you enlist the
          service of a specialist company (e.g. www.sealedenvelope.co.uk) to
          do randomisation, unblinding as they can offer 24/7 cover. You
          should cost for this in your grant application.
          If the trial is not randomised, please state that this section is not
          applicable but DO NOT DELETE THE HEADING.
          Describe the type of randomisation to be used e.g. simple, block,
          stratified, minimisation. Refer to specific stats section for more details if
          applicable. If this trial does not involve randomisation, the protocol
          should state that this section is not applicable.
          Include information regarding how randomisation will be implemented
          (include who will be doing it, where and how including the procedure to
          be used out of hours if applicable). Specify who will hold the
          randomisation list.
          Describe how subjects will be assigned to treatment groups e.g. through
          consecutive allocation of subject numbers, and the use of a Trial Subject
          Log.

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          Describe the procedure for replacements.
          Describe the approach to be used to conceal allocation (e.g. sealed
          envelopes, telephone central allocation office).
          You must prepare a trial specific SOP on the randomisation, blinding and
          unblinding procedure. Please refer to sponsor‟s SOP for information on
          preparing this (INV/S06).
          Include following statement if the trial is single or double:
          Upon randomisation, patients will be given a study specific patient card,
          which will have the study title, IMP details, patient trial number and the
          contact details of the Principal Investigator and out of hours contact
          details in cases of emergency.


8.3       Emergency unblinding

          Specify the procedure to be used for unblinding should there be an
          emergency, especially the procedure to be used for code-breaking
          during out of hours (there must be 24 h cover for code breaking) and
          accountability of responsibilities.
          The protocol should describe circumstances where blinding of a
          participant can be broken such as in a medical emergency where
          knowledge of the blinded treatment is necessary for the treatment of an
          adverse event, or where a child in a participants household accidentally
          takes an IMP.
          If this trial does not involve blinding, then the protocol should state that
          this section is not applicable but do not delete the heading as we need to
          know that this is not an issue.
          [Your trial specific SOP on unblinding must be forwarded in the JBRU to
          the TC who will file it in the JBRU TMF]




8.4       Screening assessments

          Need to list all the planned screening assessments, including Physical
          Examination, Medical History and Concomitant Medication. Need to
          include any assessments and or procedures done as part of routine
          care, but which will be used to screen patients eligibility.




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8.5       Baseline assessments

          Need to list all the planned baseline assessments that will be done once
          the patient has been entered into the trial and before their first dose of
          the IMP.


8.6       Treatment procedures

          Add IMP dosing details.


8.7       Subsequent assessments

          Describe all study procedures and assessments, including those that are
          part of routine care. Breakdown into visit numbers as appropriate.
          If home dosing, compliance should be checked at each visit. Diary cards
          should be checked at each visit.
          Include any follow-up assessments.


8.8       Flowchart of study assessments

          Add table of all procedures/tests/IMP administration to be done at each
          visit.


8.9       Methods


  8.9.1       Laboratory procedures

          The protocol needs to describe how samples will be handled during the
          trial, especially if the samples need certain precautions and special
          treatment and storage including any specific shipping
          arrangements. This is even more important if the samples will be
          shipped out of the site for analysis elsewhere. [In which case an
          agreement will have to be in place]. These procedures might be
          described in an SOP, in which case the protocol can make a reference to
          this document. However, you should include the following details:
               Name and address of the laboratory.
          In this section you also need to list any laboratory used which is not part
          of the standard accredited hospital routine laboratories within the trial
          site that will be involved in the analysis of any sample. An example
          would include a Research Laboratory that will perform a PCR specifically
          for the trial samples that is not part of normal routine analysis.

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          Please ensure that any samples to be sent outside the UK are
          mentioned in this section with details of to whom and where the samples
          will be sent. Please ensure that if any data/samples are being sent
          outside the UK, this is mentioned in the patient information sheet, to
          ensure patients consent to this.
          You will be expected to provide to any central lab used for research
          purposes a trial site file entailing a current approved version of the
          protocol, MHRA, R&D and REC approvals. You should request the GCP
          certificate from the head of that lab and file it in your ISF. You need to
          ensure that the lab has SOPs on “urgent safety measures” and “serious
          breaches”.


  8.9.2      Radiology or other procedures

          Describe any other procedures here as applicable – add extra sections if
          necessary.
          Describe any medical devices that will be used (document if they hold a
          CE mark).
          For medical devices, you would need to provide a copy of the device
          product characteristics, as well as the CE-mark certificate. If not CE-
          marked or CE-marked but used outside it's indication this should be
          included in your risk assessment and you would need to pay special
          attention to the SAE reporting section, to be reported by the
          manufacturer of the device to the MHRA.
          Outline the risk of these other procedures. Include the risk statement as
          provided by the Medical Physics Expert/ Clinical Radiation Expert with
          regards to radiation exposure (eg from CT scans and x-rays).
          If tissue samples are to be taken and stored, document that consent will
          be obtained, that there is an appropriate licence in place and that if data
          is to be transferred outside of the EU, consent for this will be obtained.




8.10      Definition of end of trial

          Define the end of the trial. In most cases the end of the trial will be the
          date of the last visit/ telephone follow up/ home visit by the last
          participant. Any exceptions should be justified.


8.11      Discontinuation/withdrawal of participants and „stopping rules‟

          The protocol should:

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               describe under what circumstances and how subjects will be
                withdrawn from the trial
               give details of documentation to be completed on subject withdrawal
                (including recording reasons for withdrawal and any follow-up
                information collected with timing)
               state whether withdrawn subjects would be replaced and how.
               state under what circumstances the trial might be prematurely
                stopped.
          Remember the safety profile of the IMP(s) and the objective(s) of the
          trial. It may be necessary to give the circumstances under which
          treatment may be resumed.


9         Name and description of all drugs used in the trial
          For this section of the protocol you might find the following document
          useful to read:
          “Guidance on Investigational Medicinal Products (IMPs) and other
          medicinal products used in Clinical Trials”
          This document can be downloaded at:
          http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-
          10/guidance-on-imp_nimp_04-2007.pdf
          This section of the protocol should list all the drugs to be used in the trial.


9.1       Name and description of each IMP

          Name each IMP including all comparator(s) and placebo.
          If the trial uses a licensed drug, specify the generic name only, unless a
          specific brand must be used, for example as per an IMP supply
          agreement (e.g. if IMP is to be supplied free of charge by the
          manufacturer). Also, please add statement that any brand of the IMP
          can be used, if that is the case.


9.2       Source of IMPs including placebo

          If the IMPs to be used in the trial are being provided or manufactured by
          a company specifically for use in the trial please provide details of the
          arrangement. If the IMPs are being sourced from hospital stock please
          insert the following statement, and list the IMPs as applicable:



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          „The following IMPs will be sourced from routine hospital stock and their
          handling and management will be subject to standard procedures of the
          pharmacy‟.
          Please note that hospital pharmacy do not usually supply IMPs free of
          charge for trials.


9.3       Accountability procedures for the investigation                                 product(s),
          including the placebo(s) and comparator(s), if any.

          State who will be responsible for drug accountability (usually it is the
          hospital pharmacy department), and how used and unused IMP will be
          retuned to pharmacy or supplier and how and when the drug will be
          destroyed. For example:
          All used/unused IMP(s) that are dispensed should be returned to the trial
          pharmacist. They will be responsible for maintaining & updating the drug
          accountability log, in the hospital pharmacy file. Drug destruction will be
          conducted, once agreed by the sponsor and in accordance to local
          pharmacy practice, and this will be documented on the drug destruction
          log in the hospital pharmacy file.
          Also, describe any reconstitution or other preparation that will need to be
          done, and who will do this and where.


9.4       Route of administration, dosage, dosage regimen, and treatment
          period(s) of the IMPs.

          This section should be precise and complete. Remember to include
          dosage for all subjects throughout the trial period, taking particular care
          to changes doses as infants and children grow. You should include the
          frequency and timing of dose in each part of the trial, methods for
          individualised doses, etc.


9.5       Dose modifications

          You should give details here on required dose modifications, for example
          in the case of certain of adverse events (specify the exact dose
          modifications and events), and also the stopping rules (see also section
          8.11).


9.6       Assessment of compliance

          Define procedures for:
                   Monitoring (e.g. watching subject swallow pills and checking their
                    mouth afterwards, getting patients to complete a diary card).
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                   Recording of subject compliance information (what will be
                    recorded, when and where).
                   Details of follow-up of non-compliant subjects.


9.7       Post-trial IMP arrangements

          Describe what arrangements are in place should the IMP be provided to
          trial subjects post trial participation. If there are not arrangements then
          you need to state that there will be no arrangements.


9.8       Name and description of each NIMP

          Give the full name of all other drugs which are non investigational
          medicinal products (NIMPs) but which will be used by the subjects as
          part of their normal routine care, e.g. background treatment, rescue
          medication, challenge agents. If there are no NIMP to be used then you
          need to state that there will be no NIMPs used.
          Include that NIMP suspected Adverse Drug Reactions (ADR) or side
          effects will be reported through the yellow card system.


10        Recording and reporting of adverse events and reactions
          Under this section, the protocol needs to include the following definitions:


10.1      Definitions

          Adverse event means any untoward medical occurrence in a subject to
          whom a medicinal product has been administered, including occurrences
          which are not necessarily caused by or related to that product;
          Adverse reaction means any untoward and unintended response in a
          subject to an investigational medicinal product which is related to any
          dose administered to that subject;
          Serious adverse event, serious adverse reaction or unexpected
          serious adverse reaction means any adverse event, adverse reaction
          or unexpected adverse reaction, respectively, that:
               results in death,
               is life-threatening,
               requires hospitalisation or prolongation of existing hospitalisation,
               results in persistent or significant disability or incapacity, or
               consists of a congenital anomaly or birth defect;

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          Important medical events that may not be immediately life-threatening or
          result in death or hospitalisation but may jeopardise the subject or may
          require intervention to prevent one of the outcomes listed in the definition
          of serious will also be considered serious.
          Unexpected adverse reaction means an adverse reaction the nature
          and severity of which is not consistent with the information about the
          medicinal product in question set out:
           (a) in the case of a product with a marketing authorization, in the
          summary        of   product      characteristics      for  that product,
          (b) in the case of any other investigational medicinal product, in the
          investigator's brochure relating to the trial in question.
          Suspected unexpected serious adverse reaction is also known as a
          SUSAR.


10.2      Recording adverse events

          All adverse events will be recorded in the hospital notes in the first
          instance.
          A record will also be kept in the CRF of ALL adverse events, whether
          believed to be related or unrelated to the treatment. If you do not plan to
          record certain adverse events in the CRF (for example, if your trial is a
          phase IV trial of a licensed medication used within its license with a well
          established safety profile) please state it here and provide justification.
          However, all SERIOUS adverse events must be recorded in the CRF.
          If the investigator suspects that the disease has progressed faster due to
          the administration of the IMP, then he will report this as an unexpected
          adverse event to the sponsor.
          Also include if applicable:
          Clinically significant abnormalities in the results of objective tests (e.g.
          laboratory variables, x-ray, ECG – make specific to trial) may also be
          recorded as adverse events.
          The record of adverse events will include the following.
              Clinical symptoms: a simple, brief description.




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              Severity. The following categories will be used:
              Mild: the adverse event does not interfere with the volunteer‟s daily
              routine, and does not require intervention; it causes slight discomfort.
              Moderate: the adverse event interferes with some aspects of the
              volunteer‟s routine, or requires intervention, but is not damaging to
              health; it causes moderate discomfort.
              Severe: the adverse event results in alteration, discomfort or
              disability which is clearly damaging to health.
              Relationship to treatment: The assessment of relationship of adverse
              events to the administration of IMP is a clinical decision based on all
              available information at the time of the completion of the case report
              form. The following categories will be used:
              Definitely: There is clear evidence to suggest a causal relationship,
              and other possible contributing factors can be ruled out.
              Probably: There is evidence to suggest a causal relationship, and the
              influence of other factors is unlikely.
              Possibly: There is some evidence to suggest a causal relationship
              (e.g. the event occurred within a reasonable time after administration
              of the trial medication). However, the influence of other factors may
              have contributed to the event (e.g. the patient‟s clinical condition,
              other concomitant events).
              Unlikely: There is little evidence to suggest there is a causal
              relationship (e.g. the event did not occur within a reasonable time
              after administration of the trial medication). There is another
              reasonable explanation for the event (e.g. the patient‟s clinical
              condition, other concomitant treatments).
              Not related: There is no evidence of any causal relationship.
              Not Assessable
              Expectedness: The following categories will be used:
              Expected: An adverse event that is classed in nature as serious and
              which is consistent with the information about the IMP listed in the
              Investigator Brochure (or SmPC if Licensed IMP) or clearly defined
              in this protocol.
              Unexpected: An adverse event that is classed in nature as serious
              and which is not consistent with the information about the IMP listed
              in the Investigator Brochure (or SmPC if Licensed IMP)
          Seriousness as defined for an SAE in section 10.1.



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          Collection, recording and reporting of adverse events (including serious
          and non-serious events and reactions) to the sponsor will be done
          according to the sponsor‟s SOP(INV/S05).




10.3      Procedures for recording and reporting Serious Adverse Events

          All serious adverse events will be recorded in the hospital notes and the
          CRF, and the sponsor‟s SAE log. The SAE log must be reported to the
          sponsor at least once or twice per year.
          All serious adverse events will need to be reported to the sponsor on an
          SAE form unless stated in the protocol that some expected SAEs will not
          be reported to the sponsor, with a justification as to why they will not be
          reported.
          The Chief or Principal Investigator will complete the sponsor‟s serious
          adverse event form and the form will be faxed to the sponsor on 020
          7380 9937, within one working day of his / her becoming aware of the
          event. The Chief or Principal Investigator will respond to any SAE
          queries raised by the sponsor as soon as possible.
          You may choose not to report EXPECTED SAEs to the sponsor for
          example if they are expected to occur on a regular basis and offer no
          further new information to your safety profile e.g. neutropenic sepsis.
          These events must continue to be recorded in the source data and CRF,
          however you may state that you will not complete an SAE form and
          forward it to the sponsor. Please provide the rationale for doing so.
          All SUSARs must be notified to the sponsor immediately (or at least
          within one working day) according to the sponsor‟s written SOP.


          Example of exception:
          Example: As the IMPs used in this trial are licensed in the UK and used
          within their marketing authorization, EXPECTED SARs (as outlined in
          the SmPCs and listed below – please list) will be RECORDED in the
          subjects‟ hospital notes and in the CRF. However, SAE forms will not be
          completed and sent to the sponsor.
          It is important to note that the SmPC will only refer to reactions that are
          expected to occur in the indication for which the drug has a marketing
          authorisation. Please document which version of the SmPC is being
          referenced but add that the most up-to-date version of the SmPc will be
          used during the trial.

               Managing serious adverse events in a multi-centre trial
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          The protocol needs to have clear instructions of the reporting lines and
          timeframe for serious adverse events. These instructions will need to
          include where the investigator (PI) will send the reports to: e.g. if the PI
          sends the report directly to the sponsor, or whether the CI reviews the
          report first before it is notified to the sponsor and how safety information
          will be disseminated to all other PI sites.
          Reporting to the sponsor will be done as per the sponsor‟s SOP and
          using the UCL SAE form (INV/S05).


  10.3.1 Notification of deaths

          The protocol needs to be explicit as to whether, how and when the chief
          investigator will notify deaths (expected or unexpected) to the sponsor.
          The following statements are examples of what needs to be stated in the
          protocol:
          ―All deaths will be reported to the sponsor irrespective of whether the
          death is related to disease progression, the IMP, or an unrelated event‖.
          This statement should be used for phase I/FTIM trials.
          ―Only deaths that are assessed to be caused by the IMP will be reported
          to the sponsor. This report will be immediate‖.
          ―All deaths, including deaths deemed unrelated to the IMP, if they occur
          earlier than expected will be reported to the sponsor‖.
          The protocol needs to specify the timelines of such reports.


  10.3.2 Reporting SUSARs

          The sponsor will notify the main REC and MHRA of all SUSARs.
          SUSARs that are fatal or life-threatening must be notified to the MHRA
          and REC within 7 days after the sponsor has learned of them. Other
          SUSARs must be reported to the REC and MHRA within 15 days after
          the sponsor has learned of them.
          In a double-blind trial, the procedure for unblinding in the event of a
          SUSAR must be described (refer to sponsor‟s SOP on randomisation,
          blinding and code-breaking for more information (INV/S06).

10.3.2.1     Reporting              SUSARs          in     International    Trials        (include       if
        applicable)

          The overall sponsor of the trial is responsible for reporting SUSARs
          which occur outside of the UK to the MHRA. UCL, as sponsor of the UK
          site only, will report SUSARs occurring in the UK to the MHRA.


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  10.3.3 Annual safety reports

          The sponsor will provide the main REC and the MHRA with an annual
          safety report (ASR). The ASR will be prepared, using the sponsor‟s ASR
          form, by the Chief investigator or a delegated PI, reviewed by the
          sponsor and when necessary be referred to an independent committee
          (independent to the trial) such as the safety committee. This will be
          done in accordance with the sponsor‟s SOP (SPON/S17).


  10.3.4 Annual progress reports

          An annual progress report (APR) will be submitted to the REC within 30
          days of the anniversary date on which the favourable opinion was given,
          and annually until the trial is declared ended.
          The chief investigator will prepare the APR.


  10.3.5 Pregnancy

          Describe the procedure in place to:
               record and notify pregnancies to the sponsor (use sponsor‟s SOP),
               follow-up of pregnant subject: Describe in detail the process for
                monitoring and managing a pregnancy.
               follow-up of child born to a pregnant trial subject, including male trial
                subject who is the partner of the pregnant woman. (How long will
                follow-up be for).


  10.3.6 Reporting Urgent Safety Measures (SPON/S15)

          Regulation 30 of the Medicines for Human Use (Clinical Trials)
          Regulations 2004 [Statutory Instrument 2004/1031], as amended by
          Statutory Instrument 2006/1928 states “the Sponsor and the Investigator
          may take appropriate urgent safety safety measures in order to protect
          the subjects of a clinical trial against any immediate hazard to their
          health or safety. If measures are taken, the Sponsor shall immediately
          and in any event no later than 3 days from the date the measures are
          taken, give written notice to the MHRA and the relevant REC of the
          measures taken and the circumstances giving rise to those measures.”
          In order to prevent any delays in the reporting timelines the sponsor has
          delegated this responsibility to each PI site. Therefore the PI must report
          any urgent safety measures to the MHRA directly, and in parallel to the
          sponsor.


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          Please refer to the following website for details on clinical trials safety
          reporting:
          http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines
          /Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htm




10.3.7 Notification of Serious Breaches to GCP and/or the protocol
       (SPON/S15)

          Any Deviations, Violations,Potential serious breaches, urgent safety
          measures will be recorded in the last section of this protocol:

          24. PI‟s Log of (Protocol &/or GCP) Deviations/Violations/Potential serious
          breaches/Serious breaches/Urgent safety measures (See SPONS15:“SOP
          for the recording and reporting of Deviations/Violations/Potential serious
          breaches/Serious         breaches/Urgent    safety      measures”        in:
          http://www.ucl.ac.uk/joint-rd-unit)


          Regulation 29A of the Medicines for Human Use (Clinical Trials)
          Regulations2004 [Statutory Instrument 2004/1031], as amended by
          Statutory Instrument2006/1928, contains a requirement for the
          notification of “serious breaches” of GCP or the trial protocol:
          (1) The sponsor of a clinical trial shall notify the licensing authority in
          writing of any serious breach of -(a) the conditions and principles of GCP
          in connection with that trial; or (b) the protocol relating to that trial, as
          amended from time to time in accordance with regulations 22 to 25,
          within 7 days of becoming aware of that breach.
          (2) For the purposes of this regulation, a “serious breach” is a breach
          which is likely to effect to a significant degree –
                  (a) the safety or physical or mental integrity of the subjects of the
                  trial; or
                  (b) the scientific value of the trial.
          The sponsor will be notified immediately of any case where the above
          definition applies during the trial conduct phase. The sponsor‟s SOP on
          the „Notification of violations, urgent safety measures and serious
          breaches‟ will be followed.


10.4      The type and duration of the follow-up of subjects after adverse
          events.

          This section needs to describe the type and duration of follow-up care for
          subjects following an adverse drug reaction.
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          This section of the protocol also needs to specify how long after the last
          dose of IMP has been administered to the subjects will adverse events
          and reactions be recorded and reported.
          Please include „Any SUSAR related to the IMP will need to be reported
          to the Sponsor irrespective of how long after IMP administration the
          reaction has occurred.‟


11        Data management and quality assurance


11.1      Confidentiality

          Include: „All data will be handled in accordance with the Data Protection
          Act 1998.
          The Case Report Forms (CRFs) will not bear the subject‟s name or other
          personal identifiable data. The subject‟s initials, date of birth and trial
          identification number, will be used for identification.‟


11.2      Data collection tools and source document identification

          Include „Case report forms will be designed and produced by the
          investigator, according to the sponsor‟s CRF template. The final version
          will be approved by the sponsor. All data will be entered legibly in black
          ink with a ball-point pen. If an error is made, the error will be crossed
          through with a single line in such a way that the original entry can still be
          read. The correct entry will then be clearly inserted, and the alterations
          will be initialled and dated by the person making the alteration.
          Overwriting or use of correction fluid will not be permitted.‟
          Describe procedures for data collection and recording. The protocol
          must specify which data is to be recorded directly onto the Case Report
          Form (CRF) and which data is recorded firstly into source documents,
          such as medical notes and patient questionnaires. If data is not to be
          recorded in the CRF but only recorded in source documents this must be
          clearly identified.   Inlcude a table or list identifying source
          documentation, and whether or not this is to be transcribed into the CRF.
          Describe whether the data are from a standardised tool (e.g. McGill pain
          score) or involves a procedure (in which case full details should be
          supplied). If a non standard tool is to be used, detail on reliability and
          validity should be given.
          The methods used to maximise completeness of data should be
          described (e.g. telephoning subjects who have not returned postal


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          questionnaires) and data collection forms should be included as
          appendices.
          Include statement: „It will be the responsibility of the investigator to
          ensure the accuracy of all data entered in the CRFs. The delegation log
          will identify all those personnel with responsibilities for data collection
          and handling, including those who have access to the trial database.‟




11.3      Data handling and analysis

               Describe what software (e.g. Access, MACRO) is to be used for data
                entry (NB Excel is not a suitable system for data entry in a clinical
                trial).
               Provide detailed methods implemented to ensure validity and quality
                of data (e.g. double entry, cross validation etc)
               Describe how data will be stored and backed up, and how security
                will be ensured and whether data will be transferred. If data are to
                be transferred, describe the secure method of transfer. Document if
                there is a disaster recovery plan.
               Consider management of data across sites if multi-site trial. Where
                data are transferred electronically it must be done in accordance with
                the Data Protection Act 1998 as well as UCL Information Security
                Policy and Trust Information Governance Policy. There should be a
                documented record of data transfer and measures in place for the
                recovery of original information after transfer.
               Statement of who is responsible for data entry and quality, and who
                is responsible for data analysis. Data analysis should be done
                independently of data entry. If the JBRU statisticians are to do
                analyses, they should be included as collaborators in publications.
               Include statement regarding adherence to Data Protection Act 1998.


12        Record keeping and archiving
          Specify location and duration of record retention for:
                   site files, CRFs and consent forms
                   the trial database
          Please include the statement „Chief Investigators are responsible for the
          secure archiving of trial documents (for each site, if multi-site trial) and
          the trial database.‟


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13        Statistical Considerations

          Give name of statistician involved in trial design and also name of person
          to be involved in data analysis. Please note that you must have the input
          of a statistician in the design and analysis of the trial.
          For international trials whereby UCL are the named sponsor for UK sites
          only, you will need to be explicit in terms of what information relates to
          the trial as a whole such as sample size and what relates to the UK sites
          only (i.e. sample size for the UK sites), and whether the power
          calculation is based on UK sites only or on all sites in all countries
          involved.


13.1      Endpoints


  13.1.1 Primary endpoints

          A full description of the primary endpoint; it‟s definition, when it is
          measured, any rules, references or programs for calculation of derived
          values and what form it will take for analysis (e.g. continuous,
          categorical, ordinal).


  13.1.2 Secondary endpoints

          For each secondary endpoint, detail as for primary outcome above.


13.2      Sample size and recruitment


  13.2.1 Sample size calculation

          Details of the precision or power calculation used to estimate the
          required sample size (for analysis of the primary outcome), including:
               estimates used (e.g. size of the clinically important effect to be
                detected, drop out / non compliance rates)
               assumptions made (e.g. assumptions of Normality)
               relevant justification (i.e. appropriate references or clinical
                arguments), (justification should be provided for the effect size
                considered)
               allowance for planned subgroup analyses
               chosen levels of significance and power (describe how level of
                significance relates to level of clinical significance)

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               methods / formula / software used with reference
          For international multi-centre trials only, if the power of the trial is based
          on the UK centres only, you must insert the following statement:
          „The power of the trial based on the UK centres alone is x%.‟
          If x<80%, the following statement should be added as well:
          „Therefore only descriptive analyses will be performed using the UK
          data. Tests of efficacy of the intervention will only be performed after
          combining the data with those from the other international centres.‟


  13.2.2 Planned recruitment rate

          An estimate of the recruitment period for the trial (calculated based on
          the expected number of eligible and recruited participants available per
          year) with justification that the required sample size will be attainable in
          practice.


13.3      Statistical analysis plan


  13.3.1 Summary of baseline data and flow of patients

               Detail of the variables to be used to assess baseline comparability of
                the randomised groups including for each factor: a definition, any
                rules, references or programs for calculation of derived values, what
                form it will take for analysis (e.g. continuous, categorical, ordinal)
                and how it will be reported (eg means, standard deviations,
                medians, proportions).
               Detail of the number of eligible patients for the trial, the number
                consenting and the number randomised. Also a breakdown for each
                group of the numbers of participants assigned, receiving the
                intended treatment, completing the study protocol, and analysed for
                the primary outcome. This information should be displayed as a flow
                diagram (http://www.consort-statement.org/).


  13.3.2 Primary endpoint analysis

          Plans for statistical analyses of the primary outcome including:
               Summary measures to be reported
               Method of analysis (justified with consideration of assumptions of the
                method, structure of the data (e.g. unpaired, paired, hierarchical) etc)


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               Plans for handling multiple comparisons, missing data, non
                compliers, spurious data and withdrawals in analysis
               Plans for predefined subgroup analyses
               Statement regarding use of intention to treat (ITT) analysis
               Detail of any non statistical methods that might be used (e.g.
                qualitative methods)


  13.3.3 Secondary endpoint analysis

          Plans for statistical analysis of each secondary outcome. Note that use
          of hypothesis tests may not be appropriate if the study has not been
          powered to address these. Secondary analyses should be considered as
          hypothesis generating rather than providing firm conclusions.


  13.3.4 Sensitivity and other planned analyses


13.4      Randomisation

          Include detail and justification for each of the following:
               subject / cluster randomised design (randomising individuals or
                groups (eg general practices, wards)
               type of randomisation to be used - simple, block, stratified,
                minimisation (block size should not be stated in the protocol to
                maintain blinding)
                        o if using stratified randomisation or minimisation, include
                          definition of stratification/minimisation variables (should
                          only consider variables that are likely to be strongly
                          prognostic of the outcome)
                        o if using blocked randomisation consider varying block
                          sizes.
               use of equal or unequal allocation between treatment arms


13.5      Interim analysis

          Detail of approach for interim analyses and criteria for early termination
          of the trial
          Stopping / discontinuation rules and breaking of randomisation code:
               define completion and premature discontinuation of the trial


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               describe procedure regarding decisions on discontinuation of the trial
                (e.g. interim analyses, role of data monitoring committee)
               state documentation to be completed if                  part / all of the trial is
                discontinued
               describe circumstances under which the randomisation codes may
                need to be broken and the procedure for this.


13.6      Other statistical considerations

          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 the protocol and/or in the final report, as appropriate).


14        Name of Committees involved in trial

          Describe which of the three committees will be in place for the trial: Trial
          Management Group (TMG) (all trials should have a TMG), Independent
          Data Monitoring Committee (IDMC) and Trial Steering Group (TSC).
          The terms of reference for these committees will need to be provided in
          separate documents.
          Please note for ALL phase I trials, an IDMC must be in place prior to
          trial start up, and the sponsors IDMC charter must be completed and
          signed off by IDMC members. For Phase I/II trials the safety committee
          will be asked if an IDMC is required. Each member will need to sign the
          UCL IDMC charter prior to becoming a member.


15        Direct Access to Source Data/Documents
          Include the following statement:
          The investigator(s)/ institution(s) will permit trial-related monitoring,
          audits, REC review, and regulatory inspection(s), providing direct access
          to source data/documents. Trial participants are informed of this during
          the informed consent discussion. Participants will consent to provide
          access to their medical notes.




16        Ethics and regulatory requirements

          In this section you need to describe any ethical issues that need to be
          considered and how these will be addressed.


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          The sponsor will ensure that the trial protocol, patient information sheet,
          consent form, GP letter and submitted supporting documents have been
          approved by the appropriate regulatory body (MHRA in UK) and a main
          research ethics committee, prior to any patient recruitment. The protocol
          and all agreed substantial protocol amendments, will be documented
          and submitted for ethical and regulatory approval prior to
          implementation.
          If the trial involves the use of radiation, document here if an
          Administration of Radioactive Substances Advistory Committee
          (ARSAC) licence is needed.
          If trial involves gene therapy, „main REC‟ should be replaced with
          „GTAC‟.
          For Single site trials:
          Before the site can enrol patients into the trial, the Chief Investigator or
          designee must apply for Site Specific Assessment from Trust Research
          & Development (R&D) and be granted written NHS R&D approval. It is
          the responsibility of the Chief Investigator or designee at each site to
          ensure that all subsequent amendments gain the necessary approval.
          This does not affect the individual clinician‟s responsibility to take
          immediate action if thought necessary to protect the health and interest
          of individual patients (see section 10.3.6 for reporting urgent safety
          measures).
          For Multicentre trials:
          Before sites can enrol patients into the trial, the Principal Investigator or
          designee must apply for Site Specific Assessment from Trust Research
          & Development (R&D) and be granted written NHS R&D approval. It is
          the responsibility of the Principal Investigator at each site to ensure that
          all subsequent amendments gain the necessary approval. This does not
          affect the individual clinician‟s responsibility to take immediate action if
          thought necessary to protect the health and interest of individual patients
          (see section 10.3.6 for reporting urgent safety measures).
          For centres outside the UK, before enrolling patients into the study and
          subsequent amendments, the Principal Investigator or designee must
          apply for favourable opinion within their IRB/IEC requirements (delete
          this paragraph if not an international trial).


          Within 90 days after the end of the trial, the CI and sponsor will ensure
          that the main REC and the MHRA are notified that the trial has finished.
          If the trial is terminated prematurely, those reports will be made within 15
          days after the end of the trial.

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          The CI will supply a summary report of the clinical trial to the MHRA and
          main REC within 1 year after the end of the trial.




17        Monitoring plan for the trial

          If this trial is a Phase I or Phase I/II trial, an experienced trial specific
          Phase I project manager and monitor will be hired to run this trial. The
          monitor will be expected to be on site to carry out 100% SDV on site on
          patient one while the patient is being treated.
           Please request from the TC the current CI self-monitoring template prior
          to completing this section.
          Mandatory: (Unless an external CRO/CTU is contracted to monitor the
          trial to UK Regulations).
          Include the following statement:
          The trial will be monitored according to the monitoring plan agreed by the
          sponsor, based on the self-monitoring template risk assessment. It is the
          responsibility of the CI to ensure that the sponsor‟s self-monitoring
          template is completed throughout the trial every two months and
          submitted to the JBRU at the regularity determined by the sponsor‟s risk
          assessment of the trial phase) Please state here the frequency. It is the
          responsibility of the CI to determine the monitoring risk assessment and
          explain the rationale.
          Where a trial is a multi-site trial:
          Depending on the number of sites, a trial specific monitor should be
          hired to send the PI self-monitoring template to each site, review the
          completed templates and ensure that appropriate corrective an
          preventive actions are being carried out. That monitor will be expected to
          go on site to check that the PI self-monitoring reports were completed
          accurately (AUDIT).
          The PI at each site will also be required to complete this self-monitoring
          template and return the form at the same frequency, to the CI and
          sponsor in parallel for review. It is the CI‟s responsibility to ensure that
          any findings identified in a PI‟s monitoring report are actioned in a timely
          manner and any violations of GCP or the protocol reported to the
          sponsor immediately. Any urgent safety measures at either the CI or a PI
          site must be reported by that site Investigator within 3 days, as per UK
          Regulations.




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18        Finance

          A statement of the finance for the trial such as details of funding body.


19        Insurance
          Include the following:
          University College London holds insurance to cover participants for injury
          caused by their participation in the clinical trial. Participants may be able
          to claim compensation if they can prove that UCL has been negligent.
          However, as this clinical trial is being carried out in a hospital, the
          hospital continues to have a duty of care to the participant of the clinical
          trial. University College London does not accept liability for any breach in
          the hospital‟s duty of care, or any negligence on the part of hospital
          employees. This applies whether the hospital is an NHS Trust or not.
          This does not affect the participant‟s right to seek compensation via the
          non-negligence route.
          Participants may also be able to claim compensation for injury caused by
          participation in this clinical trial without the need to prove negligence on
          the part of University College London or another party. Participants who
          sustain injury and wish to make a claim for compensation should do so in
          writing in the first instance to the Chief Investigator, who will pass the
          claim to the Sponsor‟s Insurers, via the Sponsor‟s office.
          Hospitals selected to participate in this clinical trial shall provide clinical
          negligence insurance cover for harm caused by their employees and a
          copy of the relevant insurance policy or summary shall be provided to
          University College London, upon request.
          If a medical device is to be used in the trial, there must also be indemnity
          arrangements in place, with the manutacturer, to cover the malfunction
          and breakdown of the device.


20        Publication policy
          Publication policy, if not addressed in a separate agreement.
          Statements about reporting at conferences can also be included here.


21        Statement of compliance
          Include the following statement:
          The trial will be conducted in compliance with the protocol, GCP and the
          applicable regulatory requirement(s).

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22        References

          List of the literature and data that are relevant to the trial, and that
          provide background for the trial. Please ensure the text contains
          appropriate cross references to this list.




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23. PROTOCOL TRAINING LOG:

                                                                                                I confirm that     I
                                                                                                understand        &
                                                                                                agree to work to

            Name of Staff (Capital letters):         Job Title:                                 this SOP
                                                                                Training
                                                     Department:                Date            SIGNATURE              Name of Trainer         Signature   Date

    1



               2
               2
               2

               3
               3


               4



               5



               6




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          Trial Title:

          Sponsor ID N0:                                          Principle Investigator:

          EudraCT N0:                                             Site name:

                                                                                                I confirm that     I
                                                                                                understand        &
                                                                                                agree to work to

            Name of Staff (Capital letters):         Job Title:                                 this SOP
                                                                                Training
                                                     Department:                Date            SIGNATURE              Name of Trainer         Signature   Date

               7



               8



               9



               1
               0

               1
               1


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24. PI‟s Log of (Protocol &/or GCP) Deviations/Violations/Potential serious breaches/Serious breaches/Urgent safety measures                                                              (See
SPONS15:“SOP for the recording and reporting of Deviations/Violations/Potential serious breaches/Serious breaches/Urgent safety measures” in: http://www.ucl.ac.uk/joint-rd-unit)

Is this a                                    Date         Corrective Actions                      Preventative Actions                            Date                   Date
1. Deviation                                 1. the event                                                                                         the event was notified urgent safety
                                             took place                                                                                           by the PI     to the measure was
2. Violation                                                                                                                                      JBRU                        reported by the
                                             2. the PI
3. “Potential Serious breach”                became                                               (e.g. protocol amended, trial halted)           (if     either     SI
                                                                                                                                                                              PI to the MHRA
                                                                                                                                                                              and MREC
4. “Serious breach”                          aware of the                                                                                         definition are below
                                             event                                                                                                met)
5. “Urgent Safety measure”
according to the 2 SI definitions below




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Is this a                                   Date         Corrective Actions              Preventative Actions                     Date                   Date
1. Deviation                                1. the event                                                                          the event was notified urgent safety
                                            took place                                                                            by the PI     to the measure was
2. Violation                                                                                                                      JBRU                    reported by the
                                            2. the PI
3. “Potential Serious breach”               became                                       (e.g. protocol amended, trial halted)    (if     either     SI
                                                                                                                                                          PI to the MHRA
                                                                                                                                                          and MREC
4. “Serious breach”                         aware of the                                                                          definition are below
                                            event                                                                                 met)
5. “Urgent Safety measure”
according to the 2 SI definitions below




1. Definition of “Serious Breach” according to Regulation 29A (SI 2006/1928)
(2) For the purposes of this regulation, a ―serious breach‖ is a breach which is likely to effect to a significant degree –
(a) the safety or physical or mental integrity of the subjects of the trial; or
(b) the scientific value of the trial‖.

2. Definition of “Potential serious breach”: A breach which is investigated as a breach potentially meeting the definition of “serious breach” above.

3. Definition of “Urgent safety measures” according to Regulation 30 (SI 2004/1031).



 The sponsor and investigator may take appropriate ‗urgent safety measures’ in order to protect the subjects of a clinical trial against any immediate hazard
 to their health or safety. The sponsor shall immediately and in any event no later than 3 days from the date the measures are taken, give written notice to the
 licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

 Regulation 30 of the Medicines for Human Use (Clinical Trials) Regulations 2004(SI 2004/1031) was amended by (SI 2009/1164):

 For paragraph 2 of regulation 30 of the Medicines for Human Use (Clinical Trials) Regulations 2004 (urgent safety measures) (a), substitute the following
 paragraphs—

 ―(2) If measures are taken pursuant to paragraph (1), the sponsor shall—


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 (a) where paragraph (3) applies, as soon as possible; and

 (b) in any other case, immediately, and in any event no later than 3 days from the date the measures are taken, give written notice to the licensing authority
 and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

 (3) This paragraph applies for any period during which a disease—

 (a) is pandemic; and
(b) is a serious risk to human health or potentially a serious risk to human health.‖




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