1. International Rare Cancers Initiative
IRCI
BALLAD A TRIAL TO EVALUATE THE POTENTIAL BENEFIT OF ADJUVANT CHEMOTHERAPY FOR SMALL BOWEL ADENOCARCINOMA (IRCI-002)
Version 1 (16th April 2015)

2. Study Details Coordinated by CRUK Clinical Trials Unit, Glasgow
Sponsor - Greater Glasgow and Clyde Health Board (GGCHB) and University of Glasgow
Chief Investigators - Professor Jeff Evans & Professor Richard Wilson
Funded by CRUK as part of the International Rare Cancers Initiative and on UKCRN database (18655)
Study will be conducted according to ICH GCP guidelines
Study conducted in accordance with the EU Directive 2001/20/EC
Trial carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Edinburgh (2000), Washington (2002), Tokyo (2004), Seoul (2008) amendments
Please note that this presentation has been prepared as part of your site initiation. These slides are a compliment to the protocol, all site staff must have read and understood the protocol and the study requirements prior to signing off the initiation acknowledgement sheet.

3. Study Team Chief Investigators: Professor Jeff Evans & Professor
Richard Wilson
Trial Statisticians: Jim Paul & Caroline Bray
Project Management: Judith Dixon-Hughes
Clinical Trial Co-ordinator: Anna Morris
Sponsor Pharmacist: Samantha Carmichael
Pharmacovigilance: Lindsey Connery/Sinead Traynor
Clinical Trial Monitor: Michaela Rodger
Sponsor Representatives: Michael Barber/Debra Stuart

4. Study Design/Objectives
An open-label, randomised, controlled, multi-centre, global trial with disease free survival as the primary end point.
Objectives
Assessment of the efficacy of observation versus 24 weeks of adjuvant post-operative chemotherapy in resected stage I-III small bowel adenocarcinoma (SBA).
Assessment of the efficacy of 24 weeks of adjuvant post-operative fluoropyrimidine ‘monotherapy’ regimen versus fluoropyrimidine plus Oxaliplatin combination chemotherapy regimen in resected stage I-III small bowel adenocarcinoma (SBA).

5. Study Endpoints Primary Endpoint
Disease free survival (defined as time from randomisation to recurrence, development of new primary or death from any cause).
Secondary Endpoints
Overall survival, cost-effectiveness, toxicity, clinico-pathological and molecular profiling of SBA.

6. Inclusion Criteria R0 resected stage I, II or III SBA
No evidence of residual or metastatic disease at laparotomy or on CT/MRI imaging of chest, abdomen and pelvis.
Patients must be registered and randomised within 12 weeks of surgery and commence chemotherapy within 14 weeks of surgery
ECOG Performance Status of 0 or 1
Absolute neutrophil account ≥ 1.5 x109/l
Platelet count ≥ 100 x 109/l
Haemoglobin ≥90 g/l (previous transfusion is allowed)
AST and ALT ≤ 2.5 x upper limit of normal (ULN). (At least one of ALT or AST MUST be performed)
Creatinine clearance > 50 ml/min (calculated by Cockcroft Gault or Wright equation) or measured by EDTA
Serum bilirubin ≤ 1.5 x ULN
Signed and dated informed consent indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment.
Age ≥ 16 years
Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.

7. Exclusion Criteria
Non-adenocarcinoma histology of small bowel tumour which includes but is not confined to lymphoma, GIST, carcinoid or other neuroendocrine tumour, squamous carcinoma, melanoma or sarcoma.
Previous neo-adjuvant chemo(radio)therapy for SBA
Clinically significant cardiovascular disease (i.e. active or < 12 months since cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association [NYHA] grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension)
Pregnancy/lactation or of child bearing potential and not using medically approved contraception. (Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential)
Previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease free interval of at least 3 years and treatment was with curative intent
Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency

8. Exclusion Criteria
Known untreated coeliac disease (may be enrolled if diet controlled), untreated chronic inflammatory bowel disease or other cause of malabsorption or intestinal obstruction
Grade ≥ 2 peripheral neuropathy
Administration of any investigational drug within 28 days or 5 half-lives whichever is longer, prior to receiving the first dose of trial treatment.
Previous hypersensitivity to platinum salts
Patients with clinically significant, active infections, or any other serious medical condition in which chemotherapy is contraindicated will be excluded
Patients with untreated vitamin B12 deficiency are excluded from receiving folinic acid as part of their chemotherapy regimen. However, these patients may be eligible for treatment with capecitabine fluoropyrimidine therapy, where no folinic acid is administered as part of the treatment regimen
Patients with clinically significant sensorineural hearing impairment are excluded from receiving oxaliplatin but will be eligible for the fluoropyrimidine monotherapy provided as a clinician’s choice for patients in group 1 randomised to either observation or chemotherapy

9. Treatment Options
Group 1 patients, where there is uncertain value of adjuvant chemotherapy, will be randomised to observation versus chemotherapy. The chemotherapy will be 24 weeks fluoropyrimidine (either 5FU or Capecitabine) with or without Oxaliplatin or these patients can be randomised to receive Oxaliplatin or not as per Group 2 patients below. The clinician or patient must chose the chemotherapy regimen or to be allocated at random if the patient is randomised to chemotherapy. The choice of fluoropyrimidine chemotherapy must be specified prior to randomisation.
Group 2 patients, where there is certain value of adjuvant chemotherapy, will be randomised to receive 24 weeks fluoropyrimidine chemotherapy either with or without Oxaliplatin. The choice of fluoropyrimidine must be specified prior to randomisation.
Patients can be randomised into both groups at the one time if they so wish (e.g. can be randomised to receive either observation or monotherapy or doublet therapy)
For patients that are ineligible to participate in the randomised trial or do not wish to do so then they should be offered patient registration to allow collection of tumour and blood samples for translational research

10. Informed Consent Informed Consent Process
Two original Consent Forms to be completed by a clinician (or designee listed on study specific training and delegation log)
Two originals signed and completed by the patient
Date must be on or prior to registration
Make one photocopy
- Original to be filed in Investigator File
- Original to be given to patient
- Photocopy to be filed in hospital notes
Consent Form must not be sent to the CRUK Trials Unit, Glasgow
For Errors Noted After Consent please ensure an explanatory file note is completed and sent to CRUK CTU Glasgow with a copy remaining at site
Patient Re-consenting
If the sponsor requires patients to be re-consented then the new version of the patient information sheet and consent form must be given to the patient at the next clinic visit. The consent process should be followed as above.
If a patient cannot re-consent (i.e. patient is terminally ill) then a file note should be written to explain this as well as this being documented in the patient’s notes.
The re-consent log in the Investigator Site File should be kept up to date

11. Consent Withdrawal
All patients have the right to withdraw from the study at any time without giving a reason
If a patient indicates they wish to withdraw from the study the level of withdrawal needs to be established (i.e. consent for further treatment or withdrawal from the study as a whole)
Please record clearly in the patient’s notes the request for withdrawal and level of withdrawal
Complete the Consent Withdrawal Form and send to CRUK CTU Glasgow
No further follow-up should be collected from this patient from the date of withdrawal. The patient should be followed up as per local site practice. SAEs should still be reported for 30 days post last treatment.

12. Randomisation Process
All patients must be randomised onto the study prior to commencement of any treatment.
Check that patient has given written informed consent as per the informed consent process.
Check that patient fulfils eligibility criteria as per study protocol.
Complete Registration Form.
Site staff must contact the Cancer Research Clinical Trials Unit, Glasgow to randomise the patient. Registration to the study can be done by either telephone or fax on the following numbers:
Tel no:
Fax no: *
Mon-Thurs
Friday, except public holidays
* Faxes received outside of office hours will be processed the next working day
Each patient randomised will be allocated a unique sequential patient ID number for the study.

13. Pre Randomisation Evaluations
Within 12 weeks of trial entry the patient must have had surgery. The authorised pathology report must confirm microscopically clear surgical resection margins. A FFPE archival sample of tumour must be made available to the trial team for molecular profiling and further translational research. This can be sent after the patient has been randomised.
Within 12 weeks of trial entry a CT chest, abdomen and pelvis or CT chest and MRI abdomen and pelvis must be performed. If this is outside the required time window it must be repeated after the patient has given written informed consent for the trial.
Within 28 days of registration/randomisation written, informed consent must be provided.
Within 7 days of trial entry the following must have occurred:
Review of eligibility criteria
Medical history
Physical/Clinical assessment including height and weight
Clinical assessment of neuropathy (baseline)
Clinical assessment of sensorineural hearing impairment (baseline)
Body Surface Area
ECOG performance status
Baseline ECG
Haematology blood sample including coagulation profile
Biochemistry including U&E, LFTs, magnesium and GFR
Urine pregnancy test for all women of childbearing potential
Baseline QoL questionnaires – EQ-5D and EORTC QLQ-C30 and CR29
Archival blood sample for molecular profiling and future translational research
A questionnaire about underlying risk factors (e.g. Crohn’s disease, coelic disease, Lynch Syndrome etc.) will be completed at time of study entry

14. Treatment and Duration
Group 1: Stage I/II/III patients where there is uncertainty of the value of adjuvant chemotherapy
Patients in this group will be randomised 1:1 to adjuvant chemotherapy or observation. An initial choice must be made by the clinician or patient whether, if allocated to chemotherapy, they will receive either:
a) 24 weeks of 5-FU/FA or capecitabine
b) 24 weeks of 5-FU/FA or capecitabine + oxaliplatin
c) Either a or b allocated at random
For all options the fluoropyrimidine choice must be specified prior to randomisation (1:1)
For patients that are going into the observation v chemotherapy randomisation with the clinician’s choice of chemotherapy being used they should be consented and randomised to the study using patient information sheet A
For patients that are going into the observation v single agent chemo v double agent chemotherapy randomisation, i.e. will be contributing to both groups, they should be consented and randomised to the study using patient information sheet B
Group 2: Stage I/II/III patients where there is certainty of the value of adjuvant chemotherapy.
Patients in this group will be randomised 1:1 to 24 weeks of fluoropyrimidine based adjuvant chemotherapy with or without oxaliplatin. The choice of 5-FU/FA or Capecitabine must be specified prior to randomisation.
For patients that are going into the single agent v double agent chemotherapy randomisation they should be consented and randomised using patient information sheet C

15. Study Drugs
All drugs administered as part of the Group 1 & 2 randomisations are considered Investigational Medicinal Products (IMPs) for the purposes of this protocol.
All trial drugs for use in the trial should be taken from usual pharmacy stock; there is no provision for funding, reimbursement or discounted stock. Shelf stock will not require IMP labelling but all IMP being dispensed to patients must be labelled at site, at the time of dispensing, in accordance with all applicable regulatory requirements
Chemotherapy regimens will be administered as per institutional standard care and are the choice of the Principal Investigator at that site.

16. BALLAD Chemotherapy Regimens
The choice of regimen should be notified to CRUK CTU at the time of randomisation. The suggestions below are for guidance and differences in standard practice are permitted which must be notified to sponsor at the time of initiation.
IV Fluoropyrimidine regimens (every 2 weeks):
Folinic acid 350mg IV over 2 hrs
5-FU 400mg/m2 IV over 10 mins
5-FU 2400mg/m2 IV over 46 hrs
Oral Fluoropyrimidine regimens (every 3 weeks):
Capecitabine 1250mg/m2 PO BD for 14 days
IV Combination Fluoropyrimidine regimens (every 2 weeks):
Oxaliplatin 85mg/m2 IV over 2 hours
Oral Combination Fluoropyrimidine regimens (every 3 weeks):
Oxaliplatin 130mg/m2 IV over 2 hours
Capecitabine 1000mg/m2 PO BD for 14 days

17. Concomitant Therapies/Medications
The use of calcium or magnesium supplements is prohibited during oxaliplatin administration.
Surgery is allowed during the trial for adhesive or other obstruction, intercurrent other disease or for any other clinically appropriate reason. Continuation of adjuvant chemotherapy where appropriate may be permitted following discussion with the CI or his approved representative.
Radiotherapy is not permitted during the trial.
Drug Interactions
This list is not intended to be comprehensive, and local practice and guidelines and SmPCs should be followed for management of all other drugs. 
Warfarin - It is recommended that patients DO NOT receive concomitant capecitabine and warfarin.  
Phenytoin - Patients taking phenytoin concomitantly with capecitabine or 5-FU should be regularly monitored for increased phenytoin plasma concentrations
Allopurinol - Concomitant use of allopurinol with capecitabine should be avoided.
Antivirals - Brivudine and sorivudine MUST NOT be prescribed with capecitabine
Live Vaccines - Vaccination with a live vaccine should be avoided in patients in patients receiving 5-FU or oxaliplatin
Photosensitivity - In patients treated with 5-FU, prolonged exposure to sunlight is not advisable because of the risk of photosensitivity

18. Dose Modifications
Dose delay and dose reduction of all IMPs will be carried out as per institutional standard care (and SmPC for capecitabine). The suggestions below are for guidance, and can be discussed with the CI or his approved representative.
If any grade 1 toxicity occurs as a result of chemo, then treatment will be continued, without interruption, at full dose. For all non-haematological treatment related toxicities ≥ grade 3, treatment should be withheld until recovery to ≤ grade 1 then restarted commencing as day one of the next cycle, if medically appropriate.
If patients take more than 4 weeks to recover from chemotherapy related toxicity they will receive no further protocol mandated treatment, but will still be followed up as per the BALLAD protocol.
Wherever possible, Oxaliplatin should be dose reduced (at investigator’s discretion) rather than discontinued and can be given over a longer period of time. In the situation where Oxaliplatin is discontinued due to toxicity, adjuvant treatment can continue with 5-FU or Capecitabine alone if deemed appropriate. In this case, the dose per m2 of the single agent fluoropyrimidine can be increased to the standard single agent dose of that drug as per local practice at the discretion of the Investigator. Patients will still be considered to be on BALLAD protocol treatment and will be followed up as per the BALLAD protocol.
Crossover from Capecitabine to IV 5-FU and vice-versa is permitted if this is required to control toxicity. This crossover should be managed as per institutional standards.
For toxicities or combinations of toxicities not specifically covered in detail in this protocol, doses of chemotherapy can be reduced at the discretion of the Investigator as per local practice.
Any dose modifications must be recorded on the CRF and documented in the patient notes.

19. Dose Modifications – Haematological toxicity
The following dose modifications are provided as a guideline in the event of a haematological toxicity, however Investigators are permitted to follow their local practice for the management of haematological toxicity, with all dose modifications fully documented in the patient’s medical records and CRFs.
For patients on 3 weekly chemo
Neutrophils
Platelets
Dose Modification
≥1.5 x 109/l
and
≥75 x 109/l
None
<1.5 x 109/l
And/or
<75 x 109/l
Delay until both neutrophils and platelets are above these limits and dose reduce as below
For patients receiving Capecitabine only – modify as per SmPC
For patients receiving Capecitabine and Oxaliplatin
If > 1 delay or 1 delay of ≥>2 weeks reduce Capecitabine and Oxaliplatin doses by 25% and continue at lower dose for subsequent cycles
If further delays occur after dose reduction further reductions can be made
Following cycle 1
If on cycle 2 day 1 neutrophils are between 1 and 1.5 delay until recovery then reduce dose by 25%
If on cycle 2 day 1 neutrophils are between 0.5 and 1 delay until recovery then reduce dose by 50%
If on cycle 2 day 1 neutrophils are < 0.5 discontinue treatment
If patient delayed for 4 weeks or more study treatment will be discontinued
G-CSF management of neutropenia will be at the discretion of the local Investigator.

20. Dose Modifications – Haematological toxicity
The following dose modifications are provided as a guideline in the event of a haematological toxicity, however Investigators are permitted to follow their local practice for the management of haematological toxicity, with all dose modifications fully documented in the patient’s medical records and CRFs.
For patients on 2 weekly chemo
Neutrophils
Platelets
Dose Modification
≥1.0 x 109/l
and
≥75 x 109/l
None
<1.0 x 109/l
And/or
<75 x 109/l
Delay until both neutrophil and platelets above these limits and dose reduce as below
For patients receiving 5-FU only – modify as per local policy
For patients receiving 5-FU and Oxaliplatin
If > 1 delay or 1 delay of ≥2 weeks maintain oxaliplatin and IV 5-FU doses but omit 5-FU bolus and continue without bolus for subsequent cycles
If further delays occur despite omitting bolus reduce the oxaliplatin and infusion 5-FU doses by 25%.
Following cycle 1
If on cycle 2 day 1 neutrophils are between <1 reduce dose by 25% (and omit bolus for OxMdG regimen)
If on cycle 2 day 1 neutrophils are ≤ < 0.5 investigators may at their discretion reduce dose by 50% (and omit bolus for OxMdG regimen)
If patient delayed for 4 weeks or more study treatment will be discontinued
G-CSF management of neutropenia will be at the discretion of the local Investigator.

21. Dose Modifications – Neurosensory toxicity
The table below gives recommendations. Please see section for full details
Acute dysasthesia of the larynx may be mitigated by slowing the rate of infusion of oxaliplatin.
Regimen
G1 or G2 (if G2 ≤7 days)
G2 >7 days G3 G4
5-FU & Oxaliplatin
Full dose oxaliplatin
Reduce Oxaliplatin 25%
Discontinue Oxaliplatin
Capecitabine & Oxaliplatin

22. Dose Modifications – Diarrhoea
The table below gives recommendations. Please see protocol section for full details
Grade 2
Grade 3
Grade 4
1st occurrence
Withhold 5-FU/Capecitabine until recovered to grade Restart at full dose
Withhold 5-FU/Capecitabine until recovered to grade Restart with 25% dose reduction
Discontinue all treatment or interrupt to recovered to grade Restart with 50% dose reduction
2nd occurrence
Withhold 5-FU/Capecitabine until recovered to grade Restart at 75% of dose
Withhold 5-FU/Capecitabine until recovered to grade Restart at 50% dose
Discontinue treatment
3rd occurrence
4th occurrence

23. Dose Modifications – Other reasons
Please refer to protocol section for dose modifications related to respiratory toxicity, stomatitis, hand-foot syndrome, allergic reactions to oxaliplatin, oxaliplatin induced laryngeal spasm and abnormal liver function tests.

24. Translational Research
FFPE sample which will have been obtained at surgical resection of patient’s primary tumour prior to entry into BALLAD should be sent to Belfast for future research
One additional blood sample will be taken– a 5ml serum sample and 2 x 9ml EDTA samples (for DNA) from each patient who consents to this. If possible we would prefer it if these bloods could be taken prior to starting the adjuvant therapy.
Please refer to lab manual in Investigator Site File for full details of translational sampling

25. Assessment Evaluations While on Trial Treatment
Prior to each cycle of chemotherapy the following tests should be performed:
ECOG performance status
Toxicity Assessment (only toxicities which are grade 2 or above require entry to the CRF)
Clinical assessment of neuropathy should be performed at all study visits (oxaliplatin patients)
Clinical assessment of sensorineural hearing impairment should be performed at all study visits (oxaliplatin patients)
FBC & Biochemistry including U&E, LFT, magnesium and GFR (from cycle 2 onwards pre-cycle bloods should be performed within 2 days of treatment. For patients on anti-coagulant therapy, clotting factors should be tested at each chemotherapy visit)
QoL questionnaires (at 3 and 6 months post randomisation) 
If a patient stops their allocated treatment early or if the patient experiences treatment delays the BALLAD follow-up visits will still be due as per the protocol schedule i.e. timed relative to date of randomisation. This is the required procedure even if the patient has experienced treatment delays and is still receiving chemotherapy treatment.
Evaluations for patients on observation only: From randomisation to 6 months
Patients who are randomised to observation will only have a visit at 3 and 6 months post randomisation. At these visits the following will be performed:
FBC & Biochemistry including U&E, LFT, magnesium and GFR
QoL will be completed

26. Follow-Up Follow-up Evaluations
Patients will be followed up 9 months post randomisation and 12 months post randomisation. After that they will have visits on a six monthly basis until 3 years post randomisation and will then have annual visits for up to 7 years post randomisation. 
Follow-up CT Scanning
CT Chest Abdomen and Pelvis will be performed 12, 24 and 36 months post randomisation. (CT Chest, abdomen and pelvis is the preferred method of assessment but MRI abdomen and pelvis with chest CT may be used instead). Additional CT scans may also be conducted as clinically indicated based on symptoms, clinical markers or to accommodate sites usual scanning regimen.  
CT scans performed within 42 days of the follow-up visits may be used for disease assessment. If the time interval from CT to follow up visit is more than 42 days a new CT scan should be performed.
If a patient has reached the primary endpoint of the trial and has a recurrence or a new primary tumour (CT confirmed) then further protocol mandated CT scans are no longer required.  
Follow-up Quality of Life Assessments
EORTC QLQ-C30 and CR29 will be completed at 9, 12, 18 and 24 months post randomisation for all arms of the trial. 
The EQ-5D will be completed at 9, 12, 18, 24, 30, 36, 48, and 84 months post randomisation for all arms of the trial.
For patients that have a recurrence or have a new primary tumour the quality of life questionnaires should continue to be completed as per schedule of assessments provided it is deemed appropriate to ask the patient to do so.

27. CRFs Patients Randomised to the study Randomisation Form
Risk Assessment Questionnaire
Pre-treatment Form
QoL EORTC CLQ-C30 & CR29
QoL EQ-5D
Treatment Form
Response Form
Follow–up Form
Consent Withdrawal Form
Pregnancy Notification Form
Patient Transfer Form
Patients Registered to the study
Registration Form
Risk Assessment Questionnaire
Chemo Form
Follow–up Form
Consent Withdrawal Notification Form

28. CRF Completion
CRF completion guidelines for the study will provided to sites when available
Entries to the CRFs will be made in black ball-point pen and must be legible
Correction fluid etc. must not be used
Any errors must be crossed out with a single stroke, correction inserted and change initialled and dated
An explanation can be written next to amendment if necessary
Date format: DD/ MON/ YYYY
Please ensure all data submitted on the CRFs is verifiable in source documents
Take photocopy of all completed CRFs. Originals to be sent to CRUK CTU Glasgow

29. Pharmacovigilance Clinical Trial Regulations require:
Investigators document Adverse Events (AEs) in patient notes and the CRF
Investigators report Serious Adverse Events (SAEs) immediately and within a maximum of 24 hours to the CRUK Clinical Trials Unit, Glasgow (CTU)
The CTU (on behalf of the Sponsor) make expedited reports of Suspected Unexpected Serious Adverse Reactions (SUSARs) to the Regulatory Authority (MHRA), REC & Sponsor
The CTU and CI will produce the Development Safety Update Reports (DSURs)
All AEs must be followed:
- until resolution,
- or for at least 30 days after discontinuation of study medication,
- or until toxicity has resolved to baseline,
- or < Grade 1,
- or until toxicity is considered to be irreversible
All AE and toxicities must be graded according to the NCI-CTCAE Version 4.0
An exacerbation of pre-existing condition is an AE
All AEs must be recorded in full in the patients notes with the nature of the event, start and stop dates, severity, seriousness and causality to each study drug and outcome

30. Definition of a SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence, not necessarily related to protocol treatment, that:
Results in death
Is life-threatening (patient is at immediate risk of death from the event as it occurred)
Requires hospitalisation or prolongation of existing hospitalisation (hospital admission is required for treatment of that adverse event, even with the adverse event is not related to protocol treatment)
Results in persistent or significant disability or incapacity
Consists of a congenital anomaly or birth defect
Is considered medically significant by the Investigator

31. Reporting SAEs
SAEs must be reported immediately (within a maximum of 24 hours of knowledge of the event)
SAEs are reported using the CRUK CTU SAE report form
Site must complete the BALLAD SAE report and fax to PV office –
The CTU will acknowledge receipt of each new initial report and create SAE reference number for the event
CTU will raise queries for any inconsistent or missing information
SAEs are required to be reported locally as per your local practice (i.e. to ethics committee, local R&D)
SAEs are required to be reported for up to 30 days after stopping study drugs and ad infinitum if related to the trial drugs/ participation and are medically significant

32. Procedure for Reporting SAEs and SAE Report Processing
CTU generates DCF queries
Patient SAE and SAE form completed
Site complete SAE report form
Patient SAE and SAE form completed
CTU fax queries to reporting site
Patient SAE and SAE form completed
Site fax SAE report to CTU Fax
Patient SAE and SAE form completed
Site resolves queries
Patient SAE and SAE form completed
CTU generate SAE reference number
Patient SAE and SAE form completed
Patient SAE and SAE form completed
Site queries to be signed by Principal Investigator or delegated doctor
Patient SAE and SAE form completed
CTU fax SAE report acknowledgment receipt to site
Yes
Is SAE related
to IMA?
CTU
DCF queries required?
Patient SAE and SAE form completed
Site fax queries to CTU Fax
Patient SAE and SAE form completed
CTU data entry of SAE report onto trial database No
CTU queries entered onto trial database
Patient SAE and SAE form completed
CTU edit check of SAE report data
Patient SAE and SAE form completed
CTU Data checked final edit check generated
Patient SAE and SAE form completed
Patient SAE and SAE form completed
CTU checks SAE report data
SAE Data Flow Version 24 Oct 2014

33. Procedure for Identifying Unexpected and Related Events
A checklist will be used to identify SUSARs for expedited reporting to the Regulatory Authority, REC and Sponsor
The checklist is a list of the events expected to occur in patients receiving the study drugs in the SmPCs that have approval to be used as the Reference Safety information (RSI). For any SAE that is documented as related to protocol treatment (SAR) and is not listed on the checklist, the Chief Investigator will be contacted for an opinion of SUSAR status (unexpectedness)
The Chief Investigator is responsible for deciding if a SAR requires expedited reporting
SAEs that meet the criteria for SUSARs will be reported to the MHRA, REC and Sponsor where in the opinion of the Chief Investigator the event was:
Related (resulted from administration of any of the research procedures)
And
Unexpected (type of event is not listed in the SmPCs acting as the reference
safety informationas an expected occurrence)
 Reports of related and unexpected SAEs will be submitted within 7 days for fatal/life threatening events and 15 days for all other events. Sites will receive line listings of all new SUSARs on a regular basis

34. On-site and Remote Telephone Monitoring
Central Monitoring
Study sites will be monitored centrally by checking incoming forms for compliance with the
protocol, data consistency, missing data and timing. Study staff will be in regular contact with site
personnel (by phone/fax/ /letter) to check on progress and deal with any queries that they
may have.
On-site and Remote Telephone Monitoring
The 1st visit will take the form of a remote telephone monitoring visit:
The time & date will be agreed with a member of the Site Study Team & a separate time & date agreed with a member of the Clinical Trials Pharmacy Department
A pro forma covering the questions which will be covered during the telephone monitoring visit will be sent with confirmation of the confirmation of the agreed date
Please set aside 50 to 70 minutes for this call.

35. MONITORING (2)
The 2nd visit will take the form of an on site monitoring visit:
Investigators and site staff will be notified in advance about forthcoming pre arranged monitoring visits
All patient source documentation should be made available to enable Source Document Verification by the Clinical Trial Monitor
A full working day is required for on-site visits & arrangements should be in place to facilitate the monitor access on the agreed date
If sites are able to provide printed results/reports these must be filed in the source documents
If a site is using electronic data reporting systems or electronic records & hard copies are not available the clinical trial monitor must be permitted access to the system either by being issued with a temporary login or a member of staff available for the duration of the visit to facilitate electronic access to authorised reports/results
The pharmacy department responsible for the trial will be visited to allow monitoring of the pharmacy site file and review of security, storage and accountability of trial drugs.
All findings will be discussed at an end of visit and any unresolved issues raised as Action Points
Action Points will be followed up by the monitor until resolved

36. Investigator Responsibilities (1)
The following principles are from ICH GCP Topic E6 and apply to clinical trials of Investigational Medicinal Products:
Qualifications & Agreements:
- The Investigator should be qualified by education, training & experience.
- Thoroughly familiar with protocol & medicinal products.
- Comply with GCP and applicable regulations.
- Permit monitoring and audit by the sponsor and inspection by regulatory authorities.
- Maintain a delegation log of staff involved in the clinical trial at the trial site.
- Ensure that all persons assisting with the trial are adequately informed about the protocol, IMP and their duties and functions.
Resources:
- The Investigator should have sufficient time to properly conduct and complete the trial within the agreed period.
- Have available adequate facilities and qualified staff to conduct the trial properly and safely.
Medical Care of Trial Subjects:
- A qualified physician who is an Investigator (or co-investigator) should be responsible for all
trial related medical decisions.
- During and following participation the Investigator should ensure adequate medical care for
any adverse events (AEs).
- The Investigator should make as reasonable effort to ascertain reasons for withdrawal from the
trial (although a subject is not obliged to give reasons)

37. Investigator Responsibilities (2)
Ethics:
- Before initiating the trial there should be written and dated approval/favourable opinion
from the Ethics Committee for the protocol, patient information sheet/consent form and any amendments.
Compliance with Protocol:
- The Investigator should conduct the trial in compliance with the protocol.
- Not implement any deviation from the protocol without prior approval/favourable opinion of the IEC and the sponsor.
- The Investigator should document and explain any deviation from the protocol.
The IMP :
- Investigator has responsibility for IMP accountability at trial site
- Some/all IMP duties at the trial site may be assigned to suitably qualified pharmacist.
- Records must be maintained
- Storage of the IMP should be as specified by the regulatory requirements.
- The Investigator (or designee) should explain the correct use of the IMP to each patient.
Randomisation:
- The Investigator should follow the trial’s randomisation procedures as detailed in the protocol.
Informed consent:
- In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement (s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki.

38. Investigator Responsibilities (3)
Reports & records
– The investigator is responsible for accuracy, completeness, legibility and timeliness of the data reported to the sponsor.
- Data reported on CRFS, from source documents should be consistent with source documents or discrepancies explained.
- Corrections should be : dated, initialled, explained (if necessary) and should not obscure the original entry.
- All trial documents should be maintained as specified in ICH GCP E6, Section 8 (Essential documents for the conduct of a clinical trial).
Safety reporting:
- Investigators must report Serious Adverse Events to the sponsor as soon as they become aware of the event.

39. Other Site Staff
The Principal Investigator has overall responsibility for the conduct of the clinical trial
at the trial site.
BUT
All staff must comply with GCP.
Staff should only perform tasks delegated to them.
Staff should ensure that their details are available to the Investigator.
Staff should maintain appropriate confidentiality at all times

40. CONTACT DETAILS FOR CRUK CTU Glasgow
Project Manager Trial Coordinator
Judith Dixon-Hughes Anna Morris
Tel: Tel:
Fax: Fax:
Pharmacovigilance
Pharmacovigilance Manager Pharmacovigilance CTC
Lindsey Connery Susannah Radford
Tel: Tel:
Fax: Fax:
CRUK CTU, Glasgow
Cancer Research UK Clinical Trials Office
Level 0, Beatson West of Scotland Cancer Centre
1053 Great Western Road, Glasgow, G12 0YN