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Transcript of Drug Management and IXRS training. 2 * Exception being Peru (country specific label) and Japan (bulk...
![Page 1: Drug Management and IXRS training. 2 * Exception being Peru (country specific label) and Japan (bulk shipment into Japan, final labeling at Chugai) BO25114.](https://reader031.fdocuments.in/reader031/viewer/2022020208/56649e7e5503460f94b824d3/html5/thumbnails/1.jpg)
Drug Management and IXRS training
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2 * Exception being Peru (country specific label) and Japan (bulk shipment into Japan, final labeling at Chugai)
BO25114 • Packaging/Labeling of IMPs
Pertuzumab (active/placebo)
420 mg vial, labeled with a Multilanguage booklet label*
First study to use a 2 vial/box packaging configuration, which is enough for one dose in a cycle
Storage condition: 2ᵒC – 8ᵒC, protect from light
2 x 420 mg vials
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Pertuzumab/Placebo
Withdraw from vial and add to 250 mL IV bag (PVC or non-PVC polyolefin bags) of 0.9% sodium chloride solution for injectionGently invert the bag to mix the solution - DO NOT SHAKE VIGOROUSLYAdminister as a continuous IV infusion. A rate-regulating device may be usedUse 50ml 0.9% sodium chloride for injection to completely flush the IV tubingDiluted solution should be stored refrigerated (2ᵒC − 8ᵒC) for no more than 24 hours
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BO25114 • Packaging/Labeling of IMPs
Trastuzumab (open label)
150 mg vial (440 mg vial for US & China only), labeled with Multilanguage booklet label*
Packaging configuration = 1 vial per box
Storage condition: 2ᵒC – 8ᵒC
150 mg
150 mg
* Exception being Peru (country specific label) and Japan (bulk shipment into Japan, final labeling at Chugai)
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Trastuzumab
Mix trastuzumab 150-mg vial with 7.2 mL of SWFI (Sterile Water for Injection n.b. not supplied by sponsor)Use of other reconstitution solvents is not permitted Reconstituted solution contains 21 mg/mL trastuzumab • Volume (mL) = Body Weight (kg) × Planned Dose (mg/kg)/
21 (mg/mL, concentration of reconstituted solution)
Add reconstituted solution to 250 mL of 0.9% sodium chloride injection for administration to the patientOnce infusion prepared, administer it immediately• If diluted aseptically, infusion may be stored for 24 hours maximum at
2ᵒC−8ᵒC (36ᵒF−46ᵒF).
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BO25114 • Non-IMPs
Fluoropyrimidine (capecitabine OR 5-FU)
Platinum drug (cisplatin)
Non-IMP will NOT be managed by IXRS
Follow local pharmacy SOP/procedure with regard to non-IMP management
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Patient diary of Capecitabine
It is mandatory to use ‘Capecitabine Patient Diary’ if patient takes capecitabine
To be more user friendly, patients are required to document when a dose is missed or only partial dose has been taken
Study nurse/study coordinator will calculate total dose which patient has taken and transfer data to eCRF
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Drug Arrival at Site
Pharmacist/Study Coordinator to: Unpack shipment Check contents and condition of shipment (damage, quantity)Complete Consignment Form enclosed in the shipment with:
Actual time/date of arrival and
unpacking at site
Condition of shipment at arrival
Place study drug in monitored fridge (2ᵒC– 8ᵒC), do not freeze, use temperature logRegister IMP as arrived in IXRS using completed consignment as reference
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Depot to Site ShipmentsTemperature/Time Deviations during shipment
If arrival time later than latest acceptable time of arrival and unpacking indicated on red label:
When you try to acknowledge this shipment in IXRS, system automatically puts medication in quarantine
Medication must be stored “in quarantine” at site
Site should inform monitor
Attention:Cold Chain Information
Consigment #: Number of Boxes:If this shipment arrives at your site after:
Year Month Day Hour Minute
YYYY-MM-DD, hh.mm(Local Date) (Local Time, 24-Hour Clock)
Please do:• Place the good in quarantine storage at the correct
storage condition• Contact your monitor for further instruction
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Temperature Deviations during storage at site
Temperature sensitive study medication is expected to be stored at 2-8ᵒC in monitored refrigeratorShould the site note a temperature deviation, key question site must ask is:
How long and how many degrees did the study drug deviate from 2–8ᵒC?
Next step depends on which of the following categories applies:1. Deviation within 1-15ᵒC and ≤ 20 minutes2. Deviation within 1-15ᵒC and > 20 minutes and ≤ 4 hours3. Deviation outside 1-15ᵒC or within 1-15ᵒC but > 4 hours or total sum
of time deviations > 4 hours despite being within 1-15ᵒC
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Temperature Deviations during storage at site
1. Deviation is within 1-15ᵒC and ≤ 20 minutes
Site must call monitor and report temperature/time deviation
Monitor needs to take no further action
Monitor may authorize site to continue to use study medication
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Temperature Deviations during storage at site
2. Deviation is within 1-15ᵒC and > 20 minutes and ≤ 4 hrs
Site must report temperature/time deviation to monitor by completing PD103
Upon receipt of PD103, monitor completes ‘Final Assessment’ and authorizes continued use of study drug by signing PD103 and sending back to investigator
PTDQ does not need to be notified
Copy of signed PD103 is archived in investigator’s files and the local trial master file at the affiliate/CRO
Original to be sent to PDR-CDC
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Status ofmedication
in IXRS: Temperature Deviation ‘Available’
‘Rejected’
Releasemedication
in IXRS
Reject medication
in IXRS
Site informsMonitor
Monitor
Monitor
Yes
Nox
Register medication
‘in quarantine’in IXRS
Monitor tocheck with PTDQif the medication
can be used
Temperature Deviations during storage at site3. Deviation is outside 1–15ᵒC or within 1–15ᵒC but > 4 hrs
Monitor
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Drug Destruction
IMPs should be destroyed locally at the investigational site in accordance with study and site procedures and local regulations or returned to local or supplying Depot for destruction
Authorization for Onsite IMP Destruction Memo will be provided by Roche (signed by GSL). It must be filed in Pharmacy binder
Note to File (signed by investigator or designee) containing process must be filed in Pharmacy binder
Partially used or empty vials can be destroyed immediately (keep empty boxes)
Unused vials can only be destroyed after drugs reconciled by Monitor
Drug destruction must be documented accordingly in Drug Inventory/Dispensing Log
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Manage visit window
Randomization• Randomization should be within 28 days after screening
• Out of window = hard stop
• Contact CS/GSM for approval and authorization call
First dose (C1D1)• 1st dose should be within 3 days after randomization
• Out of window = soft stop
Subsequent dose (C2D1 to CXD1)
• Visit window is +/- 7 days
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Manage visit window-scenario
Scenario:
If dose delayed/missed on > 2 consecutive occasions, (i.e. duration between 2 doses greater than 9 weeks) patient will be withdrawn from study
Patient is dosed on C1D1
Patient missed doses on C2D1, C3D1 and on planned C4D1 visit, investigator still thinks patient should not be dosed
This patient will be withdrawn from the study
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IXRS training
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IXRS functionality
Subject Screening and Randomization
Drug Management
Collect screen patient (including screen failure patient) demographic information
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Accessing the IXRS and QRD
Each user provided with unique User ID and Password to the IXRS – via email
Upon initial access, user will be prompted to change their password• Please use a 7-digit password – no letters
Quick Reference Document (QRD, send together with user ID and password) provided to each user details of access information for each country and instructions.
BO25114
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Site user types within the study
Site User (Study Coordinator/pharmacist): Access to Acknowledge Consignment Receipt, and patient management throughout study/CLARA access to quarantine medication at site
Site User (Investigator): All study coordinator role PLUS Emergency Unblinding Module access
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IXRS Site User rolesSite User 1: Study Coordinator/pharmacistSite User 2: Investigator
Acknowledge study drug receipt
Patient Screening/Screen Fail
Patient Randomization
First Dose Date
Scheduled Drug Dispensing
Drug replacement
End Of Product/Early Discontinuation
Quarantine Medication at site (CLARA)
Screened Patient Demographic Module
Emergency Unblinding (Investigator only)
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Initial Shipment
Triggered when first patient screened at site(except South Korea)
1. Triggers prompt in system to raise initial consignment. Consignment is automatically sent to depot
2. Depot processes and dispatches consignment
3. Site receives 1st consignment and MUST confirm receipt in the IXRS ( or patient can’t be randomized)
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Menu Options in the IXRS
Register a new patient into study• Patient Screening
Activities relating to existing patients• Register this patient as screen failure• Randomize this patient into study• Register First Dose• Scheduled Drug Dispensing• Register the end of product/early discontinuation• Product Replacement• Screened Patient Demographic Module
Confirm receipt of product
Emergency Unblinding
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Main Menu
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Each menu option in IXRS requires an input and may produce an outputAll transactions will produce a confirmation sent to the users’ fax or email
IXRS Patient Transactions
PatientScreening
INPUTS OUTPUTS
• Screening date• Informed consent• Informed consent date• Consented to Roche
Clinical Repository• DOB• Gender• MetGastric study screen
number ( if applicable)
• Confirmation fax/email• Screening number
• Screen failure reason code • Confirmation fax/emailPatientScreen Failure
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Initial Patient Entry(Screening)
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IXRS Patient Transactions
Patient Randomization
INPUTS OUTPUTS
• Stratification:− HER2 positivity− Prior gastrectomy
• Patient weight
• Confirmation fax/email• Patient number• Medication number/
Batch ID for cycle 1
• Date of first dose • Confirmation fax/email
• Patient weight• Confirmation fax/email• Medication number/
Batch ID
Each menu option in IXRS requires an input and may produce an outputAll transactions will produce a confirmation sent to the users’ fax or email
First Dose
Scheduled Drug Dispensing
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Randomization
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Scheduled drug dispensing
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Scheduled drug dispensing
Output of this module
Pertuzumab:
Medication number link to a unique kit (only one kit assigned which contains two vials for one dose)
Trastuzumab:
Batch ID
Quantities of vials
Recommend dose for this infusion (calculated by latest body weight)
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Each menu option in IXRS requires an input and may produce an outputAll transactions will produce a confirmation sent to the users’ fax or email
IXRS Patient Transactions
INPUTS OUTPUTS
• End of product date• Primary reason • Confirmation fax/email
• Patient screen number• DOB • Treatment arm
End of Product
Unblinding
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Patient unblinding
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Late Randomization
If you want to randomize the patient >28 days from screening
Contact clinical science/GSM & provide justification
Clinical science approve
GSM makes the authorization call in the system
Investigator then randomizes patient
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Patient flow
* If the patient is not dosed on the date of randomization
If the patient is unblinded, then the patient should be end of the treatment
If the patient is screen failure
Screen Randomization Scheduled drug dispensing
End of treatment/
early withdraw
Screen failure *First dose date Emergency unblinding
Screen patient demographic module part 1
Screen patient demographic module part 2
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Screened Patient Demographic Module
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Screened Patient Demographic Module
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Confirmation Emails/Faxes
All transactions performed either via web or phone automatically produce a confirmation email or fax once completion of event is successful
These confirmation emails/faxes contain key details from the registered event. If correction required to data, line should be drawn through error, correct data added, signed and dated and returned to Almac Clinical Technologies. Contact your monitor first!
Patient Number: 330101Date of Birth: 05-Jun-1976
Database will be corrected by project team and updated fax sent back to site in return
If confirmation email/fax missing, these can be obtained directly from web
05-Jun-1972AB 23/09/2012
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Technical Support
Phone: Through IXRS or 1-877-738-8831AT&T Language Line is available if required
E-mail: [email protected]
Project Manager: Jonathan CousinsDesign & Implementation of IXRS
Project Manager: Hilary RossMaintenance of study IXRS
Detail can be found in QRD
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BO25114 Cardiac Event Review
& Patient-Reported Outcomes Training
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Review of CRCC procedures
What is the role and responsibility of: • Cardiac Review Committee and • Cardiac Review Committee Coordinator
What is the process for:• Reporting and sending clinical events• Collecting document collection
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Role and responsibility of CRC and CRCC
CRCPatients with potential cardiac events (e.g. symptomatic LVSD) per investigator assessment will be reviewed by independent external Cardiac Review Committee (CRC)• CRC provides independent blinded central determination of symptomatic
declines in LVEF and definite and probable cardiac deaths for reporting to IDMC
CRCC (Duke Clinical Research Institution) is the vendor who will: Raise queries using RAVE (10 day turnaround)Request/collect source documents via emailEnsure relevant variables are cleanPrepare event packetsRecord CRC adjudicationsCoordinate CRC adjudication meetings
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Overview of the CRCC Process
Investigator
CRCC
RAVE/DM/SC CRC
IDMCSource
Report
event packet
AdjudicationQuery
Notify
• Identified by site upon completion of eCRF (edit check)• Potential unreported events identified through SAEs• Potential unreported events identified through AE review or discovered during Clinical
Data Review• Potential unreported events discovered by monitor• Potential unreported events discovered by CRCC/CRC
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Potential source documents to be collected
Physician progress or consultation notes
Discharge summary
ECG tracing and report
ECHO/MUGA/cardiac MRI report
Chest X-ray report
Any other documents that CRCC deems necessary for case adjudication, e.g. cardiac catheterization report
• CRCC will be responsible for document translationif in language other than English
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Patient Reported Outcomes training
What are PROs and why are we measuring them?
Questionnaires used in this study
Timing of PRO Administration
Implementation
Do’s and don’ts
Summary
Recap Quiz
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Patient Reported Outcomes (PROs)
What are they?Standardized scales (e.g., those that have undergone rigorous testing for their reliability and validity in patients) that measure Health-Related Quality of Life (HRQoL), symptoms of disease under study and/or treatment side effects of an individual patient
Why are we measuring them?To compare general and disease-specific Quality of Life between patients treated with pertuzumab + TFP relative to placebo + TFP
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Objective for Trial Assessments
EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and Gastric Cancer Specific Module (STO-22)PRO Objective: Assess and compare HRQOL and improvement in
disease related symptoms, while assessing the side effects of therapy between treatment arms
EuroQol 5 Dimension (EQ-5D) ScalePRO Objective: Assess and compare health utility scores for
economic models
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ReconciliationResponses with Adverse Events
Results of the QLQ-C30/STO22 will not be reconciled with Adverse Event reporting, and data should not be used to solicit AE reports
Refer to section 5.3.5.12 of the protocol
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Timing of PRO Administration
Collect these data:Before patient sees investigator or interacts with any healthcare providerBefore any questions are asked related to health or concurrent illness
PROs are completed on Day 1 of each cycleCompleted during post-treatment monitoring visits
Screening/Baseline
Cycle
Post-treatment
MonitoringVisit 1
1 2 3 4 5 6 7 8 9+
Day -28to -1
-7to -1 1 22
(± 7)43
(± 7)64
(± 7)85
(± 7)106(± 7)
127(± 7)
148(± 7)
169+(± 7)
Patient-Reported Outcomes
● ● ● ● ● ● ● ● ● ●
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Importance of Complete PRO Data Set
PROs scheduled at regular intervals throughout the trial
Data must be complete for it to provide the most accurate picture of health status in longitudinal analysis
This trial has a small sample size thus it is imperative we have data on every patient in order to draw meaningful conclusions
Therefore, it is critical that information is obtained from all patients at all scheduled dates,
including when they are off study treatment
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Instructions for Site Coordinators: General Admission Guidelines
Patients should complete questionnaire without assistanceFamily members or other care-givers who come to clinic with patient should not be permitted to interact with patient during this periodIf patient needs help, study staff should help, not spouse, friend, or family memberIf patient does not understand a question, coordinator/site staff should read the question verbatim, without interpreting or offering suggestions for appropriate answersIf patient unable to complete questionnaire [e.g. reading problems, forgot glasses, too frail], interview assessment is allowed by study staff prior to healthcare intervention
• In this case, note if interview was conducted on the “other” field of the header under reason for 'not done' – write “interview administered”
Questionnaires should never be mailed to patients
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Instructions for Site Coordinators:Quality Assurance
Check for completeness • Questionnaires must be reviewed for completeness (missing items)
before patient leaves clinic and before any physical health assessment procedures undertaken• Remember, once patient leaves the site, missing data are not
recoverable!
If a patient made an error:• Have patient make corrections by placing one line through incorrect
response and then marking correct response• Ask patient to initial and date corrections on worksheet/source
document
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Instructions for Site Coordinators:Quality Assurance (cont.)
If a subject has left an item blank:• Encourage patient to give his/her opinion• Do not force subject to provide response and note that subject refused to
respond to the item or questionnaire if that is the case
If a patient prefers not to answer specific questions or entire questionnaire despite a reminder from Study Coordinator:• Do not further encourage patient to provide the answer • Note directly on questionnaire next to item that patient prefers not to
answer the item• If whole questionnaire left blank, check off the “Not Done”
box and specify e appropriate reason why: “Patient refused”
The questionnaire responses will be transcribed into the eCRF by the Study Coordinator
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Monitor Responsibilities
To train coordinators to administer the questionnaires and to check if they were administered properly
To provide translated questionnaires to sites as needed and to communicate any new language requests in timely fashion to Roche study team
To review eCRF data for accuracy of transcription from worksheets (per TMP)• To review representative number of questionnaires
• To review completion rates, evaluate compliance, follow up with sites who have not administered questionnaires immediately
To report findings from reviews to the Roche team on a regular basis
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PRO Guidelines Summary: Do’s
Administer questionnaires prior to asking any questions related to health or concurrent illnesses
Emphasize importance of their contribution to the study
Use validated version of patient’s primary language
Thank patient for their time and effort
Inform patient that they will be asked the same questions at next study visit
Immediately review the questionnaires for completeness
Make sure that patient completes paper worksheet, and that data are accurately transcribed into the eCRF
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PRO Guidelines: Don’ts
Do not discuss patient’s health status or emotions prior to administration
Do not force patient to respond to any question
Do not interpret or explain a question
Do not allow family members or friends to complete the questionnaire for patient, or to interact with patients while completing the questionnaires
Do not allow staff members to complete the questionnaire for patient*
* Except in rare cases addressed previously
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Clinical Site Monitoring
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Clinical Trial Monitor Responsibilities
Verify compliance with protocol, ICH/GCP guidelines, Federal regulations and Standard Operating Procedures
Support screening and recruitment activities
Communicate and oversee study timelines
Ensure study drug and clinical supplies are available and properly managed
Following study specific Trial Monitoring Plan
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Interactions with Site Staff
Remote (off-site) monitoring activitiesFrequency depending on study phase and site activities
On-Site monitoring activitiesTrigger for on-site monitoring visits: • 1st patient randomized• Issues/Risks identified• Accumulated workload
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Frequency of Remote Monitoring
During patient screening & randomizing:Every 4 to 6 weeks (can be more frequent, depending on number of patients screened/randomized or issues/risks identified)
Treatment phase:Every 6 to 8 weeks (can be more frequent, depending on number of patients randomized or issues/risks identified)
Follow-up phase:At least every 12 weeks (can be longer, depending on number of patients still in follow-up and follow-up visit frequency)
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Remote Monitoring Activities
Patient Recruitment
Review of data in eCRF
Non-IMP supplies and sample management
Site facilities
Data collection
Pertinent and essential documents
Source documents for cardiac safety review
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On-Site Monitoring Activities:Triggers for on-site monitoring
First patient randomizationVisit will occur as soon as possible after first patient randomization to study at your site
Urgent issues/risksThat cannot be addressed by the monitor via phone or email contact
Accumulated workload
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On-Site Monitoring Activities (cont.)
Informed Consent (for all patients)
Routine SDV and compliance checks
Equipment
Check pertinent and essential documents
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Tips for Good SDV and Record Keeping
Source Data Verification:Fully document ICF process in source documentsRetain and file all source documentsIf Monitor cannot use electronic source, certified copies of each unique document (not page) must be printed, signed and dated
Maintain complete & current file of:Enrolment logsEligibility Screening Forms (ESFs)Delegation of Responsibility FormsEC/IRB records and correspondenceSAE reports (ensure all SAEs are reported as per your IRB requirements)IXRS notifications and worksheets
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To ensure a successful Monitor visit
Adequate space for monitoring
Connectivity to internet
Completion of e-CRFs on an ongoing basis
Availability of e-CRFs and access to source documents
Access to regulatory documents
Access to study drug inventory documents
Investigator time and availability to meet with Monitor
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Study Specific TrainingSystems & Processes
RaveElectronic Data Capture (EDC) system
Targos:Tumor tissue HER2 testing
Covance: Central Lab, Sample shipment
IXRS Almac: Patient randomization, drug managment
Clinical Trial Portal (CTP): Distribution and tracking of SUSARs
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Q&A