drug management and ixrs training. 2 * exception being peru (country specific label) and japan (bulk...

Drug Management and IXRS training

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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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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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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17

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

IXRS training

20

IXRS functionality

Subject Screening and Randomization

Drug Management

Collect screen patient (including screen failure patient) demographic information

21

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)

25

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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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


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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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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38


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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

http://www.abselcom.com/products/virtual-call-center/

BO25114 Cardiac Event Review

& Patient-Reported Outcomes Training

42

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

43

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

46

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

47

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

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

60

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

drug management and ixrs training. 2 * exception being peru (country specific label) and japan (bulk...

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