CONFIDENTIAL

Genentech, Inc. Protocol GO27912

Covance Central Laboratory ProceduresNovember 2011

This document contains confidential and proprietary information and is the exclusive property of Covance Central Laboratory Services Inc. The reproduction, distribution, modification, performance or other use of this document, or any of the information contained herein, in whole or in part, without the express written

consent of Covance Central Laboratory Services Inc, is prohibited.

CONFIDENTIAL2

Presentation Training Objectives

• Ensure you understand the steps needed to ensure subject safety and increase the likelihood of having evaluable subjects at the end of the study

• Ensure your site has the collection kits and supplies needed throughout the study

• Use the collection kits according to protocol and visit schedule

• Ensure properly completed requisition forms so that specimens can be processed without delay

• Collect samples according to protocol requirements and accepted medical practices

• Optimize subject safety by minimizing test cancellations or missed visits

• Pack and ship specimens according to the procedures associated with your region and the needs of your study

• Contact Covance to order additional supplies or learn the answers to questions you might have

CONFIDENTIAL3

Central Laboratory Topics

• Supplies provided by Covance CLS• Collection kit use and inventory management• Requisition completion• Specimen collection and packaging• Courier arrangements• Contacting Covance CLS

This presentation provides specific details about:

CONFIDENTIAL4

Covance Central Laboratory Services

• Devoted exclusively to clinical trials• Combinable data• Global capabilities

Location Est.

Indianapolis, Indiana, USA

1986

Geneva, Switzerland

1992

Singapore 2000

Shanghai, China 2007

Kawagoe City, Japan

2010

CONFIDENTIAL

Supplies Provided By Covance CLS

CONFIDENTIAL6

First Covance CLS Communication

• Correct mistakes and enter any missing information

• Fax completed form to Covance CLS within 48 hours

• Ensures:– Study supplies shipped to

appropriate location

• E-mail addresses used only for study related issues – e.g., reminders of upcoming

holidays

Confirm site contact information

CONFIDENTIAL7

• To obtain the highest quality specimens possible, store collection supplies at the recommended +4°C to 25°C (+39°F to 77°F)

• Expired kits or kits/supplies in excess at end of study must be destroyed at site, do not return to Covance CLS

Visit-specific collection kits

Initial Supplies (1/4)

Visit

Screen,

CTC/CAP,

Arm C/D Urine DNA

C1D1,

C1D8Unscheduled

# Kits 3 kits each 2 kits each 1 kit

CONFIDENTIAL8

• Shipping boxes – Ambient and frozen for shipments to Covance

– Insulated ambient for shipments to Genentech

• CTC samples

• Site specific shipping documents – Air waybills, UPS shipping labels, Commercial Invoices,

return address labels

– Supplied in envelopes designated by shipping condition

Shipping supplies

Initial Supplies (2/4)

CONFIDENTIAL9

Initial Supplies (3/4)

• Generic• Provided in most local languages• Kit information tips• Requisition completion tips• Resupply• Inventory control tips

Quick Reference Guide

CONFIDENTIAL10

• Provided in English• Protocol-specific:

– Laboratory Visit Test Schedule

– Mock laboratory requisitions

– Specimen collection and processing information

• Packaging and shipping instructions• Laboratory certifications

– Renewals to be found at www.covance.com

• Holiday Observances• Covance CLS contact information• Courier contact information • Section to file Covance CLS communications

Covance CLS Investigator Manual

Initial Supplies (4/4)

Review manual prior to first subject visit

CONFIDENTIAL

Collection Kit Use and Inventory Management

CONFIDENTIAL12

Kit Inventory Review

• Lost, damaged or expired kits

• Check inventory carefully and request replacement kits• Allow enough delivery time before scheduling subjects • Inform Covance CLS of lost, damaged or expired kits to ensure

automatic resupply functions properly

Review for expired kits in preparation of visits

Expiration Date

Kits are automatically resupplied, except:

CONFIDENTIAL13

2. Investigator collects

specimen and ships to Covance CLS

4. Review of kits received. Resupply

is triggered by:•Kit inventory levels

•Patient’s visit schedule

1. Kits are shipped to

investigator site

3. Kits are received at

Covance CLS

Automatic Kit Resupply

Contact Covance CLS to adjust / stop

automatic resupply

CONFIDENTIAL14

Covance CLS Resupply Requests

• Replacement of damaged, lost or expired kits• Shipping supplies

• Secure website• Confirmatory e-mail sent providing

the work order reference number

Request the following supplies from Covance CLS:

Allow a minimum of 7 working days for the deliveryof your resupply order

Order supplies online:www.covance.com/kitordering

CONFIDENTIAL15

Accession Number

•• Protocol, site number and visit

name are encoded• Located on:

– Kit box

– Requisition

– Each tube and vial

• 1 Accession Number per kit• Reference this number with

queries to Covance CLS• Do not interchange kits between sites

or protocols• Do not interchange tubes between kits

A unique identifier assigned to each kit (example: R593812)

Interchanging kits or kit components can lead to test cancellations

CONFIDENTIAL16

Collection Kit Content (1/2)

• Requisitions• Collection tubes and transport vials

– Pre-labeled with test names

• Needles and holders• Packaging materials

– Incorrect or missing subject identifier could cause cancellation of testing

• To label replacement tubes and vials• Discard if not needed• Write the test name and subject

identifier on label

SM8 Serum CAP 1234

SM8 Serum CAP 1234

Contents are specific to visit on kit label

2 extra bar coded labels

Write subject’s identifier on labelswhen drawing specimens

CONFIDENTIAL17

• Include one of each of the following for CTC samples:– 10 mL CellSave Preservative Tube

• Green bar printed on label – 21-gauge butterfly needle – Specimen Collection Bag

• Samples collected with these kits are shipped to Covance CLS and Genentech

• Specimen details provided on slides 31-33 of this presentation

Collection Kit Content (2/2)

CTC/CAP and Day 1 Kits

CONFIDENTIAL

Requisition Completion

CONFIDENTIAL19

Laboratory Requisition (1/2)

• Provided in English• Use a black ballpoint pen

– Draw single line through incorrect information

– Date and initial correction

• Includes:– Subject demographic section, special

instruction(s), administrative question(s)

– Optional testing: check box to order testing

– Collection instructions and shipping condition when not enough space on 1st page

Completion is mandatory for sample processing

CONFIDENTIAL20

Laboratory Requisition (2/2)

• 3-Part NCR (CTC/CAP and Unscheduled):– Ship white copies to Covance CLS

– Ship pink copies to Genentech with CTC/CAP

– Retain yellow copies for your records

• 2-Part NCR (all other visits):– Ship white copies to Covance CLS

– Retain pink copies for your records

NCR Copies

CONFIDENTIAL21

Laboratory Requisition Completion (1/2)

Completion of demographics is mandatory for sample processing

Clear + Consistent + Complete = Query Free Requisitions

To calculate specimen stability

To assist in site communication

To identify subject

CONFIDENTIAL22

Laboratory Requisition Completion (2/2)

• CTC/CAP and Arm C/D Urine DNA requisitions– Is patient on or off study treatment?

• C1D1, C1D8, C6D1/C3XD1 and Unscheduled requisitions– Provide PK collection date and time

– DD/MMM/YYYY and 24 hour clock

• Optional Testing– Mark appropriate check box to identify testing to be performed

Provide information using check boxesor written entries

Incomplete information triggers queries

CONFIDENTIAL23

Use of Unscheduled Kits

• C6D1/C3XD1– This kit is used to draw the GDC-0941 PK samples for patients at

C6D1 or crossover patients at crossover Cycle 3

• Arm C/D Urine DNA– This kit is used to draw the Urine Tumor DNA for Arm C and D patients

for all visits after Screen where the Urine Tumor DNA is collected

• This includes regular visits and crossover visits

• CTC/CAP– This kit is used to draw the CTC and plasma and serum CAP samples

every six weeks starting at C1D1

• Unscheduled– This kit is used to draw unscheduled samples that have been approved

by the CRO

CONFIDENTIAL24

C1D1 Visit

• Pharmacogenetic, CTC/CAP and Urine DNA samples must be drawn pre-dose

• In addition to collecting C1D1 kit, also collect – CTC/CAP kit for all patients– Urine DNA kit for all Arm C/D patients

• The Pharmacogenetic sample is required for all patients unless the local regulatory agency prohibits drawing the Pharmacogenetic sample

CONFIDENTIAL

Specimen Collection and Packaging

CONFIDENTIAL26

Specimen Types Returned to Covance CLS

• Visit test schedule (table of tests per visit) provided in:– Study Protocol– Covance CLS Investigator Manual

• Detailed collection and handling instructions provided in:– Covance CLS Investigator Manual– On requisitions within kits

Specimen Type Frozen

Serum √

Plasma √

Whole Blood √

Urine √

CONFIDENTIAL27

Specimen Management (SM)

• Upon sample receipt Covance CLS will:– Register samples in Covance CLS tracking system

– Verify subject’s ID and sample condition

– Store samples at appropriate temperature

– Forward samples to specified laboratory for analysis on schedule directed by Genentech

Testing not performed and not reported by Covance CLS

CONFIDENTIAL28

Collection Key Points (1/3)

• Select proper collection tube(s)• Thoroughly mix blood by inverting tube• Do not draw whole blood samples first

– Avoids potential tissue thromboplastin contamination and clotting

• Serum – Allow blood to clot upright for 30 minutes

• Urine– Provide adequate sample volume; cap tightly

Good Quality Data Begins With Good Quality Samples

CONFIDENTIAL29

Centrifugation

Collection Key Points (2/3)

• Room temperature: Serum CAP

• +2 to 8°C: Plasma samples– Tubes may be centrifuged under ambient condition (room temperature) if a

refrigerated centrifuge is not available

• Proper speed and time– Refer to Covance CLS Investigator Manual for specific settings

• May vary from sample to sample• Example: minimum of 1500 x g for 15 minutes

• Clot and serum must be well separated

• Cells and plasma must be well separated

• Do not centrifuge when testing requires whole blood or urine samples

• Use pipette provided in kit to transfer serum/plasma into proper pre-labeled aliquots

• Plasma: Avoid the red cell layer

Specimen transfer

CONFIDENTIAL30

Storage and shipping condition

Shipping frequency

Collection Key Points (3/3)

• Frozen -70°C• If -70°C not available, samples may be stored at -20°C for up to one

week

• Day of collection• Back up samples shipped within 1 week

• Place the collection tube in an ice/water bath and maintain chilled until centrifugation

• Centrifuge within 60 minutes of collection• Transfer plasma into PRIMARY and BACKUP vials

Special PK processing/ instructions

CONFIDENTIAL31

Samples Not Returned to Covance CLS (1/2)

• Avoid backflow from CellSave tube during collection – Place the patient’s arm in a downward position– Hold the tube with the stopper upmost– Make sure the solution inside the tube does not touch the

stopper or end of the needle during venipuncture

• Mix tube immediately to prevent clotting– Inadequate or delayed mixing may result in inaccurate test

results

Specimen Type Ambient

Whole Blood CTC

CONFIDENTIAL32

Samples Not Returned to Covance CLS (2/2)

• Return CTC samples ambient to Genentech with pink copy of the requisition

• Use the shipping supplies provided by Covance CLS• Ship Monday through Wednesday to:

Genentech Sample Management550 Grandview DriveBLDG 47, Room 1230 (471230)South San Francisco, CA 94080

650-225-2034Email: 2027912-ctc-d@gene.com

• Do not return samples to Covance CLS

Specimen Type Ambient

Whole Blood CTC

CONFIDENTIAL33

CTC Packaging Key Points

• Follow details provided in Covance CLS Manual• Required materials provided within the shipping box or in Covance kit

1. BM01DA Shipping Box

2. BM08WFA Foam Liner

3. BM08AV440964 Bubble Mailer

4. BM08GEL Gel Pack

– The BM08GEL Gel Pack needs to

rest in ambient conditions for 72 hours

prior to pack-out

5. Pressure Bag (provided in Covance kit)

6. Absorbent (provided in Covance kit)

CTC Shipments to Genentech

CONFIDENTIAL34

Packaging Key Points (1/4)

• One Accession Number: – Per Specimen Collection Bag

– Per shipping temperature

• Include white copy of requisition in outside pouch (make bar code visible) with ambient samples

Insert tubes into Specimen Collection Bag

CONFIDENTIAL35

Ambient samples

Packaging Key Points (2/4)

• Prepare Gel Pak (thermal insulator) to insulate ambient samples– Take Gel Pak from kit

– Fill to indicated line with ambient water

– Let gel form or massage absorbent pack until gel forms

– Evenly distribute gel in bag while expelling air

– Seal tightly

– Wrap Gel Pak around Specimen Collection Bag containing ambient samples

– Do not place specimens directly into gel

CONFIDENTIAL36

Frozen samples

Packaging Key Points (3/4)

• Place Specimen Collection Bag in Styrofoam container– Group shipments as much as possible

• Use recommended amount of dry ice• Completely surround samples with dry ice

CONFIDENTIAL37

Packaging Key Points (4/4)

• Ambient + Frozen – Place ambient samples in dedicated section of shipping box

• Replace lid and close box securely• Place site’s address label on shipping box

– Pre-printed with site’s address and provided by Covance CLS

• Attach shipping documents to outside of box – Keep a copy at the site

If a combination box being used

All shipping conditions

CONFIDENTIAL38

Reasons for processing delays

Sample Processing Delays

• Missing, incomplete or inconsistent data on requisitions

• Incorrect subject identifiers on returned containers• More than one subject per Accession Number• Incorrect visit kit used• Incorrect sample condition

• Covance CLS will query the site• Samples will not be shipped to referral lab until all

queries are resolved

Sample processing will be performed upon receipt of the samples

CONFIDENTIAL

Courier Arrangements

CONFIDENTIAL40

Courier Information

• Courier contact information is communicated to the sites in Covance CLS Investigator Manual

• US only: United Parcel Service (UPS)– Saturday morning pickups

• Confirm Saturday availability/pickup time with UPS• Delivered to Covance CLS on Sunday

• US and Canada: Locate dry ice supplies (site’s responsibility)• IATA certification may be required for dry ice shipments per country

regulations• Consolidate shipments when possible

– Time and cost effective

To Covance To Genentech

Canada US Canada US

Ambient N/A N/A Fed Ex Fed Ex

Frozen Fed Ex UPS N/A N/A

Dry Ice Provider

Site Site N/A N/A

CONFIDENTIAL41

Shipping Documents (Canada)

• Provided pre-printed by Covance CLS• Complete required information • Send/attach to appropriate shipping box

– Ensure Commercial Invoice is included to avoid delivery delays

• If shipping on Friday, check “Saturday Delivery” on air waybill

Commercial InvoiceAir waybills and Commercial Invoices

CONFIDENTIAL42

UPS Shipping Labels (US)

• Provided pre-printed by Covance CLS• Dedicated to Covance CLS shipments

– Use dedicated UPS phone number (866-961-3790) to schedule pickup

• Attach to appropriate shipping box• Courier details in Covance CLS

Investigator Manual

UPS shipping labels

Ensures Friday shipments to be delivered on Saturday

CONFIDENTIAL43

Pickup Information

– Last Call Time, latest time to schedule same day pickup – Last Pickup Time, latest time for courier pickup– Transit Time to Covance CLS– Provide exact pickup location

• Transit Time to Covance CLS:– 24 hours sites: Ship Monday through Friday– 48 hours sites: Ship Monday through Thursday

• Consider customs/local holidays before shipping– Refer to Covance Central Laboratory Investigator Manual or

http://www.covance.com/products/clinical/central-lab/global-logistics.php– Do not ship one day before holidays (2 days if inbound transit is 48 hours)

• If sample pickup is missed, FROZEN samples remain at instructed temperature

Prior to first shipment to Covance CLS, contact your courier to determine/confirm:

Contact Covance CLS Investigator Support Services if you need further advice

CONFIDENTIAL

Contacting Covance CLS

CONFIDENTIAL45

Contact Covance CLS

Who to Contact

• To add/change information at investigator’s site– Contact telephone and fax numbers

– Covance’s CLS supplies delivery address

– Sample pickup address

• Query resolution• Resupply

– Place orders

– Adjust automatic resupply

– Stop automatic resupply when enrolment is complete

• Courier issues

• To order pickup • To track packages

Contact courier

CONFIDENTIAL46

Primary Reference Material

• Covance CLS contact information– Toll Free and Direct Numbers

telephone numbers

– If Toll Free unavailable, call telephone operator for collect call to Covance CLS

• Courier contact information • Sample collection instructions• Packaging instructions

Refer to Covance CLS Manual

CONFIDENTIAL

THANK YOU !