Cold Chain Designfor Mega-Scale Clinical Trial - A Case Study

Ray GoffDirector,

Pfizer Vaccines R&D

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Clinical Trial Distribution - A Case Study

Great challenge of this mega-scale clinical trial. Trial will be critical to determine the position of conjugate

pneumococcal vaccines in the prevention of pneumococcal disease.

• The burden of community–acquired pneumonia (CAP) among the elderly ishigh and has increased over the last decades. CAP ranks among the top-5causes of death for the elderly.

• The primary objective of the planned trial entitled CAPiTA (Community Acquired Pneumonia Immunization Trial in Adults) is to establish the efficacy of 13-valent PnC vaccine in the prevention of a first episode of vaccine-serotype specific pneumococcal CAP in 85,000 community-dwelling adult persons aged 65 years and older.

• This trial is performed entirely in The Netherlands.

• More details are published in “ The Netherlands Journal of Medicine,October 2008, Vol. 66, No. 9; Hak, et al. Rationale and design of Community–Acquired Pnuemonia Immunization Trial in Adults.”

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Clinical Trial Distribution - A Case Study

Great challenge of a mega-scale clinical trial .

Stage 1 Initially enrollment was planned for 85,000 subjects in 6-8weeks. Study was double blinded supply and placebo with temperature controls at 2-8ºC, covered Netherlands country, involved regional hospital associations and public relations. This study will lay clinical knowledge foundation for CAP for adults and is supported by medical academia.

• Uptake of study was slow. At week 5 it became apparent that studyrecruitment would take longer than 12 weeks and extend to possibly 20 weeks -end of year.

Stage 2 The second year brought other challenges with new staff,expanded recruitment areas, larger GP base, and another 56 weeks tocomplete the last 55,500 enrollment.

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Best Practices

Be Flexible and Adapt to Challenges

Be Risk Conscious - Solution Oriented

Be Assurance Focused- Innovation Driven

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Steps to Managing Change and Risk

Plan with Partners

Assess Risk

Evaluate Possibilities

Rank Probability / Impact

Propose Plan to Management

Implement Plan (C and/or M)

Manage KPIs

Be prepared to Pro-Act

Update new plan with partners

Implement activities

Adapt to challenges – go back to first step

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Partner Team

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Stage 1 Cold Chain & Secondary Packaging

Weeks 1 thru 5 shipments were in insulated product carriers (51minutes @ 22C) stacked inside pallet shipper inside temperaturecontrolled 40ft tractor trailer. The pallet shipper filled with carrierswas later transferred to temperature controlled vans.

Weeks 6 thru 12 shipments were in upgraded insulated carriers(6 hrs @ 23C) stacked inside temperature controlled 40ft tractor trailer. Insulated carriers were then loaded into temp controlled van. Pallet shipper eliminated due to drop in volumes.

Weeks 2 thru 8 air shipments used nomadic shipper (thickpolyurethane shipper rated at 48 hrs and weighing 54lbs.). Upon arrival at Netherlands airport shipper was transferred to temperature controlled vans.

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Cold Chain & Secondary Packaging

Product required 2-8C temperature control

3 Thermal Layers designed into Study

Vehicles (temperature controlled)

Pallet shippers (insulated and cooled)

Insulated Containers

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Stage 1 Distribution Overview

156 shipments from UK to few sites in NL.

Ground / sea from 40ft tractor trailer to sprinter vans across ferry to EU and on to clinical sites. Air shipment from UK to Cologne to NL.

Week 1 thru 5 large quantities to a few sites - concept was large, quick, centralized and consolidated. Build stock at site. Study only 8 weeks long.

Week 5 thru 12 smaller quantity and more sites, enrollment tapering off - concept was smaller more outreaching, scattered fixed site locations. Stock only what is likely.

On-going collection of data confirmed Air shipment max 24 hrs and Ground / sea max 32 hrs.

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Stage 1 Ground Transportation Flow

Warehouse Shuttle Ferry Vans(deliver supplies)

Tractor Trailer

Clinic/Hospitalthen

delivery to homes

Vans(pick up returns)

Shuttle FerryWarehouse Tractor Trailer

Original route planned for 48 hrs.10

Stage 2 Ground Transportation Flow

Warehouse Shuttle Ferry Truck & Vans(deliver supplies)

Luton Truck

Clinic/Hospital

Luton TruckPick-up returns

Shuttle FerryWarehouse Luton Truck

Original route planned for 48 hrs.11

Stage 1 Air Transportation Flow

Warehouse Van Storage Airplane Vans(deliver supplies)

Clinic/Hospital

Vans(pick up returns)

Shuttle FerryWarehouse Tractor Trailer

Original route planned for 48 hrs.12

Stage 2 Air Transportation Flow

AirplaneWarehouse Storage Truck &Vans(deliver supplies)

Van

Clinic/Hospital

Luton Truck

Pick-up returnsShuttle FerryWarehouse Luton Truck

Original route planned for 48 hrs.13

Stage 2 – General Route & Transportation

NL

TransferPoint

Dover

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Stage 1 Delivery Time Segmentsby Air and /or Ground/Sea Shipments

Total Ground/Sea AirDELIVERY PROFILE

30%

25%

20%

15%

10%

5%

0%

16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25

Hours

25-26 26-27 27-28 28-29 29-30 30-31 31-32

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Stage 2

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31-32hrs

30-31hrs

29-30hrs

28-29hrs

27-28hrs

26-27hrs

25-26hrs

24-25hrs

23-24hrs

22-23hrs

21-22hrs

20-21hrs

19-20hrs

18-19hrs

17-18hrs

16-17hrs

CAPITA 1 DELIVERY PROFILE

30%

25%

20%

15%

10%

5%

0%

TOTAL GroundSeaAIR

Stage 1 & 2 Delivery Time Segmentsby Air and /or Ground/Sea Shipments

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TYPES OF SHIPMENTS

Total AIR13%

Total Ground Sea87%

TotalAIR TotalGroundSea

Stage 1 Delivery Time SegmentsAir Shipments

AIR SHIPMENTS DELIVERY TIMES

23-24hrs11%

22-23hrs26%

Up to 17hrs36%

21-22hrs5%

17-19hrs11%

19-21hrs11%

Up to 17hrs 17-19hrs 19-21hrs 21-22hrs 22-23hrs 23-24hrs

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Stage 1 Delivery Time SegmentsGround/Sea Shipments

GROUND SEA SHIPMENTS DELIVERY TIMES

Up to 24hrs1%

30-32hrs11%

24-26hrs11%

26-28hrs47%

28-30hrs30%

Up to 24hrs 24-26hrs 26-28hrs

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Stage 2 Delivery Time Segmentsfor Ground/Sea Shipments

1% 0%8%

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GROUND SEA SHIPMENTS DELIVERY TIMES

26-28hrs 28-30hrs 30-32hrs

24-26hrs33%

Up to 24hrs58%

Up to 24hrs 24-26hrs 26-28hrs 28-30hrs 30-32hrs

Temperature Monitoring Study

Entire study used Sensitech TempTale®4 temperature monitors for vehicles and product containers.

Protocol was written to control placement,database for reporting.

TempTale®4s were placed:

Inside product container

Inside cool compartment of tractor trailer

documentation and

Front of outside tractor trailer for ambient reading

Back of outside tractor trailer for ambient reading

Inside cool compartment of van

Front of outside van for ambient reading

Back of outside van for ambient reading.

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Temperature Monitoring

Ambient Air Temperature

Van TransportTruck Transport

Ferry Portion of Trip

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VaccineResearchTemperature Monitoring

Reefer Temperature

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10/21f2.08 6:00AM 10/21f2 812:00PM

10/22[2.0 812:00 AM

10/22[.20 8 16:00 AM

Date /Time

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Temperature Monitoring

Product Temperature

Truck Transport Van Transport

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VaccineResearchTemperature Monitoring Design

Typical Temperature Dataset for each Shipment

3 0 . 0 � - - - - � - - - - - - � - - - - - - � - - - - - � - - - - - - � - - - - �

0�©: I , _

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10/21 f.2008 16: 0 AM 10 /22[2.0. 812:00 AM 10 /22[2 .· 8 6:00 AM

Date/ T ime

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Stage 1 Temperature Study Findings

Product temperatures are in excellent range.

44% of shipments would have been an excursion if thermallayer around the product was not present. Vehicle reefer withproduct alone is not enough.

The start temperature has large impact on when productgo beyond alarm limits. Pre-conditioning of coolant and assembly is critical.

will

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Stage 1 Product TemperaturesGround/Sea Shipments

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Stage 2 Product TemperaturesGround/Sea Shipments

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29 29

2 Temperatureshipments

Stage Scatter Diagramfor 255

August OctoberSept

Stage 2 Distribution Overview

255 shipments from UK to NL sites.

Ground/ sea from Luton truck to sprinter vans across ferry to EU and on to clinical sites

Air shipment from UK to NL

Week 1 thru 32 small volume and more scattered sites, progressive roll-out enrollment, hybrid concept was smaller more outreaching, scattered fixed sitesthroughout EU country, mobile medical units (MMU) to support small enrollment locations. Stock only what is likely. Manage logistics and inventory weekly.

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Stage 2 - Cold Chain and Secondary Packaging

Week 1 thru 32 shipments are in insulated product carrier (6hrs @ 23C) stacked inside temperature controlled Luton Truck.The pallet shipper and 40ft Tractor trailer were eliminated. Thecarriers are later transferred to temperature controlled vans.

Air shipments used Polar Thermal 48 hr shipper. Reusable Polartherm bags rated for 48 hrs and weighing 26lbs. Upon arrival at EU country they were transferred to ambient or temperature controlled vans. Bags picked up weekly by returns Luton truck.

Fuel prices at end of Stage 1 were 3x of start price and Stage2 started at 3x and went to 5x. Today it is at 2.5x start price. Carrier bag upgrades and vehicle decisions negated impact of fuel price increases

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Results

Improvements-

Distributions: Loop method & lowered delivery time under 24 hrs,Supply Planning: improved communication and accuracyCold chain - Zero shipping excursions and proof of performance Risk Avoidance- plans in place for top risk concerns Temperature/ shipping information database

Sustainability-

Re-useReduce carbon footprintAvoid carbon footprint

Cost savings- Over five hundred thousand dollars. If designed as a traditional study- at least a million dollars

Cost avoidance- No shipping excursions, over two hundred thousand dollars. Lower site inventory, over three hundred thousand dollars

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Design Stage 1 & 2Mega Scale Study - Challenges

Size of study, number of subjects & sites

Speed to conduct study,

Outsourcing and internal level of control (turnover)

Supplies

inventory

temp control & cold chain

expiration dating

Temperature profile (season and geography)

Mode / route of transportation air, sea, and ground (strikes)

Distribution Network vs. geography of sites (weather delays)

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Shipping Excursions

Shipping excursion rate for this Mega-study = 0%

Pfizer

Pfizer

Pfizer

Vaccines

Vaccines

Vaccines

R&D

R&D

R&D

for last 2 years in EU = 1.2%

worldwide rate = 2.6 %

before 2006 = 4% to 15%

Percent of shipments exceeding 2-8◦ C = 21% to 92%Representative sample of 1,000 non-Clinical GMPshipments

*Sensitech shipping study data – Internal Document

Average cost of one (SE) shipping excursion = $ 3,137 plusleast 48 staff labor hours (2007 currency)

Average study SE cost = $ 150,576 and 2,304 staff hours

at

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Packaging

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Adapting Distribution to Site Inventory Blocks

IBC- Inventory Block Carton

Lowest loss inventory size for average site.

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Sustainability Stage 2

•Lightweight for airshipments

•Reusable

•Fits distribution loop

•Greater payloadthan previous

shipper

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Sustainability & Cold Chain Stage 1 & 2

Carriers easier for drivers and clinics to handle. Lightweight,reusable, improved insulation to cover possible van/truckbreakdown or delay at site. Stage 2 Upgrade to 6 hrs coverage.

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Cold Chain & Sustainability

PolarTherm Pallet System is made for thermal protection. The palletsystem is thenlater a van.

loaded into a temperature controlled tractor/trailer and

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Background Slides

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Results

Process Improvements Distributions: Loop method- transportation already paid for by return activities, lowered majority of delivery time under 24 hrs, Supply Planning: improved by including regional managers in site delivery process, site inventory load became more accurate less loss. Cold chain management -significantly reduced shipping excursions (0%), Risk Avoidance- plans in place for the most likely and most impact events.

Sustainability- Re-use of packaging, return transportation not part of packaging carbon footprint, avoid carbon for new package, avoid carbon for labor and disposal of new packaging and avoid carbon for lower payload and heaver packaging,

Cost savings- Greater payload and lighter weight shipping, fewer total packages purchased and shipped, fewer temperature monitors and documentation. Several hundred thousand dollars.

Cost avoidance- No shipping excursions. Average 4% = over a hundred thousand dollars. Lower site inventory loss by 5% = over two hundred thousand dollars

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