Enabling > Global Pharma March 17, 2010 Pharma & Biotech Supply Chain World Asia Achieving Effective & Successful Trial through accurate Demand Forecasting

Enabling > Global Pharma

March 17, 2010

Pharma & Biotech Supply Chain World Asia

Achieving Effective & Successful Trial through accurate Demand Forecasting of Clinical Supplies

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Copyright @ Karmic Lifesciences 2010Copyright @ Karmic Lifesciences 2010 22

Speaker Profile

Qualifications- MD in General Medicine, MD in Community Medicine- Diploma in Public Health and Diploma in Industrial Health- Diploma in Management from the Jamnalal Bajaj Institute of Management Sciences

Previous Experience- Dean & Director, Clinical Research Education and Management Academy (CREMA), Mumbai- Professor & Head of Dept. of Community Medicine, Grant Medical College, Mumbai- Vice-Chancellor’s nominee to the Academic Council of the University of Mumbai- Medical Administrator of the Mahatma Gandhi Memorial Hospital- Joint Director of Medical Education & Research- Director of the prestigiousHaffkine Institute, Mumbai- Administrator of Maharashtra Medical Council - a licensing/regulatory body of Govt. of Maharahtra for MBBS doctors Contribution- Two Chapters for the API Textbook of Medicine- 21 published research papers, 7 editorials and 61 articles- Presence at International and National Conferences for Presentation of Scientific Papers- Editorials for journal of Association of Physicians of India- Editor of Indian Journal of Occupational Health and My Doctor

Awards- Has been awarded three orations and WHO Fellowship- Awarded the Best Referee by Journal of Association of Physicians of India (JAPI), for 2007

Dr. Shreekant SapatnekarMedical Director Karmic Lifesciences

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Agenda

Overcoming "supplies stock out" situation through effective demand forecasting

Building an effective aggregate demand forecasting strategy at the distribution point

How to ensure infrastructure of local depot network for clinical supplies is ready to achieve operation and cost efficiency

Achieving effective and successful trial through accurate demand forecasting of clinical supplies

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Introduction to Clinical Trial Supplies Chain

The “Clinical Trial Supply Chain” refers to the activities involved with planning, sourcing, transporting and distributing clinical trial materials including

Investigational Product, Clinical Equipment & Supplies to the Clinical Trial Sites and Investigators

Sponsor/ Manufacturer

Global Carrier Local CarrierCRO

Site 3

Site 2

Site 1

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Illustrative Supply Chain for Clinical Trials

Applicable Import

Application & Approval

Overall IP Trial Related Demand

Forecast calculated by Sponsor/CRO

IVRS portal automatically predicts inventory & minimum

order quantity/Site can manually use

portal/phone to order shipment from Central

Depot

IP Shipped & Received at Airport

IP Stored at Central Supplies Depot

IP Shipped to Site in required shipping

conditions

IP Delivered to Site in controlled conditions

IP Reaches at Site, verified for physical

appearance, temperature integrity,

proper quantity by analyzing data

logger

Investigator maintains IP accountability in IP Log

IP Return/Disposal as per Study

Protocol

Shipment of Clinical trial Supply as per Shipment order from Sponsor including:

Correct Destination for Shipment

Accurate Packaging Condition

Accurate Quantity

Temperature Integrity

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Special Conditions Pertaining to Clinical Trials Supply Management

Requirement to manage the supplies involved in supporting clinical trials Global Trials Multiple Countries & Regulations Multiple Locations Multiple Investigators Multiple Trial Medications/”Drug Kits” Data Collection/Reporting Devices (e.g., PDA’s, cell phones, remote sensors)

Need to coordinate delivery of supplies to multiple active sites Different sites may have different recruitment timelines, recruitment period, rate of

recruitment and no. of patients recruited Randomization of medication administration may trigger resupply at variable intervals

requiring variable safety stock at each site Flexibility and speed of delivery is critical Consideration of special packaging and handling requirements (e.g. cold shipping)

Historical data from older trials to understand IP and supply chain requirements Variability in the number of patients enrolled, number of investigators, geographic

distribution of trials will create larger variability in inventory and distribution of drug kits

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Clinical Trial Supplies Challenges

Randomization/

Stratification

Variable Enrolment & Drop-Out

Rate

Complex Regulatory

Requirements

Cold Chain Transport

Multiple

Distribution

Interfaces

Expiration

Dating/Disposal

Multiple

Dosing/Weight

Based Dosage

Adaptive Trial Design

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Clinical Supply Chain

Optimization

Clinical Supply Chain Optimization

$Risk 100% Protocol

Adherence

Avoid Stock-Outs

Avoid IP Spoilage

Optimized Transport Costs

Optimized Storage Costs

Optimized Re-Order Frequency

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Framework for Managing Effective Clinical Supplies

No. of Patients No. of Sites Correct IP Dosing

Determination (Multiple/Weight Based etc.)

Duration of Treatment

Patient Randomization

Patient Recruitment Rate

Patient Drop-out Rate

Back-up Site Supplies

Type of Medication

Source of IP Procurement (COA etc.)

Supply Lead Time

Delivery Conditions

Type of Packaging

Country Of Shipment

Import Regulations

Mode of Transport (Air Connectivity)

Time to Shipment

Storage Conditions during transit (Cold Chain etc.)

Local Support for clearing

Type of Medication

Storage Conditions as per Study Protocol

Drug Stability Capacity

Limitation Disposal as per

Protocol Disposal Facility Hazard to

Environment Documentation

Accurate Demand

Forecasting

Transport in Controlled Conditions

Robust Site Inventory

Mgmt

Proper IP Storage & Disposal

Correct Procurement

Patient Randomization

Patient Recruitment Rate

Patient Drop-out Rate

Use of IVRS for Automated Inventory Mgmt

Back-up Site Supplies

Supply Lead Times

Advance “Stock-Out” Intimation

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Accurate Demand Forecasting Overcoming “Supplies Stock-Out” Situations

Safety Stocks Calculating Safety Buffers Accurately based on previous statistics and data

Minimum Stock Level for Re-order Determining appropriate Trigger Points for Stock Re-Order

Cognizance of Supply Lead Times Integrating Supply Lead Times with Re-Order Trigger Points

Cognizance of IP Expiry Dates Factoring IP Expiry Dates into Demand Forecasting

Close Monitoring of Recruitment & Drop-out Rate at Sites Monitoring of recruitment & drop-out rates Updating demand forecast for next 90 days

Use of IVRS/IWRS Automated Inventory Management, Patient Randomization, Visits & Related IP Usage Seamless integration from Central Storage to Sites Trigger-Based: Min/Max Stock Levels Predictive: Safety Stock + Prediction Window

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Accurate Demand Forecasting Aggregate Demand Forecasting Strategy at Distribution Point

Use of Demand Forecasting, Decision Modeling Tools & Monte Carlo Simulation

Determining correct overall IP quantity IP Unit Packaging Weight & Volume Calculations Dosing Schedule/Multiple Dosing Weight Based Dosing

Determing IP quantity for individual sites Planned Recruitment Rates Planned Drop-Out Rates

Provision for moving IP to rescue sites Monitoring of recruitment & drop-out rates Updating demand forecast for next 90 days

Calculating Safety Stocks Provisioning for Buffers

Superimposing IP quantity on weekly time scale

Refining and updating forecast on a weekly basis

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Safety Stock

Q

0

Illustrative Demand Forecasting at Central Depot & Sites

Safety Stock

Q

0

Safety Stock

Q

0

Safety Stock

Q

0

Safety Stock

Q

0

Safety Stock

Q

0

Investigational site




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Managing Clinical Supplies for Cost & Operational Efficiency Ensuring Robust Infrastructure of local depot network for clinical supplies

Infrastructure Specifications Space Requirements Storage Requirements Cold Chain Packaging Distance Connectivity IT & Technology Automation (Tracking, IVRS etc.)

Vendor RFP & Selection Get capability data & quotes from multiple vendors Select highest quality vendor Negotiate bulk costs

Training of Local Depot Staff Processes Systems

Defined Depot Workflow Defined Workflow & Process Chart Defined Shipment Frequency (Days/No. Of Pick-up/Drop times etc.)

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Continuous Data Generation, Tracking, MIS & Analysis of SLAs

Use of Web Based CTMS/IVRS

Clinical Supplies Operational Reports Supplies Shipped Supplies Used Supplies Expired Supplies Returned No. Of Inventory Turns Frequency of Order Stock-outs faced

Clinical Supplies Cost Reports Shipping Costs Local Storage Costs’ Expiry Costs Costs Per Patient

Managing Clinical Supplies for Cost & Operational Efficiency

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Key Statistics $ 300 Mn Clinical Research Industry 1200 ongoing clinical trials $ 1.2 Bn Clinical Research Industry by 2012 growing at a 40% CAGR 1.3 Bn Patient Population, more than 70% treatment naïve 1500+ hospitals with potential for clinical research activities 31,000+ medical graduates and 700,000 science graduates pass out every year

India Advantages Faster, cost-effective studies

~ 30% reduction in trial completion timelines with extremely fast patient recruitment ~ 50-60% cost reduction compared to other locations including USA and Europe Large treatment-naive patient population with a population of 1.3 Bn+ Strong, well-credentialed physician base with 1 Mn+ qualified and practicing doctors Strong ICH-GCP Compliance and increasing quality levels at par with global standard Government Initiatives and support via an increasingly progressive regulatory environment

Key Statistics $ 300 Mn Clinical Research Industry 1200 ongoing clinical trials $ 1.2 Bn Clinical Research Industry by 2012 growing at a 40% CAGR 1.3 Bn Patient Population, more than 70% treatment naïve 1500+ hospitals with potential for clinical research activities 31,000+ medical graduates and 700,000 science graduates pass out every year

India Advantages Faster, cost-effective studies

~ 30% reduction in trial completion timelines with extremely fast patient recruitment ~ 50-60% cost reduction compared to other locations including USA and Europe Large treatment-naive patient population with a population of 1.3 Bn+ Strong, well-credentialed physician base with 1 Mn+ qualified and practicing doctors Strong ICH-GCP Compliance and increasing quality levels at par with global standard Government Initiatives and support via an increasingly progressive regulatory environment

A recent survey led by 'A.T. Kearney' ranks India very close, or even slightly more advanced than China, due to the progressive regulatory environment and commitment to tight timelines; allowing global biopharmaceutical companies the ability and confidence to conduct clinical trials in country.

A recent survey led by 'A.T. Kearney' ranks India very close, or even slightly more advanced than China, due to the progressive regulatory environment and commitment to tight timelines; allowing global biopharmaceutical companies the ability and confidence to conduct clinical trials in country.

Historical 2003-04 2005-06 2006-07 2008-09

No. of Trials ~200 221 1070

Est. Size ($ Mn) 60 95 150 300

Clinical Trials in India

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India Clinical Supply Chain Highlights

Clinical Trials Import Regulations T-License from DGFT for all clinical trials Application made along with DCGI Form 44 Application Processed in 4 weeks

Samples Export Regulations ICMR Norms for export of samples including tissue, blood, plasma samples etc. Approval for specific sample exports

Transport Infrastructure Presence of Global Carriers including World Courier, Blue Dart, DTDC etc. Use of Cold Chain and transport in dry ice conditions as necessary Few Central Labs have own local transport & supply chain infrastructure e.g.

Metropolis

IT Infrastructure Automated Tracking Use of Data Loggers Use of IVRS increasing

Site Storage Infrastructure All large clinical sites have -2 to -8 and upto -80 degree cold storage facility Most Sites have IT & Telecom infrastructure for use of IVRS

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Dummy/Dry Run carried out (i.e. Dummy IP is sent to the

site with the temperature logger in the shipment)

IP Quantity Calculation IP distribution per site (No of patients * Duration of

Treatment)

IP T-License Procurement & Import

IP Delivered @ the Airport with appropriate storage

conditions

IP Delivered @ Karmic with appropriate storage

conditions

IP Accountability, Storage & Site requirement calculation

Sites informed about Dry Run

IP shipment checked at sites for transit time, breakage,

storage conditions etc.

If Favorable Results

Reporting the results on “0” min

Root Cause Analysis

IP distributed to Trial Site(s) as per quantities calculated

NO

YES

Karmic Clinical Supply Chain Management

IP Dispatched to Site

Corrective Action

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Illustrative Clinical Supplies Case Study

Study Description No. of Patients: 210 Phase : III Therapeutic Area:

Oncology Screen failure: 25% Patient drop-out rate:

15% Treatment Groups: 2 Dose Level: 2 Study-Level

Randomization Weight-Based Dosing Kit Types: 2 Product Storage

Conditions: -2 to -8

degrees C Product Shelf-life: 12

months IVRS Method: Predictive

Karmic Approach Import License from DGFT procured in 4 weeks IP reached Mumbai airport in cold chain with proper packaging and

storage conditions Karmic team had informed Sponsor of Custom Clearance process

as well as a local festival holiday well in advance and requested them to make necessary arrangements to store the study drug at the airport for 48 hours before custom clearance

Karmic further got exact no. of boxes and packaging dimensions for the consignment in advance as well for planning shipping to sites

Custom clearance formalities were completed after the holiday was over. Karmic personnel were personally present to collect shipment at clearing house and the study drug was transferred within 4 hrs from the airport to Karmic’s outsourced Central Storage Depot within controlled conditions

The Central Storage Depot made necessary arrangements to unpack the consignment, make smaller batches and ship pre-determined initial order quantities to the sites on the same day through the use of the local carrier. The shipment was done in controlled cold chain conditions using dry ice and data loggers

The balance study drug was stored at -2 to -8 degrees for a period of upto 12 months post which the IP would expire

The average time for the study drug to reach at site was 14+ hrs (including air transport and local transfer). All the sites received the study drug as per the appropriate condition with “Zero” damage.

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Key Steps for Success

- Start forecasting at the time of regulatory application.- Identify shipment services provider and documentation well before study

approval from regulatory agency- Site inspection and feasibility report for IP Management- Training for the Site & IP handling staff

Planning

- Provide study medication type and storage condition to courier service provider so that it will help for good packaging and shipment to different trial location

- Identify the cycles of shipment to all study sites.- Target time to reach final destination (Study site) Therefore Tracking

Procurement

- Site selection strategy should incorporate special transport regulation requirement of local region (e.g. 2 different rules for Octroi duty; UP vs. Bengal)

- Site selection strategy should include air and local transport facility- Confirm the temperature requirements during shipment and local transit

before initiating the shipment process- Before shipment initiation, find out local holiday and weather conditions

Transport

- Consider storage facility at site and make necessary arrangement before study supply shipment reach to site including training

- Conduct a dry run before sending actual the study supply at sites - Disposal facility should be available near site- Disposal facility should comply with local Environmental Laws- Adhere to SOPs for disposal of surplus- Check list of documents to be produced before & after supply disposal

Storage & Disposal

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Conclusion

Supply Chain Management in Outsourced Clinical Research

conducted by a CRO is a challenge of moderate degree

Criticalities are few but important

Modern techniques like Demand Forecasting, Use of IVRS/IWRS

and IT based Tracking are essential

Human behavioral factors as important as the external factors

that result in uncertainties. These must be considered in the

planning and training process

Anticipation of pitfalls, planning, capacity building, adherence to

SOPs and constant monitoring can address most of the issues

Neither easy – nor difficult. Doable with specific inputs.

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Thank You

Enabling > Global Pharma

Dr. Shreekant Sapatnekar

Medical Director

Karmic Lifesciences Tel: +91-22-32597223 (D)

+91-22-25650404 (O) Ext. 215

+91-22-25610403 (F)

+91-9833192331 (M)

E-Mail: [email protected]

Web: www.karmiclifesciences.com

Documents

Enabling > Global Pharma March 17, 2010 Pharma & Biotech Supply Chain World Asia Achieving Effective & Successful Trial through accurate Demand Forecasting