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Integrated DevelopmentIntegrated Development

Pharmaceutical Advisors LLCJuly 2005

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Integrated Development StrategiesIntegrated Development Strategies

• Required Between:– Discovery & Development Organizations– Within Development Organization– Between Development Organization and

Commercial Organization– With RSOs/Suppliers

• Acceleration/Compression Requires Timeline:– Forward from nomination and…..– Backwards from projected NDA filing date

and approval/launch target

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Start No Later Than…Start No Later Than…

• Candidate Nomination– Transition from Discovery to Development– Candidate Nomination Guidelines

• Agreed Criteria Which Need to be Met to Nominate new Drug Candidate

• Drives Discovery Strategies from Lead Identification/Optimization to Candidate Nomination

– Ensures candidate selection process is driven by agreed targets/goals across portfolio of candidates

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Must Be Forward Looking and…Must Be Forward Looking and…

• Candidate Nomination– Candidate Nomination Document

• Summary of Data/Rational for Progression of Candidate to Development

– What are Positive Features of Candidate?– What are Issues/Flaws

• For Management Review and Approval• Approval Formally Triggers activities to Progress

Candidate to Phase I– integrated planning required to ensure efficient

transition– need to define process for managing this transition

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Work Back From Commercial GoalsWork Back From Commercial Goals

• Candidate Nomination Document (CND) Template– Table of Contents

• Biological Profile• Market Positioning/Rationale• Competitive Situation• Pharmacokinetics/Pharmacodynamic Summary/Issues

(ADME)• Safety Information/Issues• Drug Substance Technology/Issues• Physical Pharmacy/Dosage Form Issues• Bulk Supply Status/Issues• Intellectual Property Status/Issues

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Approved Indicated Products

UnapprovedProducts

Target Product Profile

ParameterLong ActingAnti-XXXXX

Long ActingXX Agonist

XXXInhibitor

Minimum Desired

ClassExample

XXXXX XXXXX XXXX

EFFICACY

ΔFEV1(vs baseline)

XXX-XXX ml(28-31%)

XXXml(20%)

XXX ml(500 mcg dose)

XXX ml(X%)

>XX%

Quality of Life Indicators #

Improvement Improvement Improvement XXX XXX

Development of Tolerance

no no no (?) XXX XXX

DiseaseModification ##

no no ? XXX XXX

# Post dose exercise challenge## Reduction in the rate of XXXXXX

Considering a Target Product ProfileConsidering a Target Product Profile

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Approved Indicated Products

UnapprovedProducts

Target Product Profile

ParameterLong Acting

Anti-XXXLong ActingXX Agonist

XX InhibitorMinimum Desired

SAFETY

Safe to Use in Combination

yes yes ? XXX XXX

Anti-XXXX X yes - - XXX- XXX-

XXX Stimulation XX - yes - XXX XXX-

GI Disturbances(nausea, vomiting)

- -?

(at elevated doses)

XXX XXX

SpecialPopulations

X X ? XXX XXX

PHARMACOKINETICS

Dosing XX mcg OD XXmcg BID XXX mcg OD XX XX

Delivery XXXXX XXX PO XX XX

OTHER

Annual Cost of Rx (Direct)

$XXX $XXX $X $X

Reduction in Indirect Costs

Considering a Target Product ProfileConsidering a Target Product Profile

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Link to Development PlanningLink to Development Planning

• Early Development Plan (EDP)– Developed After Approval of CND– Integrated Plan for all Key Activities Leading

to IND• To be updated as required by significant changes

in strategies/issues• Provides overview of ongoing development

activities, issues, timing • Requires Matrix Team to Manage

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Early Development PlanEarly Development Plan

• Early Development Plan Template– Table of Contents

• Clinical Plan/Strategy• Drug Safety Evaluation Plan• ADME Evaluation/Plan• DS/DP Strategy/Issues• IP Overview/Strategy/Issues• Other

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Making the TransitionMaking the Transition

Early Development Plan• Clinical Plan/Strategy• Drug Safety Evaluation Plan• ADME Evaluation/Plan• DS/DP Strategy/Issues• IP Overview / Strategy/

Issues• Financial

Integrated Development• Executive Summary• Marketing Strategy• Regulatory Strategy• Pre-Clinical Strategy• Clinical Strategy• Chemical Development• Manufacturing• Supply Chain • Financial

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Integrated Plan Contents IIntegrated Plan Contents I

Executive Summary • Key Objectives (can include a draft package insert)• Major Milestones & Decision Points• Risk Management Strategy• Financial Overview (project P&L, costs, resources, outsource requirements, etc)

Marketing Strategy• Key Indications • Global Market Forecast (regions, revenues, longevity, etc)• Product/Brand Image (size, color, dose, formulation, packaging, etc)• Trademark & Patent issues• Competitive Environment

Regulatory Strategy• Country/Regional issues (NDA, MAA, JNDA, PAI timelines, acceleration)• Regulatory Environment (pertinent guidelines, regional differences, etc)• Safety & Efficacy Targets

Pre-Clinical Development Strategy• PK studies required (protocol descriptions, pivotal vs. non-pivotal)• Toxicology/Pathology (protocol descriptions, pivotal vs. non-pivotal)• Clinical Development Strategy• Studies required (protocol descriptions, pivotal vs. non-pivotal)

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Integrated Plan Contents IIIntegrated Plan Contents II

Clinical Development Strategy• Studies required (protocol descriptions, pivotal vs. non-pivotal)

Chemical Manufacturing & Control (CMC) Development• Primary API batches• Route & filing strategy• Salt selection strategy• Stability batches• Technology transfer & scale-up• Manufacturing• Dosage form manufacturing site requirements• Delivery systems requirements• Storage & transport requirements• Analytical method development• Process & technology transfer requirements

Supply Chain • Volumes (typically units and kgs per year)• Sourcing• Distribution

Financial• Capital required• P&L, ROI etc

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Why All This Planning So Early?Why All This Planning So Early?

– Formalizes product development across the business– Provides a common, consistent planning framework across

diverse business segments/therapeutic areas– Ensures alignment with business objectives/high-level

strategies– Provides management with a high-level overview of a

complex project– Provides multi-disciplinary project teams with a clear intent

and roadmap– Holds key decision data for review, approval, “go/no go”

etc– Provides a basis for monitoring/managing the progress of

the project– Achieves consistency across projects– Guides planning at lower levels of detail

The Integrated Development Strategy is the guide to developing a drug candidate

and the business case for continued project funding.

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Common QuestionCommon Question

• Why all this planning? Our strategy is to license out in Phase II…– Ok if future milestone payments from

partner are not needed!– What if partner relationship changes?! – Often more is done than needed because of

lack of understanding about phase-appropriate development and quality!

– When is GMP material needed?– When do you start collecting NDA

documentation?

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The Development Strategy ProcessThe Development Strategy ProcessThere are usually three levels of strategy and planning There are usually three levels of strategy and planning

documents maintained throughout the lifetime of the product documents maintained throughout the lifetime of the product development effortdevelopment effort

Integrated Development Strategy (IDS)

Integrated Development Strategy (IDS)

Integrated Development PlanIntegrated Development Plan

Prepared by:Project TeamApproved by: Senior ManagementUpdated/Reviewed: QuarterlyAccountable: Project Team Leader

Prepared by:Project TeamApproved by: Senior ManagementUpdated/Reviewed: MonthlyAccountable: Project Team Leader

Pre-Clinical Development PlanPre-Clinical Development Plan

Clinical Development PlanClinical Development Plan

Regulatory Development PlanRegulatory Development Plan

Marketing Development PlanMarketing Development Plan

Prepared by:Sub-Team LeadersApproved by: Project Team LeaderUpdated/Reviewed: WeeklyAccountable: Sub-Team Leaders

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Timeline Compression Timeline Compression

• Presents Significant Challenges to Technology Development– Requires earlier investment of resources

• API can activities lead the way when compressing clinical timelines

• Invest in time critical activities early– Technology– Materials

– Better integration of activities with partners essential • Internal • External

• Integration of Activities Dictate that During Phase II:– Critical technology must be:

• Developed• Demonstrated at scale• Used to support preparation of:

– Phase III clinical supplies– ICH stability supplies

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Timeline Compression ImpactTimeline Compression Impact

CMC Investments then Precede Clinical Phase Preclinical I II III Review

API/DP Enabling TechnologyPhase I API/DP Supplies

API/DP TechnologyPhase II API/DP Supplies

Commercial TechnologyPhase III API/DP Supplies

Nomination PhI PhII PhIII NDA/MAA Approval

LaunchAPI/DPEnabling Technology &Supply Manufacturer

API/DPTechnology/Supplies

RM API DP

PhIII Supplies

RM API DPLaunchPlanning

RM DP DP StabilityAPI PAIn Planning

RM API DP ICH Stability ICH DP StabilityPlanning

DP Technology

API Technology

Raw Materials API Activities DP Activities Enabling

Phase II Becomes The BattlegroundPhase II Becomes The Battleground

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The Phase II BattlegroundThe Phase II Battleground

• Often under-considered by both out-licensing and commercially integrated firms– Resource limitations– Poor integration– Emphasis on clinical

• Integration of drug development activities – Balancing risk of investments against speed– Risk of CMC investments

• versus unknown clinical outcomes– Speed

• Delayed CMC investments put CMC activities on critical path to filing

• Huge potential impact on time, cost and clinical flexibility that directly impacts value

For Out licensing and Integrated companies alike

The Phase II BattlegroundThe Phase II Battleground

Nomination PhI PhII PhIII NDA/MAA Launch

APIForm

DP

API

CommercialTechnology

Window

CHANGE

PotentiallyImpacts

Filing Date

Clinical Efficacy Determination

The Phase II BattlegroundThe Phase II Battleground

Nomination PhI PhII PhIII NDA/MAA Launch

APIForm

DP

API

CommercialTechnology

Window

CHANGE

PotentiallyImpacts

Filing Date

Clinical Efficacy Determination

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Are You Ready Now?Are You Ready Now?

Will You Be Ready?