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Integrated Development
Pharmaceutical Advisors LLC
July 2005
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Integrated 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…
• 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…
• 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 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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Considering a Target Product Profile
Approved Indicated Products
Unapproved
Products
Parameter
Long Acting
Anti-XXXXX
Long Acting
XX Agonist
XXX
Inhibitor
Class
Example
XXXXX
XXXXX
XXXX
ΔFEV1
(vs baseline)
XXX-XXX ml
(28-31%)
XXXml
(20%)
Quality of Life Indicators
#
Improvement
Development of
Tolerance
Disease
Modification ##
Target Product Profile
Minimum
Desired
XXX ml
(500 mcg dose)
XXX ml
(X%)
>XX%
Improvement
Improvement
XXX
XXX
no
no
no (?)
XXX
XXX
no
no
?
XXX
XXX
EFFICACY
# Post dose exercise challenge
##Reduction in the rate of XXXXXX
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Considering a Target Product Profile
Approved Indicated Products
Unapproved
Products
Long Acting
Anti-XXX
Long Acting
XX Agonist
XX Inhibitor
Safe to Use in Combination
yes
yes
Anti-XXXX X
yes
XXX Stimulation XX
Parameter
Target Product Profile
Minimum
Desired
?
XXX
XXX
-
-
XXX-
XXX-
-
yes
-
XXX
XXX-
GI Disturbances
(nausea, vomiting)
-
-
?
(at elevated doses)
XXX
XXX
Special
Populations
X
X
?
XXX
XXX
Dosing
XX mcg OD
XXmcg BID
XXX mcg OD
XX
XX
Delivery
XXXXX
XXX
PO
XX
XX
Annual Cost of Rx (Direct)
$XXX
$XXX
$X
$X
SAFETY
PHARMACOKINETICS
OTHER
Reduction in Indirect Costs
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Link 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 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 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 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 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?
– 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 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 Process
There are usually three levels of strategy and planning documents
maintained throughout the lifetime of the product development effort
Integrated Development
Strategy (IDS)
Prepared by:Project Team
Approved by: Senior Management
Updated/Reviewed: Quarterly
Accountable: Project Team Leader
Integrated Development Plan
Prepared by:Project Team
Approved by: Senior Management
Updated/Reviewed: Monthly
Accountable: Project Team Leader
Pre-Clinical Development Plan
Clinical Development Plan
Regulatory Development Plan
Prepared by:Sub-Team Leaders
Approved by: Project Team Leader
Updated/Reviewed: Weekly
Accountable: Sub-Team Leaders
Marketing Development Plan
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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 Impact
CMC Investments then Precede Clinical Phase
Preclinical
I
II
III
Review
Commercial Technology
Phase III API/DP Supplies
API/DP Technology
Phase II API/DP Supplies
API/DP Enabling Technology
Phase I API/DP Supplies
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Phase II Becomes The Battleground
Nomination
PhI
PhII
PhIII
NDA/MAA
Approval
API/DP
Enabling Technology &
Supply Manufacturer
Launch
API/DP
Technology/Supplies
RM
API
DP
PhIII Supplies
DP Technology
API Technology
RM
RM
RM
Raw Materials
API Activities
API
DP Activities
API
DP
DP
ICH Stability
Enabling
API
DP
DP Stability
Launch
Planning
PAIn Planning
ICH DP Stability
Planning
The 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
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The Phase II Battleground
Nomination
PhI
PhII
PhIII
Commercial
Technology
Window
NDA/MAA
API
Form
DP
API
CHANGE
Potentially
Impacts
Filing Date
Clinical Efficacy Determination
Launch
The Phase II Battleground
Nomination
PhI
PhII
PhIII
Commercial
Technology
Window
API
Form
API
DP
NDA/MAA
Launch
CHANGE
Potentially
Impacts
Filing Date
Clinical Efficacy Determination
Are You Ready Now?
Will You Be Ready?
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