Upload
doannga
View
218
Download
0
Embed Size (px)
Citation preview
The Future is Now –
A “Pre-mortem” on Breakthrough Medicines
Jim Spavins, SVP Pfizer – PTx Pharm SciIFPAC MeetingArlington, VA
January 25, 2016
What is a “Pre-mortem”?
Pfizer Confidential │ 2
Nobel Laureate and Psychologist Daniel Kahneman is known as “the father of behavioral economics” and is an expert on the psychology of unbiased thinking and decision making.
You can see his discussion of “pre-mortem” on YouTube:
https://www.youtube.com/watch?v=f432ultnPQI
Situational Analysis
• Breakthrough Therapies based on transformation science are real
• Need to be fast AND with quality and reliability
• CMC has generally not been rate-determining, but transformational products could change that (hopefully they will!)
• CMC could “fail” in many ways:– Not having clinical supplies to do the breakthrough studies– Not being able to do tech transfer or “scale-up” (or by suppliers)– Not generating process understanding or sufficient controls– Not having adequate regulatory justification or guidance– Not passing inspections
Pfizer Confidential │ 3
“Success is Predicting Failure” – Henry Petrowski
• Our approaches to avoid/predict “failure”
– Leverage computational/predictive methods (gain insights faster and cheaper)
– Next generation manufacture (Portable, Continuous, Modular Manufacture) AND associated next gen controls
– Big Data and associated IT (overlap with computational methods)
– Workforce Planning– Regulatory interactions for mutual understanding
A call for continued industry and regulatory interaction for mutual understanding.
Pfizer Confidential │ 4
Surely I Overstate the Concern…..
Pfizer Confidential │ 5
1 mile Estimate x
-from Misbehaving - Richard Thaler
x
a) 3 inchesb) 30 inchesc) 30 feet
(not to scale, for sure)
Breakthrough Medicines Are Real
Pfizer Confidential │ 6
US – Breakthrough Designation – Last 2 year – over 20 approvals
-source FDA website
Acceleration Requires Earlier Investment for Program
Pfizer Confidential │ 7
Cost of Accelerated Program Divided by Cost of Base Case ProgramNot Adjusted for Attrition
~ Budget Neutral
1 Accelerated Program Costs ~2.5 X 1 Base Case Program
Tail of Base Case Program is 2X remaining costs for an
Accelerated Program
Very Unique Opportunity for Pharma Industry
Pfizer Confidential │ 8
New “Biology”
Big Data/Analytics
Public Policy
New Opportunities to bring molecules
to market
Source: FDA pathway features are derived from the FDA Draft Guidance on BTD; the times to approval are estimates.
Reasons To Believe - Different Acceleration Pathways At FDAPathway When to submit Qualifying feature Features Recent examples (time
to approval)a
Fast-track designation
Ideally, no later than the pre-BLA or pre-NDA meeting
• Treats a serious condition• Nonclinical or clinical data
demonstrate the potential to address unmet need
Actions to expedite development and reviewRolling review
Xalkori (~5.3 years)Kalydeco (~5.8 years)
Accelerated approval pathway
Discussed during development process
• Treats a serious condition• Meaningful advantage over
available therapies• Demonstrates an effect on a
surrogate endpoint or clinical endpoint
Approval based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a drug's clinical benefit
Kyprolis (~6.8 years)Iclusig (~4.7 years)
Priority review designation
With original BLA, NDA or efficacy supplement
• Treats a serious condition• If approved would provide a
significant improvement in safety/effectiveness
Shorter clock for review of marketing application (6 months compared to the 10-month standard review)
Xtandi (~5.2 years)Adempas (~6.4 years)
Breakthrough therapy designation (BTD)
With IND or afterIdeally, no later than the end-of–phase 2 meeting
• Treats a serious condition• Preliminary clinical evidence
indicates it may demonstrate substantial improvement over available therapies
All fast-track featuresIntensive guidance on efficient drug development during IND, beginning as early as phase 1Organizational commitment
Gazyva (~6.2 years)Imbruvica (~4.8 years)Sovaldi (~5 years)
Pfizer Confidential │ 9
“Manufacturing Matters to Innovation”
“It is one thing to develop something and get it to work once in a lab. It is a different thing entirely to make a million or 10 million.” “Manufacturing
is Alive!”
“The Future of Manufacturing is Innovation”
Pfizer Confidential │ 10
Making This a Priority Across The Industry
Pfizer Confidential │ 11
Innovation is not a laboratory discovery, a concept, or a prototype. Innovation is the process of taking a new idea or concept to the market…. If this part of the innovation process fails, you don’t have an innovation; you had a promise
- G. Pisano – Producing Prosperity
Pfizer Confidential │ 12
Digital Design – Important for Early/Rapid Insight
One Experiment or 10,000 simulations?
Leverage Fundamental Material Science and Digital Design
New Computationaland PredictiveModeling ToolsApplied from
Molecular Design to Manufacture
Pfizer Confidential │ 13
Speed, Quality,Cost,
Reliability important across
the continuum- Modified from Dierk Raabe, Max-Planck Institut für Eisenforschung)
Modeling Solves Encapsulation Process
New Hopper Design• Overcame issue• Implemented at site• Filed in NDA & MAA
• Why?‐ Commercial process
equipment re-design speed
• How?‐ Test different impeller
designs using DEM (Discrete Element Modeling) to identify the go forward design
Low Risk of Adverse Impact on Performance
High Risk of Adverse Impact on Performance
Pfizer Confidential │ 14
Advances in Computational and Predictive Modeling Create New Manufacturing Opportunities
Novel Powder Mixing Technology
creates
MaterialScience
EngineeringModeling
+ Continuous Processing
Miniaturization
Modularity
Portability
Pfizer Confidential │ 15
Better Process Controls
+
PAT Locations within the PCMM Oral Solid Dose Unit
PAT 1 (NIR)Post CMT
Potency & Blend Uniformity
PAT 2 (NIR)Post TSWG
Granule Formation
PAT 4 (FBRM)Post Granule
SizingPSD
Diversion 2Post Granule Sizing
Diversion 3Tablet Eject Chute
Diversion 1Post Fluid Bed
Drying
PAT 3 (NIR)Post Granule
SizingPotency & Granule
Uniformity, Moisture
Combi TesterTablet Hardness
Thickness, Weight
PAT 5 (NIR)Feed FramePotency &
Blend/Granule Uniformity
Continuous Mixing and Direct Compression
Pfizer Confidential │ 19
Stage Appropriate Control Strategy: A Development Continuum
The platform is equipped with monitoring, modeling and control capability to ensure product quality – higher level control with combination of different components.
To realize the vision of an adaptable and agile manufacturing paradigm, there is a need to balance the online and offline analytics to the stage of development..
Low
Medium
High
Process Control: Comprehensive Closed loop control strategy Release: Online (RTRt)Process Control:
MSPC/SQC(parameters & attributes), MPCon CPPRelease: Combination of Online and Offline Process
Monitoring/Control: SPC/MSPC/SQC, (parameters & attributes)Release: Offline
Imp
act
Early Clinical Late Clinical Commercial
Development Stage Pfizer Confidential │ 20
Pfizer Confidential │ 21
Pharma Investing in Continuous Manufacturing, Continuous Validation and End-to-End Data Integrity
Investments in continuous manufacturing Requires radically smaller plants, better manufacturing efficiencies such
as quality control, lower costs and shorter cycle time Encouragement by regulatory authorities e.g., FDA, and leveraging the
latest in technology for in-line particulate monitoring using near-IR, remote identification testing
Industry - Academia collaborations working to further develop the concept e.g., MIT - Novartis
Several drug manufacturers are now investing in continuous manufacturing
Modular Pharmaceutical Sites Shorten ConstructionTime Periods and Lower Costs
Shift towards modular and even disposable processing suites 30-40% smaller footprint 50% less energy usage 20% less total project costAlready major companies with on-market solutions GE’s Kubio (Xcellerex) modular plant Thermo Fisher single-use bioreactorExpansion to modular drug substance and fill/finish capabilities
Modular pharmaceutical and biologics facilities
Pfizer Confidential │ 22
More I mpact on Predictive Tools - The Impact of Adding Desiccant to the Packaging using ASAP.
Pfizer Confidential │ 23
Without desiccant
With desiccant
FreeThink – Example of Widely Available Tools
Pfizer Confidential │ 24
DisclaimerNo interest
in this company
The Importance of Investing in Big Data, Data Analytics and Predictive Models
Knowledge & Insight
Will not suffice !!
Data
Pfizer Confidential │ 25
Workforce Planning/Talent Management
Pfizer Confidential │ 28
1. Business Goals & Strategic Direction
2. Future Skills/Capabilities
3. Internal Supply
4. External Market Available
6. Action Plans (e.g.)
5. Reconcile as to Internal Shifts
–Recruit strategically
–Source talent/capability
–Anticipate business impact
–Develop in a purposeful manner
Need to be “Bold” and Work Together
“Bold” “Bolder” “Boldest”
• Understand this is a “new” significant challenge
• Industry pre-competitive collaboration on elements needed for acceleration
• Continued Joint industry/ regulatory discussion on this new challenge
Pfizer Confidential │ 29