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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”?

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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

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“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.

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Surely I Overstate the Concern…..

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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

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US – Breakthrough Designation – Last 2 year – over 20 approvals

-source FDA website

Acceleration Requires Earlier Investment for Program

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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

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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)

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“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”

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Making This a Priority Across The Industry

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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

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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

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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

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Advances in Computational and Predictive Modeling Create New Manufacturing Opportunities

Novel Powder Mixing Technology

creates

MaterialScience

EngineeringModeling

+ Continuous Processing

Miniaturization

Modularity

Portability

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Better Process Controls

+

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GCON/GEA/Pfizer YouTube video

https://www.youtube.com/watch?v=tPmcwyfuqhE

What is Different from Today?

Traditional Facility PCMM

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Next Generation Equipment Allows Greater Process Control

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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

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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

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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

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More I mpact on Predictive Tools - The Impact of Adding Desiccant to the Packaging using ASAP.

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Without desiccant

With desiccant

FreeThink – Example of Widely Available Tools

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DisclaimerNo interest

in this company

The Importance of Investing in Big Data, Data Analytics and Predictive Models

Knowledge & Insight

Will not suffice !!

Data

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Data Needs to be Fully Connected

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Planning for the Workforce of the Future

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Workforce

Workforce Planning/Talent Management

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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

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From Pfizer Compassionate Use Patient’s Mom