Pharmaceutical Drug Development

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PharmaceuticalDrug Development

• May 2005
• Paul A. Bien,
• Senior Director, Global Project Management
• Pfizer Global Research and Development
• La Jolla

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Drug Development Goal
Develop an approvable label for a new medicine
Doability
Safety Efficacy
Commercial Value Medical Need
to an eagerly awaiting world.
3
From Idea to Market
Complex Process

gt800 Million
5000-7000 Compounds
12-15 Years!
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RD Costs have Grown Dramatically
5
In 2004, Pharmaceutical Companies Spent 53
Billion on RD. This represents an increase in
spending of 70 in 10 years!
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RD Expenditure as a Percentage of Annual
Revenues (by Industry)
Pharmaceutical RD Spending is the Highest
Pharmaceutical RD
17.0
Computer Software Services
10.5
Electrical Electronics
8.4
Office Equipment Services
7.8
Telecommunications
5.3
Leisure Time Products
3.9
Automotive
3.8
Aerospace Defense
1.2
Metals Mining
.73
Paper Forest Products
All Industries
3.9
Based on data from PhRMA Annual Survey and
Standard Poors Compustat, a division of
McGraw-Hill
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NME Approvals are Declining
43
8
RD Output Doesnt Match Input
Only 3 out of 10 Marketed Drugs Produce Revenues
that Match or Exceed Average RD Costs
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Summary

• Pharmaceutical RD is high risk
• R D costs have grown dramatically and
  disproportionately to RD output
• The result is decreased RD Productivity
• What contributes to this risk?

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Portfolio Risk

• Technical risk (regulatory)
• Commercial risk
• Probability that commercially important elements
  will not be achieved
• Competitive environment shifts from current best
  estimate
• Operational risk
• Probability that the project cannot be executed
  as planned
• Resources
• Unexpected data
• Task execution
• Changed strategy or regulatory requirements

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Attrition
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Why Do Candidates Die?

Animal toxicity, chemical stability, superior
compound
On average, it takes 24 drug candidates to yield
1 marketed product
Human PK, toleration, formulation
No. candidates
Efficacy/safety, differentiation, dose/c.o.g.
Non-approval
Long-term safety
Preclin. Phase I Phase II Phase
III Registration
Market
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Todays Focus RD Process
100 Discovery Ideas
Millions of Compounds Screened
Preclinical Pharmacology
Preclinical Safety
1 2 Products
Clinical Pharmacology Safety
Discovery
Exploratory Development
Full Development
Phase I
Phase II
Phase III
0
15
10
5
Idea
Drug
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Levers for Productivity

• The number of compounds entering the pipeline
• The survival of those compounds
• The speed with which compounds progress through
  the pipeline
• The cost of advancing compounds
• The value of those compounds

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Drug Discovery Process
First Human Dose

• Potency
• Selectivity
• PK
• Formulation
• In vivo screening

• Assay and reagent development
• Target Screening

Lead Optimization
Assay Development
Pre-Clinical Evaluation
Target Identification
Lead Discovery

• Typically in vitro screening
• Selection of active chemical
• templates for optimization

• Conceptual and
• exploratory research
• Competitive information
• Experimentation

First Regulatory Toxicity Dose

• Bulk drug scale-up

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Target Identification
Methods Literature Search (1) Clinical
Experience (3) Genomics (32) Non-Genomics
(60) Other (4)
Strategy
15 global Pharmaceutical Companies (n 888
projects)
Source Centre for Medicines Research
International (2002)
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Getting the Compound

• Identify Chemical Matter
• Newly Synthesized
• Compound Bank
• Natural Sources
• Structure based drug design
• Acquisitions/Licensing
• Develop Assays for Compound Screening

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Lead Discovery
Example receptor
Target
ligand
Signal
receptor
signal A
Signal blocked
X
Other signals not altered (specificity safety)
signal B
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Compound Selection and Enhancement
Discovery Project Team Goal
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In Addition to Activity

• Solubility
• Metabolic stability
• Absorption
• Safety
• Crystallinity

"Drug-ability"
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Confidence in Safety

• Will blocking the signal be safe?

isolated
in vitro
in vivo
healthy volunteers
patients

• Monitor and predict RISK
• Needs to begin even earlier!

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Biomarkers Emerging Tools

• Signals used to monitor drug action
• May reflect safety or efficacy
• Enable quicker internal decision making in
  Discovery and Developmentact as bridge
• Increase attrition
• Lower costs
• Speed up development of drugs with traditionally
  low clinical do-ability
• Projects with high development costs
• Drugs with marginal projected value

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Drug Development Process
NDA
Phase II
Phase III
Phase I
Preclinical
Discovery
Phase I
Phase II
Phase III
Phase IV
Preclinical
Post-Marketing
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Pre-Clinical Phase Key Questions

• Safety
• Pharmaceutical Sciences
• Can pre-clinical and clinical bulk be efficiently
  synthesized (API, Drug Substance)?
• Can we identify and manufacture a delivery
  formulation (Drug Product)?
• Is the formulation stable?
• Pharmacokinetics
• What does the body do to the drug (ADME)?
• What effect does the drug have on other drugs or
  enzymes?
• Can data help predict human PK and dose?
• Clinical
• What is the predicted PK, dose, and TI?
• What is the best clinical plan?

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Investigational New Drug (IND)

• In USA, submit for FDA review
• All preclinical data
• Chemistry, Manufacturing, and Control (CMC)
• General investigational plan
• Proposed clinical studies
• Previous human experience (if any)
• If no objections within 30 days, proceed to humans

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Phase I Focus on Safety and Tolerance

• What is the safe dosage range?
• How long does the drug stay in the body?
• How is the drug eliminated?
• Small numbers of healthy volunteers
• In some cases, patients with disease (e.g.
  oncology)
• Defines toleration, safety, pharmacokinetics, and
  pharmacodynamic properties
• Single dose, multiple dose, few days or weeks
• Tests food effects, biomarkers
• Generally takes from 6 months to a year

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Phase II Testing the Hypothesis

• Do we have efficacy?
• Do we have proof of mechanism and value?
• Is the compound safe?
• What is the proper dose?
• Small numbers of patients with the targeted
  indication
• Tests clinical efficacy hypothesis
• Identifies appropriate therapeutic dose range and
  dosing regimen
• Assesses short term safety under more extended
  dosing
• Capture early quality of life (QOL) data

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Commercial Considerations

• Do we have confidence that the drug will
• Fill a medical need?
• Be differentiated from others?
• Have commercial value?

Business Decision
Discovery
Exploratory Development
Full Development
Phase I
Phase II
Phase III
0
15
10
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Phase III Full Development

• Is the compound efficacious?
• Is the compound safe?
• Does it work better than the competitor agent?
• Can it be manufactured efficiently?
• Large numbers of patients with the desired
  indication(s)
• Pivotal studies to establish efficacy and long
  term safety
• Uses the best dosage form within the therapeutic
  dosage range
• Manufacture and packaging of supplies
• Continuing toxicological evaluation
• Data sufficient for registration and approval by
  WW Regulatory authorities

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Clinical Development Plans Vary
Years
6
0
1
2
3
4
5
Safety
Efficacy
Large Scale
Safety
Efficacy
Large Scale
Based on historical examples to deliver first
approval Source McKinsey
analysis
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New Drug Application (NDA)

• Submit NDA to FDA using a recently adopted format
  
• Known as CTD (Common Technical Document)
• Based on ICH and FDA guidelines
• Used for both US, Europe, and Japan
• NDA contains five modules
• Module 1 Administrative information pertinent
  to local guidelines (including proposed labeling,
  packaging info)
• Module 2
• Clinical overview and written and tabulated
  summaries (safety, efficacy, clinical
  pharmacology)
• Non-clinical overview and written and tabulated
  summaries
• Summary of Chemistry, Manufacturing and Controls
  (CMC)
• Module 3 Quality overall summary
• Module 4 Non-clinical reports
• Module 5 Clinical study reports

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FDA Review and Approval Process

• Advisory Committee meeting
• Requested by FDA
• Based on first in class, safety issue, data
  interpretation, etc.
• Labeling negotiations
• Rapid responses to FDA queries
• NDA approval by FDA
• Product Launch!

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First Impressions Count!
Over 80 of Eventual Prescribers Initiate Use in
the 1st Year
Trial
100
Rapid Penetration in the Market is Vital
50
0
Launch
1Yr
2Yrs
3 Yrs
Source Walsh/PMSI
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Phase IV Post-Submission

• Post-Marketing Surveillance
• Adverse events
• Long-term effects on morbidity/mortality
• New Formulation(s)
• Controlled-release / Transdermal / Syrup
• New Indication(s)
• Additional populations, new dosage forms
• Increased focus on outcomes
• Pharmacoeconomics
• Long-term endpoints
• Quality of life
• Benefits in local settings
• Comparison with Competitor Products
• Highlight key marketing features

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Phase IV Post-Submission (cont.)

• Regulatory Requirements
• New Drug Submission (NDS) Annual Reports
• Drug Safety Surveillance (DSS)
• Serious Adverse Event (SAE) Reports
• Periodic Safety Update Reviews (PSUR)
• Drug InformationMedical Affairs
• Answering questions from medical community
• Developing relationships/partnerships with
  physicians and healthcare institutions

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Risks to RD Productivity

• Highly competitive market place
• Rising costs and complex RD
• Increasing size of clinical trials
• Poor returns on expensive Discovery technology
• Inefficiencies and poor strategies
• Competition for licensing candidates
• Weak investor market
• Regulatory and political pressures
• Cost containment and price controls
• Rising global healthcare costs
• Global price disparities

An Industry Under Pressure
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Pharmaceutical Consolidation Trends 1988 PMA
Members
Abbott Laboratories G.D. Searle Procter
Gamble American Cyanamid Glaxo Rhone
Poulenc A.H. Robins Hoechst Rorer Astra Hoffman-
LaRoche R.P. Scherer BASF ICI Roussel Beecham
Laboratories Johnson Johnson Sandoz Boehringer
Ingelheim Knoll Schering Plough Boots
Pharmaceuticals Eli Lilly SmithKline
Beecham Bristol-Myers Marion Laboratories Squibb
Carter-Wallace Merck Sterling Drug Ciba
Geigy Merrell Dow UpJohn Company Connaught
Laboratories Monsanto Warner-Lambert DuPont
Pharmaceuticals Pfizer Wellcome Fisons
Corporations Pharmacia Zeneca
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Pharmaceutical Consolidation Trends 2005 PhRMA
Members
Abbott Laboratories Procter Gamble American
Home Products Glaxo SmithKline Astra Zeneca
Hoffman-LaRoche Aventis BASF Johnson
Johnson Boehringer Ingelheim Schering
Plough Eli Lilly Bristol-Myers
Squibb Merck Novartis Pfizer
No new entrants!
Mergers and Acquisitions enable companies to
rapidly expand RD, build product pipelines, and
expand into new therapeutic areas.
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Benefits

• Our mission is to provide relief and hope for
  millions of people around the world And we
  must do so as quickly as possible because
• The patient is waiting!