Molecular Development
21st Century Pharmaceuticals
Joseph M. Palma, MD, MPH, CPE
Institute of Defense Analyses
March 29, 2007
571-437-7948
josephpalma@cox.net
jpalma@ida.org
Networks
E-Coli Transcription Regulatory Network
Barabasi, Albert-Lazlo, et al. Network Biology: Understanding the Cell’s
Functional Organization, Nature Reviews, Genetics. 2004 Feb;5:101-113;
and Aggregation of topological motifs in the E. coli transcriptional
regulatory network, Dobrin, Q. K. Beg, A.-L. Barabasi, Z. N. Oltvai, BMC
Bioinformatics 5, 10 (2004).
Global Regulators And Their Regulated Operons And
Functions In The Regulatory Network Of E. Coli
Global
Regulator
Directly
Regulated
Operons
Total
Regulated
Operons
Modules
Regulated
Function
IHF
21
39
15
integration host factor
CspA
2
24
5
Cold shock protein
CRP
72
112
21
cAMP receptor protein
FNR
22
38
16
anaerobic regulator, regulatory gene for nitrite and
nitrate reductases, fumarate reductase
HNS
7
22
5
DNA-binding global regulator; involved in chromosome
organization; preferentially binds bent DNA
OmpR
6
20
3
Response regulator for osmoregulation; regulates
production of membrane proteins
RpoN
12
17
4
RNA polymerase sigma 54 subunit
RpoS
14
24
8
stationary phase sigma factor
ArcA
20
21
6
Response regulator protein represses aerobic genes under
anaerobic growth conditions and activates some anaerobic
genes
NarL
13
15
5
Two-component regulator protein for nitrate/nitrite
response
Radu Dorbin et al, BMC Bioinformatics. 2004; 5: 199
E-Coli
Transcription Regulatory Network
Radu Dorbin, et al, BMC Bioinformatics. 2004; 5: 199
Meds
E-Coli
Transcription Regulatory Network
BMC Bioinformatics. 2004; 5: 199
Outline
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•
Background
Status
Strategy
Challenges
System Issues
Insights
Considerations
Background
• Broad Spectrum Countermeasures against
Emerging and Bioengineered Agents
Status
• Development System
• Traditionally One-Bug:One Drug
• New Strategic Directioin
– Network Based Pharmaceuticals
• One Drug:Multiple Bugs
• Strategy Alignment
• Resources and Needs
Relevant Competencies
• Research and Technology Centers of Excellence:
– World Class Laboratories
• Research and Technology Centers of Excellence
• Advanced Product Development
• Pharmaceutical and FDA Regulatory Depth & Expertise
– Human and Animal Protection
– Long-Standing FDA Regulatory Interface
• Technical Expertise and Depth
– Logistics
• Extensive Legal, Acquisition & Procurement Expertise
– Information, Informatics and Bioinformatics
– Innovation
Strategy
• Components
–
–
–
–
Characterization of the host-pathogen interaction
Diagnostics and Therapeutics
Preventive Measures
Information Systems and Bioinformatics
• Challenges
–
–
–
–
–
Innovation
Technical
Pharmaceutical
Industrial
Oversight
Orchestrating
Information
The Strategy
Reporting
Orchestration
Execution
Technology,
Bioinformatics,
Knowledge
Development
& Management
Timelines
Metrics
Trends
Documentation
Accountability
Challenges
• Pharmaceutical Development Challenges
– Radiological, Biological, Chemical Network Similarities
– Human Disease States Likely Share Networks
– Portfolios: Current vs Orthogonal
• Technology Development
• Knowledge Development and Integration
– Information and Bioinformatics
• Product Development
• Competencies
• Integration of Network Development
Current Process
Project Scope
A
Vaccine
Concept Refinement
Disease
requirements
Product
Requirements
Approach
Definition
Approach
Candidate
Discovery
Candidate
Downselect
Technology
Development
Candidate
Optimization
Candidate
Selection
Milestone A
First in Human
Pharmaceutical
Concept Refinement
Milestone B Proof
of Concept
B
Commit to product
type
Target ID/
Validation
Commit
to target
Lead
Generation
Lead Selection
Technology
Development
Lead
Optimization
Candidate
Selection
Preclinical
Milestone A
First in human
Phase I
Production &
Deployment
Phase III
Milestone C
NDA/BLA filing
Program
Initiation
C
System Development &
Demonstration
Phase II
Milestone B Proof
of Concept
Commit to
Phase III
File
Phase III
Phase II
FOC
IOC
C
System
Development &
Demonstration
Phase I
Preclinical
A
Disease/
Target Family
Selection
Program
Initiation
B
Phase III
Milestone C
NDA/BLA filing
Operations
& Support
Launch
BLA
Approval,
Launch
IOC
Production &
Deployment
File
NDA
Approval,
Launch
Post
Launch Review
FOC
Operations
& Support
Launch
Lifecycle
Management
Post
launch review
A Snapshot of the
Industry Pharmaceutical Process
Target
Identified
Assemble
Target
Assessment
Team
DP0
Evaluate
Target
Develop
Project
Charter
Target
Selected
No Go or
Revise Charter
In-Depth Pharmacology,
PK/PD, Prelim Safety &
Toxicity, Identify/Qualify
Biomarkers
Form
Project
Team
Create
TPP(s)
Establish
DP1 G/NG
Criteria
In Vitro
POC
Testing
Discover
Lead Ab
Candidates
Tissue
Profiling
(Norm,
Dis)
DP1
DP2
Select
Initial
mAb(s)
Establish
DP2 G/NG
Criteria
Candidates
In Vivo
POC
Testing in
Disease
Models
No Go or
Revise TPP
Select
Candidate
mAb(s)
No Go or
Revise TPP
DP3
Establish PK/PD &
Toxicity Levels,
Biomarker Dvmt
Mkt & Competition
Analysis
IND
MDECISIONS
ETRICS
Establish
DP3 G/NG
Criteria
Proceed
to Pre-IND
Studies
Establish
IND G/NG
Criteria
CMC Activities
(Process Dvmt, Mfg)
Initiate CMC Activities
(Cell Line, Process Dvmt)
File IND &
Start Ph I
Establish CDP &
G/NG Criteria
No Go or
Revise TPP
No Go or
Revise TPP
Initiate Mkting &
Commercial
Activities
Phase I
Clinical Trial(s)
(Safety, PK/PD)
CMC Activities
(Process Dvmt,
Mfg Scale-up)
Proceed
to Ph II
No Go or
Revise TPP
Phase II
Clinical Trial(s)
(Safety, PK/PD, Efficacy)
Proceed
to Ph III
Mfg Process/
Formul/Presen
Fixed
Phase III
Clinical Trial(s)
(Safety, Efficacy)
No Go or
Revise TPP
Prepare
&
File BLA
No Go or
Revise TPP
Commercial
Readiness
TPP= Target Product Profile
DP = Decision Point
BLA
Submitted
Site
Inspection
PMS
Readiness
FDA
Approval
Launch
Product
Product
Launched
Current Industry View
Pharmaceutical
Process
Meds
Clinical Data
Analysis
NDA
Registration
Rework
& Optimize
Full Development
Candidate Medicine Tested in
3-10,000 Patients (Phase III)
Studies in 100-300
Patients (Phase II)
Extensive Safety
Studies
Large Amounts of
Candidate Medicine
Synthesized
Rework
& Optimize
Studies in Healthy
Volunteers (Phase I)
Formulations
Developed
Candidates
Candidate
Development
Exploratory Development
Early Safety
Studies
START
Project Team
and Plans
Synthesis
of Compounds
Screening
Discovery
Rework
& Optimize
Adapted from information provided by Pfizer Pharmaceuticals, Inc
Network Development
“Very Dynamic”
ENTERPRISE-WIDE OVERSIGHT & METRICS THROUGHOUT
FDA ENGAGED THROUGHOUT
PROCESS ANALYSIS TECHNOLOGY METRICS
Candidates
Selected
Approaches
Optimize
Candidates
Optimized
Phase I
Small Human Test
Milestone B
Phase II
Points
1
Milestone C
Phase III
(File NDA)
Approved
Post
Launch Reviews
2
E-IND
Multiple Approaches
are Matured &
Multiple Drug Candidates
Manufactured
3
Several Proteomic Candidates
& Technologies
Several Small Molecule Candidates
& Technologies
Several Metabolic Candidates
& Technologies
Select the Best &/or
Integrate multicomponent
Human Test All Candidates
IND
Milestone A
Several Genomic Candidates
& Technologies
Select Candidates
& Approaches
Validate Targets and Test
Various Approaches
Optimize
Tes KEY t Network Components
Define KEY Network Components
Requirements
Develop one or More Network-Specific
Countermeasures and Determine on
Integration into a “Cocktail”
5
One Product or Multi-component
Cocktails
Optimize
MASSIVELY PARALLEL
AND
ORTHOGONAL DEVELOPMENT
6
Orthogonal
Network Network
Pharmaceutical
Current
B
A
Concept Refinement
Disease/
Target Family
Selection
Commit to product
type
Target ID/
Validation
Commit
to target
Lead
Generation
Lead Selection
Technology
Development
Lead
Optimization
Candidate
Selection
Preclinical
Milestone A
First in human
4
Phase I
Program
Initiation
C
System Development &
Demonstration
Phase II
Milestone B Proof ofCommit to Phase
Concept
III
Phase III
Milestone C
NDA/BLA filing
IOC
FOC
Production &
Deployment
File
NDA
Approval,
Operations
& Support
Launch
Lifecycle
Management
Post
launch review
Orthogonal Reviews
Phase I
E-IND
Pre-Clinical
2
3
IND
Genomics
MEDS
Proteomics
Immunologic
Metabolomics
Summary of Differences
Current Approach
Network Development
Requirements
Characterize Pathogen (sequences, key proteins,
virulence factors, Antigen immunogenicity…) Identify
protein family, targets, validate role in disease.
Characterize Network (Establlish network type<hierarchy, free
scale, random>), Illustrate mechanism of pathogenic action and
key network nodes, as well as sequencing, character of key
proteins, virulence factors, potential targets, etc, as in Stage
Gate.
Approach/Leads
Determine vaccine platform approaches or identify
lead candidates
Determine critical nodes, validate targets, identify candidate
molecules and platforms for development, identify lead
candidates against nodes & validate the nodes, identify all
relevant development technologies, & select orthogonally.
Candidate
Discovery
Understand the biological and chemical character of
molecules or vaccine components to be optimized.
Characterize the Network components that are shared and their
biology and chemistry, as well as uni or multi component
potential formulations. Establish animal models/FDA
engagement/correlates of efficacy. Make orthogonal decisions.
Optimization
Candidate activity characterized; assays developed,
toxicity and PK studies done, structure of the
compound is optimized.
Multiple candidates undergo similar studies and work. 2 animal
rule is tested. Multiple candidates are tested by themselves and
in combinations against mutliple nodes. Orthogonal decisions.
Candidate
Selection
Pre-clinical toxicology, immunogenicity, dose ranging,
formulation studies and PK studies done. IND material
is prepared as is the IND application.
Similar but for multiple candidates. E-IND/IND materials and
applications are prepared. Reviews and decisions are
ORTHOGONAL.
Phase I
Human testing in 10-20 healthy volunteers for
safety/toxicity, ADME, PK. Metabolites.
E-IND: Human testing under tailored protocol (possibly
microdosing) for toxicity with candidates (as one and/or
multicomponent formulation(s). Optimal formulation(s) is(are)
advanced to IND at different doses, and undergo ADMET, PK,
Metabolite testing; and 2-Animal testing for efficacy/or
correlates. Also there is human testing in other infectious
diseases for “broad spectrum” activity and effects.
Advancement decisions are orthogonal.
Phase II
Traditional human testing in larger number of
volunteers with the disease.
2-animal rule testing for biodefense – animal numbers to be
determined with the FDA. Human volunteers with infectious
diseases treated under protocols for broad spectrum activity.
Phase III
Traditional large trials in humans with the disease.
2-animal rule testing for biodefense – animal numbers to be
determined with the FDA. Human volunteers with infectious
diseases treated under protocols for broad spectrum activity.
Phase IV
Traditional post-launch Studies
Increased monitoring of human adverse events.
Integrating Decisions
for the Multiple Network Projects
Concept
Development
Technology Development
4 years
System Development &
Demonstration 3-4 years
2 Animal Rule/Surrogates
To INDA
E-IND
IND
Discovery Discovery
& Early Development
Idea
Network
Discovery
Proposal
FDA
Review
EUA
Phase I
Confirmation of
Profiles
Phase II & III
Ongoing Reviews
NDA
FORMULATIONS
MANUFACTURING
Integrating Oversight
•Academia
•Industry
Industry Partner
Thrust Area
Thrust
AreaLeader
Leader
Disc. PTL
Discovery
Lead
Production
Continued FDA
Process Scale-up
Req for
Dev
Leads
Production and
Deployment
Development
Development Lead
PTL
Industry Partner PTL
Market
Operations
and Support
System Issues
Technology
• Knowledge
– Network Knowledge-Base Development
– Skills in Innovation, Research, Clinical Research, Network
Formulations, Development, Manufacture, FDA, Quality
Assurance, Oversight of Integrated Effort
– Polyvalent Technologies: Knowledge Enhancement
• Associated Skills
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Animal Models and Surrogate Development
GLP/cGMP/Pilot Lot Production Capabilities
Expertise in “FULL SPECTRUM” Pharma Development
Expertise in “FULL-SCALE” Manufacturing
Strategic Business Development: Industry, Academia,
Orchestrated International Integration
Knowledge and Information
• Integrating Knowledge and Information
– Bioinformatics
• Dynamic Understanding of Networks
• Knowledge Development and Application to Development
– Multiscience and Multidiscipline
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Valuation of Orthogonal Analyses of Multiple Projects
Detailed Analysis of Scientific Endeavors
Status and Maturity of Each Technology
Project Stage of Development
Judgments on Manufacturing and Production
Process and Programmatic Reviews
– Business, Legal and IP, Contracting with Partners
Product Development
• Scale-up
– Network-Based Pharmaceuticals
• “Broad Spectrum”
– Evaluation for non-Biodefense Applications
• Production Platforms
– Genomics, Proteomics, Immunologics, Metabolomics
– Cells, Plants, Animals, “eggs”, Protein Scaffolds,
Alternatives
• Oversight of Projects & Integration Across Projects
– Internal Cognitive Excellence vs
– Reliance on External Experience
Competencies
• Comprehensive Development
– Research through Development to Licensure and Patient
• Pharmaceutical Process “in detail”
– Multiple Scientific Pathways
– Multicomponent Pharmaceuticals
• Robust Post-Licensure Studies
– Broad Spectrum Endeavors
– Infectious Diseases: Common Networks
– Network Commonalities:
• Biological, Chemical, Radiological
• Human Disease States
– Knowledge Development and Information Management
– FDA Critical Paths, 2 Animal Rule, Licensure of Network
Pharmaceuticals
Insights
•
Need Broad Spectrum Development Enterprise
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•
Core Competencies Resident in the Organization – Do they Align?
Cross-Cutting Integration of Information Systems
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Infuse Milestone Decision Process with Scientific, Medical and Pharmaceutical Judgment
Recognize Multiple Technical Challenges
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Implement Orthogonal Development Strategy
Develop Detailed Expertise in “The Science” under Development
• In Detail: “at the bench” and “all the way to the bottle and patient”
Integrate “Other Government,” Industry, Academia, International Partners
Decision Processes Not Necessarily Positioned to Adapt to Network Development
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Knowledge Development; Bioinformatics; Information and Knowledge Management
Pharmaceutical Requirements Not Focused on Network Development
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–
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Grounded in Science, Medicine and Pharmaceutical Development
“Broad Spectrum” Testing to other Infectious Diseases
May Require Multicomponent Pharmaceutical Initiative
Identify Required Intellectual and Institutional (Scientific, Medical, Pharmaceutical and Programmatic Review
Infrastructure) Capital
Structural Challenges Exist
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–
Integration of Expertise
Establish Scientific Oversight of Network Development
•
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Identify Network-Based Pilot Production Capability
•
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Incorporate Scientifically Driven Orthogonal Reviews for Development Decisions
Consider Review of National Infrastructure Requirements as DoD Contributes Capability
Identify Competences to Integrate all Network Research into Focused Product Development
Considerations
Strategic
• Integrated Strategic Oversight
– Integrate Science into Network Decision Making
• Process Management & Control
– Orthogonal Reviews
• Scientific > Pharmaceutical > Medical > Programmatic
– Tiered Metrics Drive Funding Decisions
• Technical Review and Judgment Body – Senior Body
• Funding Plans for Integration of Insights & Solutions
• Collaborations:
– National, Intl, Govt/Industry/Academia, Consortia Opportunities
• Inject Innovation Throughout
System
• Broad Spectrum Pharmaceutical Enterprise
– Network Biology
• Knowledge & Information Development & Management Activity
– Develop &/or Recruit Necessary Competencies
• Orthogonal Pharmaceutical Process & Decisions
– Scientific>Pharmaceutical>Medical>Programmatic
• Scientific and Process “Network” Metrics
– Chem, Biol, PK/PD, Safety, Toxicity, Biomarkers, Formulation
• FDA Innovation: Critical Path, 2-Animal Rule, e-IND & PAT
• Infrastructure: Partnerships
– National, Government, International, Academia, Capital
• Quantify Infrastructure Requirements
Process
•
Link Milestones to Scientific Evolution:
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–
•
Network Characterization = Key Characteristics (KC)
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•
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Establish Scientific Through Programmatic Metrics Tied to pre-Clinical Decision Points,
and to Key Decisions in Clinical Development
Establish Process Analytical Technologies Program with Metrics
Establish Expert Oversight Capability
–
–
•
•
•
Establish “Cross-Cutting” Technically Competent Project Teams
• Discovery, Optimization and Development
Metrics:
–
•
Based on Understanding of Key “Network” Components
Structure KCs to Link to Clinical Outcomes at Earliest Opportunity
Orthogonal Development
–
•
Infuse Scientific, Medical and Pharmaceutical Judgment Throughout
Will Likely be Different for Each Project
Internal or Consultant
Approach: 1. Various Scientific Endeavors
2. Multiple Candidates Under Development
3. FDA Critical Path Discussions
E-IND: Tests in Humans
IND and Milestone A: Dynamic
Phase I: After E-IND Finished and IND Filed
Organizational Considerations
• Pharmaceutical: Incorporate Network Development
– Bioinformatics for Network Development
– Orthogonal Portfolio Review
• Decision Process - Base on Scientific Validation at:
–
–
–
–
–
1.
2.
3:
4:
5:
Implementation of E-IND
Development After E-IND
Decisive Development post IND
Pre-Licensure
Process Analytical Technologies Metrics
• Quantify Institutional and Intellectual Requirements
– Establish Manufacturing Capability: At Least for Network Enterprise
– Organize Competencies: Innovation Organization; Network Expertise;
Network Animal/Surrogate Studies, Biodefense Campus Integration