Molecular DevelopmentMolecular Development2121stst Century Pharmaceuticals Century Pharmaceuticals

Joseph M. Palma, MD, MPH, CPEInstitute of Defense Analyses

March 29, 2007

571-437-7948josephpalma@cox.netjpalma@ida.org

E-Coli Transcription Regulatory NetworkBarabasi, 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).

Networks

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 16anaerobic regulator, regulatory gene for nitrite and

nitrate reductases, fumarate reductase

HNS 7 22 5DNA-binding global regulator; involved in chromosome

organization; preferentially binds bent DNA

OmpR 6 20 3Response 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 6Response regulator protein represses aerobic genes under anaerobic growth conditions and activates some anaerobic

genes

NarL 13 15 5Two-component regulator protein for nitrate/nitrite

response

Radu Dorbin et al, BMC Bioinformatics. 2004; 5: 199

E-ColiTranscription Regulatory Network

Radu Dorbin, et al, BMC Bioinformatics. 2004; 5: 199

E-ColiTranscription Regulatory Network

BMC Bioinformatics. 2004; 5: 199

Meds

Outline

• 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

Trends Documentation

Orchestration Execution

Metrics

Technology,Bioinformatics,

KnowledgeDevelopment

& Management

Accountability

Reporting

Information

Timelines

The Strategy

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

Production & Deployment

Project Scope

Vac

cine

PostLaunch Review

Milestone CNDA/BLA filing

Phase IIIMilestone B Proof of Concept

Approach CandidateSelection

Milestone AFirst in Human

BLAApproval,Launch

Product Requirements

Candidate Downselect

Diseaserequirements FilePhase IIIPhase IIPhase IPreclinical

CandidateDiscovery

ApproachDefinition

CandidateOptimization

System Development & Demonstration

IOC

Technology Development

FOCProgram Initiation

Concept Refinement

A B C

Launch

Operations & Support

Pha

rmac

eutic

al

Postlaunch review

Milestone CNDA/BLA filing

Commit to Phase III

Milestone B Proof of Concept

Committo target

CandidateSelection

Milestone AFirst in human

NDAApproval,Launch

Commit to product type

Lead Selection

Disease/Target FamilySelection

FilePhase IIIPhase IIPhase IPreclinicalLead

GenerationTarget ID/Validation

LeadOptimization

System Development & Demonstration

IOC

Technology Development

FOCProgram Initiation

Concept Refinement

A B C

Launch LifecycleManagement

Production & Deployment

Operations & Support

Portfolio

s

TargetIdentified Evaluate

Target

DevelopProjectCharter

No Go orRevise Charter

Proceedto Pre-IND

Studies

EstablishDP1 G/NG

Criteria

DiscoverLead Ab

Candidates

In VitroPOC

TestingTargetSelected

SelectInitial

mAb(s)

EstablishDP2 G/NG

CriteriaTissueProfiling(Norm,

Dis)

In VivoPOC

Testing inDiseaseModels

SelectCandidate

mAb(s)

EstablishDP3 G/NG

Criteria

In-Depth Pharmacology,PK/PD, Prelim Safety &

Toxicity, Identify/QualifyBiomarkers

Initiate CMC Activities(Cell Line, Process Dvmt)

EstablishIND G/NGCriteria

Mkt & CompetitionAnalysis

Establish PK/PD &Toxicity Levels,Biomarker Dvmt

Establish CDP &G/NG Criteria

CMC Activities(Process Dvmt, Mfg)

File IND &Start Ph I

Proceedto Ph II

Proceedto Ph III

Prepare&

File BLA

Initiate Mkting &Commercial

Activities

BLASubmitted

CommercialReadiness

SiteInspection

PMSReadiness

FDAApproval

LaunchProduct

ProductLaunched

DP0 DP1

No Go orRevise TPP

No Go orRevise TPP

No Go orRevise TPP

No Go orRevise TPP

DP2

DP3

Phase IClinical Trial(s)(Safety, PK/PD)

Phase IIClinical Trial(s)

(Safety, PK/PD, Efficacy)

Phase IIIClinical Trial(s)

(Safety, Efficacy)

CMC Activities(Process Dvmt,Mfg Scale-up)

Mfg Process/Formul/Presen

FixedNo Go or

Revise TPPNo Go or

Revise TPPNo Go or

Revise TPP

IND

AssembleTarget

AssessmentTeam Create

TPP(s)

FormProjectTeam

A Snapshot of the Industry Pharmaceutical Process

TPP= Target Product Profile

DP = Decision Point

Portfolio

s

Candidates

M E T R I C SDECISIONS

Current Industry View

Adapted from information provided by Pfizer Pharmaceuticals, Inc

Pharmaceutical Process

DiscoveryDiscovery

Exploratory DevelopmentExploratory Development

Full Development

RegistrationRegistration

Project TeamProject Teamand Plansand Plans

Project TeamProject Teamand Plansand Plans

SynthesisSynthesis of Compoundsof Compounds

SynthesisSynthesis of Compoundsof Compounds ScreeningScreeningScreeningScreening

Studies in HealthyStudies in HealthyVolunteers (Phase I)Volunteers (Phase I)Studies in HealthyStudies in Healthy

Volunteers (Phase I)Volunteers (Phase I)

Early SafetyEarly SafetyStudiesStudies

Early SafetyEarly SafetyStudiesStudies

CandidatesCandidatesCandidatesCandidatesFormulationsFormulations

DevelopedDevelopedFormulationsFormulations

DevelopedDeveloped

Extensive Safety Studies

Extensive Safety Studies

NDANDA

Studies in 100-300Studies in 100-300

Patients (Phase Patients (Phase II)II)Studies in 100-300Studies in 100-300

Patients (Phase Patients (Phase II)II)

Clinical Data Clinical Data AnalysisAnalysis

Clinical Data Clinical Data AnalysisAnalysis

Candidate Medicine Tested inCandidate Medicine Tested in3-10,000 Patients (Phase III)3-10,000 Patients (Phase III)

Candidate Medicine Tested inCandidate Medicine Tested in3-10,000 Patients (Phase III)3-10,000 Patients (Phase III)

Large Amounts of Large Amounts of Candidate Medicine Candidate Medicine

SynthesizedSynthesized

Large Amounts of Large Amounts of Candidate Medicine Candidate Medicine

SynthesizedSynthesized

Meds

Rework& Optimize

Rework& Optimize

START

Rework& Optimize

CandidateCandidateDevelopmentDevelopment

Portfolio

s

Pha

rmac

eutic

al

Postlaunch review

Milestone CNDA/BLA filing

Commit to Phase III

Milestone B Proof of Concept

Committo target

CandidateSelection

Milestone AFirst in human

NDAApproval,Launch

Commit to product type

Lead Selection

Disease/Target FamilySelection

FilePhase IIIPhase IIPhase IPreclinicalLeadGeneration

Target ID/Validation

LeadOptimization

System Development & Demonstration

IOCTechnology

Development

FOCProgram Initiation

Concept Refinement

A B C

Launch LifecycleManagement

Production & Deployment

Operations & Support

Optimize

Network Development

One Product or Multi-componentCocktails

Requirements

Several Genomic Candidates & Technologies

Def

ine

KE

Y N

etw

ork

Co

mp

on

ents

Tes

KE

Y t

Net

wo

rk C

om

po

nen

ts

Val

idat

e T

arg

ets

and

Tes

t V

ario

us

Ap

pro

ach

es

Several Proteomic Candidates & Technologies

Several Small Molecule Candidates & Technologies

Several Metabolic Candidates & Technologies

Hu

man

Tes

t A

ll C

and

idat

es

Sel

ect

the

Bes

t &

/or

Inte

gra

te m

ult

ico

mp

on

ent

Sel

ect

Can

did

ates

&

Ap

pro

ach

es

Approaches

CandidatesSelected

CandidatesOptimized

Phase ISmall Human Test

Milestone B Phase IIPhase III

(File NDA) Approved PostLaunch Reviews

E-IND

INDMilestone A

Develop one or More Network-SpecificCountermeasures and Determine on

Integration into a “Cocktail”

Optimize

Optimize

Multiple Approachesare Matured &

Multiple Drug CandidatesManufactured

FDA ENGAGED THROUGHOUT

Current

Milestone C

“Very Dynamic”Portfolio

sENTERPRISE-WIDE OVERSIGHT & METRICS THROUGHOUT

MASSIVELY PARALLELAND

ORTHOGONAL DEVELOPMENTNetwork Network

Orthogonal

Points

1

2

3

4

5

6

PROCESS ANALYSIS TECHNOLOGY METRICS

Orthogonal Reviews

Genomics

Proteomics

Immunologic

Metabolomics

Pre-Clinical

E-IND Phase I

2 3

Devel

opm

ent

Decis

ions

MEDS

IND

Portfolio

s

Summary of DifferencesCurrent Approach Network Development

Requirements Characterize Pathogen (sequences, key proteins, virulence factors, Antigen immunogenicity…) Identify protein family, targets, validate role in disease.

Characterize NetworkNetwork (Establlish network type<hierarchy, free scale, random>), Illustrate mechanism of pathogenic action and key network nodes, as well asas 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.

Portfolio

s

I n t e g r a t i n g D e c i s i o n sfor the Multiple Network Projects

Portfolio

sOperations and Support

Concept Development

Discovery

Production and Deployment

Production

Continued FDA

Market

Thrust Area LeaderDisc. PTL Development PTL

Process Scale-up

Phase II & III

Ongoing Reviews

2 Animal Rule/SurrogatesTo INDA

EUAIND

Network

CANDIDATES

Technology Development4 years

System Development & Demonstration 3-4 years

Thrust Area LeaderDiscovery Lead

Industry Partner

NDA

•Academia•Industry

Idea

Proposal

Phase IConfirmation of

Profiles

Leads Req for Dev

Network Discovery

E-IND

FDA Review

Development Lead

Discovery & Early Development

FORMULATIONSMANUFACTURING

Integrating Oversight

Industry Partner PTL

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– 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• 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

– Grounded in Science, Medicine and Pharmaceutical Development – “Broad Spectrum” Testing to other Infectious Diseases– May Require Multicomponent Pharmaceutical Initiative

• Core Competencies Resident in the Organization – Do they Align?• Cross-Cutting Integration of Information Systems

– Knowledge Development; Bioinformatics; Information and Knowledge Management

• Pharmaceutical Requirements Not Focused on Network Development– 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– Infuse Milestone Decision Process with Scientific, Medical and Pharmaceutical Judgment

• Recognize Multiple Technical Challenges– Identify Required Intellectual and Institutional (Scientific, Medical, Pharmaceutical and Programmatic Review

Infrastructure) Capital

• Structural Challenges Exist– Integration of Expertise– Establish Scientific Oversight of Network Development

• Incorporate Scientifically Driven Orthogonal Reviews for Development Decisions

– Identify Network-Based Pilot Production Capability• 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:

– Infuse Scientific, Medical and Pharmaceutical Judgment Throughout – Will Likely be Different for Each Project

• Network Characterization = Key Characteristics (KC)– Based on Understanding of Key “Network” Components– Structure KCs to Link to Clinical Outcomes at Earliest Opportunity

• Orthogonal Development– Establish “Cross-Cutting” Technically Competent Project Teams

• Discovery, Optimization and Development• Metrics:

– 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

– 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. Implementation of E-IND– 2. Development After E-IND– 3: Decisive Development post IND– 4: Pre-Licensure– 5: 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