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Molecular Development 21 st Century Pharmaceuticals

Molecular Development 21 st Century Pharmaceuticals. Joseph M. Palma, MD, MPH, CPE Institute of Defense Analyses March 29, 2007. 571-437-7948 josephpalma@cox.net jpalma@ida.org. E-Coli Transcription Regulatory Network

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Molecular Development 21 st Century Pharmaceuticals

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  1. Molecular Development21st Century Pharmaceuticals Joseph M. Palma, MD, MPH, CPE Institute of Defense Analyses March 29, 2007 571-437-7948 josephpalma@cox.net jpalma@ida.org

  2. 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). Networks

  3. Global Regulators And Their Regulated Operons And Functions In The Regulatory Network Of E. Coli Radu Dorbin et al, BMC Bioinformatics. 2004; 5: 199

  4. E-ColiTranscription Regulatory Network Radu Dorbin, et al, BMC Bioinformatics. 2004; 5: 199

  5. Meds E-ColiTranscription Regulatory Network BMC Bioinformatics. 2004; 5: 199

  6. Outline • Background • Status • Strategy • Challenges • System Issues • Insights • Considerations

  7. Background • Broad Spectrum Countermeasures against Emerging and Bioengineered Agents

  8. Status • Development System • Traditionally One-Bug:One Drug • New Strategic Directioin • Network Based Pharmaceuticals • One Drug:Multiple Bugs • Strategy Alignment • Resources and Needs

  9. 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

  10. Strategy • Components • Characterization of the host-pathogen interaction • Diagnostics and Therapeutics • Preventive Measures • Information Systems and Bioinformatics • Challenges • Innovation • Technical • Pharmaceutical • Industrial • Oversight

  11. Orchestrating Information The Strategy Reporting Orchestration Execution Technology, Bioinformatics, Knowledge Development & Management Timelines Metrics Documentation Trends Accountability

  12. 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

  13. Project Scope C B A Program Initiation FOC IOC Concept Refinement Technology Development System Development & Demonstration Production & Deployment Operations & Support Vaccine Disease requirements Approach Definition Candidate Discovery Candidate Optimization File Phase I Phase III Preclinical Phase II Launch Product Requirements Approach Candidate Downselect Candidate Selection Milestone A First in Human Milestone B Proof of Concept Phase III Milestone C NDA/BLAfiling BLA Approval, Launch Post Launch Review C B A Program Initiation FOC IOC Concept Refinement Technology Development System Development & Demonstration Production & Deployment Operations & Support Pharmaceutical Disease/ Target Family Selection Target ID/ Validation Lead Generation Lead Optimization Lifecycle Management File Preclinical Phase III Phase I Phase II Launch Commit to product type Commit totarget Lead Selection Candidate Selection Milestone A First inhuman Milestone B Proof of Concept Commit to Phase III Milestone C NDA/BLAfiling NDA Approval, Launch Post launch review Current Process Portfolios

  14. A Snapshot of the Industry Pharmaceutical Process Portfolios Candidates M E T R I C S DECISIONS TPP= Target Product Profile DP = Decision Point

  15. Meds Studies in 100-300 Patients (Phase II) Current Industry View Portfolios Pharmaceutical Process NDA Clinical Data Analysis Registration Rework & Optimize Full Development Candidate Medicine Tested in 3-10,000 Patients (Phase III) Extensive Safety Studies Large Amounts of Candidate Medicine Synthesized Rework & Optimize Studies in Healthy Volunteers (Phase I) Candidates Formulations Developed Candidate Development Exploratory Development Early Safety Studies Synthesis of Compounds Screening START Project Team and Plans Discovery Rework & Optimize Adapted from information provided by Pfizer Pharmaceuticals, Inc

  16. ENTERPRISE-WIDE OVERSIGHT & METRICS THROUGHOUT MASSIVELY PARALLEL AND ORTHOGONAL DEVELOPMENT PROCESS ANALYSIS TECHNOLOGY METRICS FDA ENGAGED THROUGHOUT Network Network C B A Program Initiation FOC IOC Concept Refinement Technology Development System Development & Demonstration Production & Deployment Operations & Support Pharmaceutical Disease/ Target Family Selection Target ID/ Validation Lead Generation Lead Optimization Lifecycle Management File Preclinical Phase III Phase I Phase II Launch Commit to product type Commit totarget Lead Selection Candidate Selection Milestone A First inhuman Milestone B Proof of Concept Commit to Phase III Milestone C NDA/BLAfiling NDA Approval, Launch Post launch review Network Development Portfolios “Very Dynamic” Points 1 2 3 4 5 6 Milestone C Phase III (File NDA) Milestone B Phase I Small Human Test Phase II Approved Post Launch Reviews Candidates Optimized Candidates Selected Optimize Approaches E-IND Multiple Approaches are Matured & Multiple Drug Candidates Manufactured Requirements IND Milestone A Optimize Several Genomic Candidates & Technologies Develop one or More Network-Specific Countermeasures and Determine on Integration into a “Cocktail” Validate Targets and Test Various Approaches Several Proteomic Candidates & Technologies Define KEY Network Components Tes KEY t Network Components Select Candidates & Approaches Select the Best &/or Integrate multicomponent Human Test All Candidates Several Small Molecule Candidates & Technologies Several Metabolic Candidates & Technologies One Product or Multi-component Cocktails Optimize Orthogonal Current

  17. Orthogonal Reviews Portfolios Phase I 2 3 E-IND Pre-Clinical IND Genomics MEDS Proteomics Immunologic Metabolomics Development Decisions

  18. Portfolios Summary of Differences

  19. I n t e g r a t i n g D e c i s i o n sfor the Multiple Network Projects Portfolios Concept Development Technology Development 4 years System Development & Demonstration 3-4 years Production and Deployment Operations and Support 2 Animal Rule/Surrogates To INDA E-IND Network CANDIDATES FDA Review IND EUA Discovery Discovery & Early Development Phase I Phase II & III Production Idea Network Discovery Confirmation of Profiles Process Scale-up Continued FDA Market OngoingReviews Proposal Req for Dev NDA Leads FORMULATIONS MANUFACTURING Integrating Oversight • Academia • Industry Industry Partner Thrust Area Leader Thrust Area Leader Discovery Lead Disc. PTL Development PTL Development Lead Industry Partner PTL

  20. System Issues

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. Considerations

  27. 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

  28. 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

  29. 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

  30. 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

  31. QUESTIONS?

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