Presentation on theme: "BIOPHARMACEUTICAL DEVELOPMENT PROGRAM BIOLOGICAL RESOURCES BRANCH"— Presentation transcript:
1 MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO CLINICAL PROOF-OF-PRINCIPLE BIOPHARMACEUTICAL DEVELOPMENT PROGRAMBIOLOGICAL RESOURCES BRANCHDEVELOPMENTAL THERAPEUTICS PROGRAMNATIONAL CANCER INSTITUTEFREDERICK, MARYLAND
2 MissionTo produce clinical-grade biopharmaceuticals under current Good Manufacturing Practices (cGMPs) appropriate for Phase I/II (dose-ranging safety and efficacy) and “proof of principle” clinical trials of innovative biopharmaceutical concepts.To manufacture high-quality laboratory-grade material to support preclinical development for selected innovative projects.
3 Key AssumptionsConcepts are selected for novelty and innovation over derivatives of existing approaches.Many projects have been previously considered by Pharma and declined due to uncertain technology, regulatory hurdles, or small markets.Clinical production is focused on meeting requirements for initial proof-of-concept trials, NOT final product requirements for commercial development.Approximately 1/10 to 1/20 clinical projects may eventually be licensed.Desired size of program is based on assumptions #1-4 (i.e., 10 to 20+ projects/year to clinic).Intellectual Property to be retained by Project Originator(s).
4 Where Does the Program Get Its Projects Peer-Reviewed Extramural ResearchSpecial CompetitionsRapid Access to Intervention Development (RAID) ProgramInter-Institute Program (IIP) for AIDS ProjectsNational Cooperative Drug Discovery GroupsIntramural NCI ResearchOther NIH Programs (NIAID)Commercial Collaborations With GovernmentThe NCI Selects and Prioritizes Candidate ProjectsBDP Provides Feasibility Analyses and Cost Estimates That Are Used in the Selection
5 Capabilities and Resources Fermentation for Recombinants: 20L, 80L, 100L and 1,000LNatural Products Fermentation: 30, 300, 3,000 GallonsHollow Fiber Mammalian Cell Production (8 Pathways)Packed Bed Mammalian Cell ProductionProcess Development and OptimizationFermentationRecoveryRefoldingPurificationAssaysEtc.Clean Room SuiteBL3 SuiteQAQCManagement of Required Out-Source Production and TestingCMC Documentation for IND Submission
6 Major Milestones in a Typical Clinical-Grade Production Project Pre-Proposal Communications With Potential Investigator-ApplicantsProposal Received by NCIInitial Review by StaffClarify Projects by Posing “Generic Questions” to ApplicantsMake Preliminary Feasibility Analysis & Cost EstimatesIdentify Any Special Concerns
7 Major Milestones (Continued) Peer Review by Selection CommitteeCommittee May Re-Define Project ScopeStaff Re-Examines Feasibility & Cost EstimatesOversight Committee ReviewStaff Present Cost and Feasibility AnalysisDetermination of Scope of ProjectRe-Evaluation of Progress at Key Milestones
8 Major Milestones (Continued) Initial Meeting of Staff With Outside InvestigatorInitial Project Team MeetingDefine DeliverablesMaterial RequirementsFormulationFillingSpecial ConcernsSafetyRegulatoryProductionAssaysSpecial ConsultantsOutline Major MilestonesDetermine Which Efforts Should Be In-House Versus Out-Source
9 Many Projects Require Substantial Attention at the Outset Expression SystemAmpicillin Selection PressureLab-scale Affinity PurificationProtein Solubility ProblemsLow YieldErrors in Genetic SequenceExtraneous Genetic MaterialPoorly Defined Production SystemInadequate Purification SchemesAnalytical ApproachesUnvalidated or Non-Existent In Vitro Potency AssayLack of Key Reagents (e.g., Antibodies to Desired Product)Poor Biochemical Characterization.
10 Many Projects Require Substantial Attention at the Outset (Continued) Regulatory and SafetyRaw Material QualificationInappropriate Cell BanksDifficult or Unidentified Toxicology SystemsFailed Vendor QualificationOtherIntellectual Property ConcernsDelays in Material Transfer AgreementsContracting Delays
11 Typical Results of One Review Cycle of Project Candidates 20 Projects Submitted for Review6 Selected2 – Clinical Development for Phase I Trials2 – Further Preclinical Development. May be re-reviewed for clinical production.2 – Production to Support Preclinical Development Only
12 Examples of BDP Projects in Various Stages During 12-Month Interval Monoclonal Antibodies (19)Other Mammalian Cell Products (3)Recombinant Proteins (14)Natural Products (1)DNA Vaccines (3)Genetically-modified Organisms for Vaccines (4) or Gene Therapy (2)Oligonucleotides (3)Synthetic Peptides (Many)Other (1)
13 Summary of Major cGMP Project Milestones During Past 12 Months Ch-EB6 MoAb (Affinity Purification Reagent) gmsCh14.18 (Anti-GD2 MoAb for Neuroblastoma Phase III Multi-Center Trial) (2 Lots) ,473 VialsPCLLUS 3-18MN Peptide Vaccine (HIV) VialsPCLUS MN Peptide Vaccine (HIV) VialsLMB-2 (Anti-TAC PE38) Immunotoxin (2 Lots) ,155 Vials1D12 MoAb (Affinity Purification Reagent) gmsHe-Fi 1 MoAb (Clinical) (2 Lots) ,070 VialsGeldanamycin (Antitumor Antibiotic) (4 Lots) gms
14 Summary of Major cGMP Project Milestones During Past 12 Months (Continued) HPV-16 E7 (12-20) Peptide Vaccine (HPV) VialsHPV-16 E7 (86-93) Peptide Vaccine (HPV) VialsHPV-16 E6 Peptide Vaccine (HPV) VialsHPV-18 E6 Peptide Vaccine (HPV) VialsMuB3 MoAb (Clinical) gmsHSV-863 MoAb (Clinical) gmsPatient-Specific Id Vaccines (Lymphoma) VaccinesPatient-Specific Peptide Vaccines Vaccines
15 Summary of Major cGMP Project Milestones During Past 12 Months (Continued) Allogeneic Pancreatic Cell Vaccine Patientsc-myb Antisense Oligodeoxynucleotide 6,000 VialsBradykinin Antagonist (Preclinical Studies) GramsEGFR VIII Peptide VialsCh 11-1F4 (Anti-Amyloidosis Antibody) GMP Chimeric CloneAnti-her2/ScFv (Preclinical) mgrPA (Anthrax Vaccine for Clinical Phase I Trials mgSEB (Staph Enterotoxin B Vaccine – 2 Lots) 1,647 Vials7G7 (B6 Anti-IL-2R MoAb [Clinical Bulk]) gms
16 Selected Examples of Projects Leading to Commercial Development IL-2 DPT (DABL-IL2) R&D supported through National Cooperative Drug Discovery Group mechanism. Licensed for cutaneous T-cell lymphoma.Anti-EGFR Antibody Manufacture of preclinical material and chimerization of antibody. Currently in licensing trials in head and neck cancer, other malignancies.Anti-GD2-IL2 Fusion Protein (Melanoma) R&D supported under National Cooperative Drug Discovery Group Mechanism. Manufacture of first clinical lot. Further development underway by company.
17 Selected Examples of Projects Leading to Commercial Development (Continued) Patient-Specific Id Vaccines for Myeloma & Lymphoma Manufacture of 30+ vaccines/year. Entering controlled trials in lymphoma. CRADAs signed for development for lymphoma and myeloma indications.Anti-CD22/PE38 Immunotoxin for Lymphoma Manufacture of clinical material for initial trials. Being developed by company.Anti-CD25/PE38 Immunotoxin for Lymphoma Manufacture of clinical material for initial trials. Licensed by company.IL7 Cytokine Manufacture of preclinical and clinical material for initial clinical studies. CRADA signed with company.
18 Selected Examples of Projects Leading to Commercial Development (Continued) Anti-Amyloid Antibody for Amyloidosis. Chimerization of Murine Antibody. Manufacture of preclinical material for evaluation. Clinical production and Cooperative Group Trials to be reviewed by DDG. Project recently licensed by outside Pharmaceutical Company.Anti-her2 Single Chain Antibody Targeted Liposomes Delivering Chemotherapeutic Agents. Process development and manufacture of initial clinical material underway. Project recently licensed and further development in collaboration with outside Pharmaceutical Company.Pancreatic Cancer Cellular Vaccines. Manufacture of material for Phase I clinical Trial. Recently licensed by outside Pharmaceutical Company that will help defer costs of material for follow-on Phase II clinical trial.
19 The Idea is Not Enough: Characteristics of Projects With Eventual Commercial Development (With Some Exceptions)What The Investigator Has Already DoneDefined Candidate MoleculeComparisons With Similar ProductsCharacteristics of Molecule Consistent With Pharmaceutical RequirementsProduction AdequateProduct Characterization AdequateLaboratory StandardIn vitro Potency AssayStability StudiesReproducible Model SystemsEarly Animal Work Includes Some ToxicologyScale-up Requirements Practical for Initial Clinical TrialsGeneral: Previous Experience of Investigator
20 SummaryA flexible and adaptive approach to facilitation of clinical proof-of-concept evaluation of promising new biopharmaceutical concepts appears to be a cost-effective approach to increasing the number of innovative clinical development candidates.
21 Dr. Gautam Mitra, Director ACKNOWLEDGEMENTSBIOPHARMACEUTICAL DEVELOPMENT PROGRAMDr. Gautam Mitra, DirectorDevelopment LaboratoryJianwei Zhu, HeadBob TestermanAndy BurnetteJuliet LuoVinay VyasYueqing XieJoan TuckerLoren WardNacole LeeXiaojin Wu
22 ACKNOWLEDGEMENTS Purification Laboratory Steven Giardina, Head Aparna KolhekarMary KoleckEarl NelsonScott JendrekTim OuelletteDavid NellisFermentationJianwei Zhu, SupervisorPhil Rothchild, SupervisorDenise EkstromGary SpencerJohn RoachRay Rose