Drug discovery and development overview

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  • 1. Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Drug Abuse and Dependence Overdosage Dosage and Administration How Supplied Clinical Studies References

2. Immunologist Tissue staining 1908 Nobel Prize for Medicine Magic Bullet Salvarsan 3. Paul Ehrlich: All who are about to embark on developing a new drug must bring to the task four essentials: brains persistence capital luck 4. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3 NDA/BLA/PMA FDA Review Approval Product Launch 5. The term includes basic and applied research as well as development activities carried on or supported in the pharmaceutical, biological, chemical, medical, and related sciences, including psychology and psychiatry, if the purpose of such activities is concerned ultimately with the utilization of scientific principles in understanding diseases or in improving health. 6. The term Discovery is used to describe the early phases of the overall biomedical discovery process, that is, the synthesis of or the search for compounds and the screening processes developed to identify lead compounds. 7. Uncured Diseases Approximate Annual Prevalence Approximate Economic Cost (billions) Cardiovascular 56,000,000 $128 Cancer 10,000,000 $104 Alzheimers 4,000,000 $100 Diabetes 16,000,000 $ 92 Arthritis 40,000,000 $ 65 Depression 17,400,000 $ 44 Stroke 3,000,000 $ 30 Osteoporosis 28,000,000 $ 10 8. National Cancer Institute National Heart, Lung and Blood Institute National Institute on Aging National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Diabetes and Digestive and Kidney Diseases 9. American Cancer Society American Heart Association Howard Hughes Medical Institute Salk Institute for Biological Studies 10. Select area of therapeutic or diagnostic interest Establish long term (5 to 10 year) goals for program Commit needed resources 11. Short term plans, 1 to 3 years Identifies areas for discovery research Allocates resources to carry out the plan people space equipment money 12. Discovery research Marketing Clinical research 13. Product Market Proprietary Aspects Technologies used Mechanism of action Regulatory agencies involved Clinical trials 14. Diagnostic Therapeutic Device Combination 15. Who will use the product? What special needs does that group have? Who will pay for the product? 16. Basic Research Feasibility Explore research/design options Lead candidate 17. Cloning Protein purification Monoclonal antibodies Carbohydrate technology In vivo genetic modification Transgenic manipulation Cell culture 18. Tool to identify new drug candidates Usually a subcellular component (enzyme, receptor, etc.) removed from a living system and studied in vitro ACTIVES: agents that stimulate or inhibit normal function 19. Receptor: any biological macromolecule which can be activated by a drug to cause a biological response or effect. 20. Agonist: a drug which binds to a receptor and elicits a biological response Antagonist: occupies (or blocks) a receptor but does not elicit a response Intrinsic activity: the measure of a drugs ability to elicit a response 21. Synthetic program High through-put screening program Compound libraries 22. Fermentation/microbial sources Plant/herbal sources Arachnid and amphibian sources Marine sources 23. Tool to identify new drug candidates Usually a subcellular component (enzyme, receptor, etc.) removed from a living system and studied in vitro 24. An active is a substance that causes inhibition or stimulation in a screening model, thereby indicating the substance may have pharmacological effect. 25. A compound that exhibits pharmacological properties which suggest its value as a starting point for drug development. 26. The process of synthesizing chemical variations, or analogs, of a lead compound, with the goal of creating those compounds with improved pharmacological properties. 27. From WSJ Jan 27, 2000: Three teams of researchers have discovered a gene for a protein that appears to prevent nerves in the brain and spinal cord from growing back after being damaged by injury or disease. 28. By studying the protein, researchers hope they can design drugs that might help regenerate damaged nerves 29. Scientist are looking for the receptor for the protein. Once it is found, drug companies may be able to design antagonists to block the effect of the protein, allowing damaged nerves to regenerate. 30. Ames Test In vitro metabolism microsomes hepatocytes liver slices 31. Compoundfromsyntheticprogram, combinatoriallibrary,chemicallibrary, naturalproductsource,etc. Invitroevaluation-human/mammal receptor/enzymeassay;reporter system Active Biochemical,tissueoranimalmodelof function Active Animalmodeloftheraputictarget Pharmacokinetics,formulation,acute toxicology Approvalforclinicaldevelopment Yes Yes No No 32. For every experiment the researcher should record: each item, source, lot number and quantity used experimental conditions, e.g., times, temperatures, pressures, etc. all calculations sampling schedule, results 33. Safety and Efficacy Chemistry/Pharmacy Clinical/Regulatory Marketing/Legal Potential Ups and Downs 34. Process not well controlled; nonreproducible results Insufficient experience to adequately predict critical parameters Process not scaleable as is Documentation incomplete, poorly recorded, poorly organized, or does not support claims 35. Introduction and Summary Assays Chemistry Pharmacy Patents Clinical Plan Regulatory Affairs Potential Liabilities Competition Candidate Potential Safety Recommendation 36. Research Development Overall objective Select a development candidate Submit an NDA Corporate Mandate Broad, Loosely defined Narrow, focused Compounds tested Many, diverse One Types of studies Few Many 37. Research v. Development Research Development Regulatory Little or none Extensive Timetable Loose, flexible Strict, constrained Recognition Innovation Speed Culture Chaotic Structured Workstyle Entrepeneurial Interdependent 38. Research Development Quantity g mg g g kg Safety Ames, P450 1 w 105 w Formulation Capsule Tablet, inject. Metabolism Radiolabeled Assay Budget Departmental Proj. Acct. No. Costs $1,000,000 39. 1. Establish raw material specifications 2. Scale-up production processes 3. Establish critical process control parameters 4. Establish final product specifications 5. Validate analytical methods 6. GLP preclinical studies 7. Prepare clinical trial material 8. Initiate stability/reliability studies 9. Establish document systems 40. New Chemical Entities (NCE) or New Molecular Entities (NME) - active ingredients never before used as drugs 41. The active ingredient intended to diagnose, treat, cure, or prevent disease or affect the structure or function of the body, excluding other inactive substances used in the drug product. 42. Identity: normally two identity tests required Strength/potency Sensitivity Specificity Purity: normally 98+% for NCEs Stability Safety and efficacy 43. The finished dosage form (tablet, capsule, etc.) that contains a drug substance--generally, but not necessarily, in association with other active or inactive ingredients. 44. Establish specifications and specification testing requirements for: identity potency/strength purity stability 45. United States Pharmacopoeia and National Formulary - designated as the official compendia pursuant to federal and some state statutes, and containing enforceable standards and specifications for strength, quality, purity, packaging, labeling, and where applicable, bioavailability of drugs 46. Nonclinical laboratory study - in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. 47. Regulations established in the U.S. in 1976 to ensure the quality and integrity of bioresearch and animal test data submitted to the FDA 48. Regulations on facilities and equipment Regulations involved in tests and controls Regulations on personnel and organization 49. Verify the quality and integrity of data submitted to FDA Inspect nonclinical laboratories engaging in safety studies for regulated products Audit ongoing and completed lab safety studies Determine degree of compliance with GLP regulations 50. Toxicology Acute toxicity Subacute and chronic toxicity Reproductive and developmental studies Mutagenicity Metabolism Pharmacology Tissue residue Environmental 51. Study of how the drug is absorbed, distributed throughout the body, metabolized and excreted (ADME) Determination of the rate constants (kinetics) for ADME 52. Engineering: Determine pilot plant requirements for preparation of clinical trial material Clinical Affairs: Begin the design of clinical studies to establish efficacy and tolerance of the new drug candidates in human beings Regulatory Affairs Prepare IND/IDE Pre-IND/IDE meeting with the FDA to discuss plans for Phase I clinical trials 53. Drug/Biologic/Component Characteristics Description of actives, excipients, components, and solvents required for formulation or assembly Analytical test methods Process or assembly instructions Processing equipment incompatibilities 54. Regulatory Affairs Regulatory status of drug substance and finished product History or status of communications with FDA World wide regulatory strategy 55. Engineering Equipment/environmental/facility requirements for manufacture Special handling requirements 56. Th