Biomedical Product Development

1. Biomedical Product Development Start with the end in mind Focus on areas of strength

2. Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Drug Abuse and Dependence Overdosage Dosage and Administration How Supplied Clinical Studies References US Package Insert Sections

3. Paul Ehrlich 1854 - 1915 • Immunologist • Tissue staining • 1908 Nobel Prize for Medicine • “Magic Bullet” • Salvarsan

4. Essentials Paul Ehrlich: All who are about to embark on developing a new drug must bring to the task four essentials: • brains • persistence • capital • luck

5. Development Time Line

6. Research and Development 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.

7. Discovery 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.

8. Idea sources Where do ideas for new products originate?

9. The Process of Discovery

10. Prevalence and Cost of Uncured Disease in the US

11. National Institutes of Health • 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

12. Private Organizations • American Cancer Society • American Heart Association • Howard Hughes Medical Institute • Salk Institute for Biological Studies

13. Share of U.S. Ethical Pharmaceutical Market by Product Class, 1995

14. The Process of Discovery

15. Strategic Plan • Select area of therapeutic or diagnostic interest • Establish long term (5 to 10 year) goals for program • Commit needed resources

16. Program Plan • Short term plans, 1 to 3 years • Identifies areas for discovery research • Allocates resources to carry out the plan • people • space • equipment • money

17. Technology Assessment • Discovery research • Marketing • Clinical research

18. Define the Target • Product • Market • Proprietary Aspects • Technologies used • Mechanism of action • Regulatory agencies involved • Clinical trials

19. Product Definition • Diagnostic • Therapeutic • Device • Combination

20. Know your market • Who will use the product? • What special needs does that group have? • Who will pay for the product?

21. Biomedical Research/Design • Basic Research • Feasibility • Explore research/design options • Lead candidate

22. Biotechnology Discovery Tools • Cloning • Protein purification • Monoclonal antibodies • Carbohydrate technology • In vivo genetic modification • Transgenic manipulation • Cell culture

23. The Screen • 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

24. Receptors Receptor: any biological macromolecule which can be activated by a drug to cause a biological response or effect.

25. Agonists and Antagonists • 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 drug’s ability to elicit a response

26. Chemical Candidate Sources • Synthetic program • High through-put screening program • Compound libraries

27. Natural Product Sources • Fermentation/microbial sources • Plant/herbal sources • Arachnid and amphibian sources • Marine sources

28. High Through-put Screening • Tool to identify new drug candidates • Usually a subcellular component (enzyme, receptor, etc.) removed from a living system and studied in vitro

29. Active An active is a substance that causes inhibition or stimulation in a screening model, thereby indicating the substance may have pharmacological effect.

30. Lead Compound A compound that exhibits pharmacological properties which suggest its value as a starting point for drug development.

31. Optimization The process of synthesizing chemical variations, or analogs, of a lead compound, with the goal of creating those compounds with improved pharmacological properties.

32. Neural Discovery 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.

33. So What? By studying the protein, researchers hope they can design drugs that might help regenerate damaged nerves

34. The Next Steps 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.

35. Safety Assessment Ames Test In vitro metabolism • microsomes • hepatocytes • liver slices

36. Candidate Flowchart

37. Quality Considerations 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

38. Product Review • Safety and Efficacy • Chemistry/Pharmacy • Clinical/Regulatory • Marketing/Legal • Potential Ups and Downs

39. Pitfalls of Research Stage • 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

40. Introduction and Summary Assays Chemistry Pharmacy Patents Clinical Plan Regulatory Affairs Potential Liabilities Competition Candidate Potential Safety Recommendation Safety Assessment Candidate

41. Research v. Development

42. Research v. Development

43. Research v. Development

44. Development Tasks 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

45. New Drug Entities New Chemical Entities (NCE) or New Molecular Entities(NME) - active ingredients never before used as drugs

46. Drug Substance orActive Pharmaceutical Ingredient 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.

47. API Requirements • Identity: normally two identity tests required • Strength/potency • Sensitivity • Specificity • Purity: normally 98+% for NCE’s • Stability • Safety and efficacy

48. Drug Product The finished dosage form (tablet, capsule, etc.) that contains a drug substance--generally, but not necessarily, in association with other active or inactive ingredients.

49. Raw Materials Establish specifications and specification testing requirements for: • identity • potency/strength • purity • stability

50. USP/NF 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