New Drug Development and Approval Process

1. New Drug Development and Approval Process

2. NEW DRUG DEVELOPMENT PROCESS • NEW CHEMICAL ENTITY • SOURCES: • Organic Synthesis • Molecular Modification • Isolation from plants • Genetic Engineering

3. PRECLINICAL STUDIES • Including • Chemistry • Physical Properties • Biological • Pharmacology • ADME • Toxicology • Preformulation

4. CLINICAL TRIALS • Phase I • Phase II • Phase III • PRECLINICAL STUDIES (Continued) • long term animal toxicity • product formulation • Manufacturing and controls • Package and label design

5. NEW DRUG APPLICATION (NDA) • Submission • FDA Review • Pre-approval Plant inspection • FDA action

6. POST MARKETING TRIALS • Phase IV Clinical Trials • clinical pharmacology/Toxicology • additional indications • Adverse Reaction Reporting • Product Defect Reposting • Product Line Extension

8. 4 Phases Of Clinical Studies In Man • PHASE 1 (Clinical Pharmacology) • fewer than 100 healthy people • design to determine that the drug is safe and the side effects might be • provide basic information about how drug works in the body • (Pharmacokinetic activity)

9. PHASE II (Clinical Investigation) • several 100 patients – disorders • evaluate dosage needed • detail how and why drug works in the body and side effect it causes • the drug must be effective and safe

10. PHASE III (Clinical Trials) • larger group of patients (2,000 to 3,000) • compare the drug with the existing drugs • provide statistics on adverse reaction

11. PHASE IV (Post Marketing Clinical Trials) • postmarketing surveillance may be required • unexpected reactions are detected, reported, and evaluated • new indications for using the drug, problems of people who take the drug

14. Some products, however, have been approved and later removed from the market for safety reasons, including the following: • Grepafloxacin HCL (Raxar) • Brofenac sodium (Duract) • Cisapride (Propulsid) • Alosetron HCL (Lotrovec) • Fenfluramine HCL (Pondimin)

15. Dexfenfluramine HCL (Redux) • Terfenadine (Seldane) • Cerivastatin (Baycol) • Mibefradil (Posicor) • Astemizole (Hismanal) • Troglitazone (Rezulin)

16. Preclinical Clinical NDA Review Post Marketing Research and Research and Development Surveillance Development Initial synthesis Adverse and reaction characterization Phase 1 Phase 2 Surveys/sampling testing Phase 3 Animal testing Short term Long term Inspection Average 61/2 Average 7 years Average 1 1/2 years years FDA 30-day safety review NDA submitted NDA approval Average of approx. 15 years from initial synthesis to approval of NDA

17. Drug Discovery and Drug Design - R and D activities on new Rx drugs for human - OTC drugs, generic drugs, biotechnology products, animal health care drugs, diagnostic products, and medical devices - development of new agents, such as vaccines to protect against poliomyelitis, measles, and influenza

18. - new pharmacologic categories of drugs including oral hypoglycemic drugs effective against certain types of diabetes mellitus • - antineoplastic or anticancer drugs, • - immunosuppressive agents to assist the body’s acceptance of organ transplant • - contraceptives to prevent pregnancy • - tranquilizers and antidepressant drugs to treat the emotionally distressed

19. New and Important Innovative Therapeutic Agents Approved by FDA 1. Efavirenz - Sustiva - to treat AIDS 2. Didanosine - Videx EC - to treat AIDS 3. Tenofovir - Viread - to treat AIDS 4. Leuprolide acetate - Eligard – prostate cancer 5. Triptorelin pamoate - Trelstar - prostate cancer 6. Lovastatin - Mevacor - hyperlipidemic 7. Treprostinil sodium - Remodulin - pulmonary arterial hypertensive

20. 8. Moxifloxacin HCl - Avelox - infectious disease 9. Montelukast sodium - Singulair - chronic asthma 10. Tegaserod maleate - Zelnorm - irritable bowel syndrome in women 11. Sodium oxybate -Xyrem - cataplexy in patient with narcolepsy 12. Galantamine HCl - Reminyl - dementia with Alzheimer’s disease 13. Fondaparinux sodium - Arixtra - deep vein thrombosis 14. Voriconazole - Vfend - infectious disease

21. SOURCES Of DRUGS • Pure organic compound • Natural or Synthetic • 3. Organometallic

22. These remedial have their origin in essentially 3 ways • Naturally occurring materials in both plants and animals • Example: Ergot, opium, curare, cinchona

23. 2. Synthesis of organic compounds whose structure are closely related to those naturally occurring compounds Example: morphine, atropine, cortisone, cocaine

24. 3. Pure synthesis in which no attempt has been made to pattern after a known naturally occurring compounds exhibiting some activity Example: antihistamine, barbiturates, diuretics, antiseptic, etc.

25. Sources of New Drugs 1. Reserpine - tranquilizers and hypotensive agent - isolated from Rauwolfia serpentina 2. Periwinkle or Vinca rosea - use as treatment of diabetes mellitus 3. Vinblastine and Vincristine - Vinca rosea - cancer, including acute leukemia, Hodgkin’s disease and lymphocytic lymphoma and other malignancies

26. Paclitaxel (Taxol)- Pacific yew tree - ovarian cancer • Dioscorea - Mexican yams - chemical steroid structure - cortisone and estrogen are semisynthetically produced • 6. Endocrine glands of cattle, sheep, and swine - hormonal substances like thyroid, insulin, and pituitary hormone replacement therapy in the human body

27. Urine of pregnant mares - rich source of estrogen • 8. Animals - serum, vaccines, toxins • 9. Renal monkey tissue - poliomyelitis vaccines • 10. Fluid of chick embryo - mumps and influenza vaccines

28. Duck embryo – rubella (German measles) • 12. Skin of Bovine calves inoculated with vaccinia virus- smallpox vaccines • 13. Cell and Tissue cultures - new vaccines for diseases AIDS and cancer

29. 14. Genetic engineering - manipulation of the helix, the spiral DNA chain of life. 2 basic technologies that drive the genetic field 1. Recombinant DNA 2. Monoclonal antibody production

30. Gene splicing - can be transplanted from higher species, such as human, into lower bacterium • to produce proteins • - human insulin, human growth hormone, hepatitis B vaccine, epoetin-alpha, and interferon are being produced in this manner.

31. 16. Monoclonal antibodies - the ability of the cells with potential to produce a desired antibody and stimulates an unending stream of pure antibody production. Example: Pregnancy testing products

32. In these test, the monoclonal antibody is highly sensitive to binding on one site on the humanchorionic gonadotropin (HCG) molecule, a specific marker to pregnancy because in healthy women. HCGis synthesized exclusively by the placenta

33. In medicine:MA are being used to stage and to localize malignant cells of cancer, and it is anticipated that they will be used in the future to combat disease such as lupus erythematosus, juvenile-onset diabetes, and myasthenia gravis

34. 17. Human Gene Therapy - used to prevent, treat, cure, diagnose, or mitigate human disease caused by genetic disorders - Human body contains up to 100,000 genes - adenine and thymine (A and T respectively), cytosine and guanine (C and G) respectively) constitute the instructions on a gene.

35. genetic diseases, gene expression may be altered, gene sequences may be mismatched, partly missing, repeated too many times, causing cellular malfunction and disease • - modification of the genetic material of living cells may be modified outside the body (ex vivo) for subsequent administration or modified within the body ( in vivo) by gene therapy products given directly to the patient

36. the first human gene therapy used was to treat adenosine deaminase (ADA) deficiency, a condition that results in abnormal functioning of the immune system. • - many companies exploring application of Gene therapy to treat sickle cell anemia, malignant melanoma, renal cell cancer, heart disease, familial hypercholesterolemia, cystic fibrosis, lung and colorectal cancer, and AIDS

37. Goal Drug - In theory, a goal drug • Would produce the specifically desired effect • Be administered by the most desired route at minimal dosage and dosing frequency • Have optimal onset and duration of activity • Exhibit no side effects

38. Following its desired effect would be eliminated from the body efficiently and completely • No residual side effect • It would be easily produced at low cost • Be pharmaceutically elegant • 9. Physically and chemically stable under various conditions of use and storage.

39. Methods of Drug Discovery • Although some drugs may be the result of fortuitous discovery, most of drugs are the result of carefully designed research programs of screening, molecular modification, and mechanism-based drug design

40. 1. Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity • Purposes: • to detect an unknown activity of the test compound or substance • to identify the most promising compounds to be studied by more sophisticated nonrandom or targeted screens to determine a specific activity

41. 2. Molecular modification - is chemical alteration of a known and previously characterized organic compound (frequently a lead compound) for the purpose of enhancing its useful as a drug

42. PURPOSES: • Enhance its specificity for a particular body target site • Increasing its potency • Improving its rate and extent of absorption • Modifying the advantage its time-course in the body • Reducing its toxicity • Changing its physical and chemical properties

43. 3. Mechanism-based drug design - is a molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process

44. PURPOSE: The intention is the interaction of the drug with specific cell receptors, enzymes systems, or metabolic process of pathogens or tumor cells, resulting in blocking, disruption, or reversal of the disease process

45. Example of Mechanism-based drug design • Enalaprilat -Vasotec - inhibits the angiotensin-coverting enzymes that catalyzes the conversion of AI to the vasoconstrictor substance AII. Inhibition of the enzymes results decreased plasma AII, leading to decrease vasopressor effects and lower blood pressure

46. Ranitidine - Zantac - an inhibitor of histamine at the histamine H2-receptors, including receptors on the gastric cells. Used to treat gastric ulcers • Sertraline - Zoloft - which inhibits the central nervous system’s neuronal uptake of serotonin, making the drug useful in the treatment of depression.

47. Lead compound -is a prototype chemical compound which has a fundamental desired biologic or pharmacologic activity.

48. Example of Lead Compound • Cephalosporin antibiotics - additional H2 antagonists from the pioneer drug Cimetidine • Large series of antianxiety drugs derived from Benzodiazepine structure and the innovator drug chlordiazepine -Librium.

49. 3. Most drugs exhibit activities secondary to their primary pharmacologic action. Example:Finasteride -Proscar was originally developed and approved to treat benign prostatic hyperplasia. Later, the same drug - Propecia was approved at lower recommended dosage to treat male pattern baldness

50. Prodrugs -is a term used to described a compound that requires metabolic biotransformation following administration to yield the desired pharmacologically active compound.