New Drug Development and Approval Process

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New Drug Development and Approval Process. NEW DRUG DEVELOPMENT PROCESS NEW CHEMICAL ENTITY SOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering. PRECLINICAL STUDIES Including Chemistry Physical Properties Biological Pharmacology - PowerPoint PPT Presentation


<ul><li><p>New Drug Development andApproval Process</p></li><li><p>NEW DRUG DEVELOPMENT PROCESSNEW CHEMICAL ENTITYSOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering</p></li><li><p>PRECLINICAL STUDIESIncluding Chemistry Physical Properties BiologicalPharmacologyADMEToxicology Preformulation</p></li><li><p>CLINICAL TRIALS Phase I Phase II Phase IIIPRECLINICAL STUDIES (Continued) long term animal toxicity product formulation Manufacturing and controls Package and label design</p></li><li><p>NEW DRUG APPLICATION (NDA) Submission FDA Review Pre-approval Plant inspection FDA action</p></li><li><p>POST MARKETING TRIALS Phase IV Clinical Trialsclinical pharmacology/Toxicologyadditional indications Adverse Reaction Reporting Product Defect Reposting Product Line Extension</p></li><li><p>4 Phases Of Clinical Studies In Man</p><p>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)</p></li><li><p>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</p></li><li><p>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</p></li><li><p>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</p></li><li><p> Some products, however, have been approved and later removed from the market for safety reasons, including the following:</p><p> Grepafloxacin HCL (Raxar) Brofenac sodium (Duract) Cisapride (Propulsid) Alosetron HCL (Lotrovec) Fenfluramine HCL (Pondimin)</p></li><li><p> Dexfenfluramine HCL (Redux) Terfenadine (Seldane) Cerivastatin (Baycol) Mibefradil (Posicor) Astemizole (Hismanal) Troglitazone (Rezulin)</p></li><li><p>Preclinical ClinicalNDA ReviewPost Marketing Research and Research and DevelopmentSurveillance DevelopmentInitial synthesisAdverse andreaction characterization Phase 1 Phase 2 Surveys/samplingtestingPhase 3Animal testing</p><p> Short term</p><p> Long term Inspection</p><p>Average 61/2Average 7 yearsAverage 1 1/2 years years</p><p> FDA 30-day safety review NDA submitted NDA approval</p><p> Average of approx. 15 years from initial synthesis to approval of NDA </p></li><li><p>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</p></li><li><p>- new pharmacologic categories of drugs including oral hypoglycemic drugs effective against certain types of diabetes mellitus - antineoplastic or anticancer drugs, </p><p>- immunosuppressive agents to assist the bodys acceptance of organ transplant- contraceptives to prevent pregnancy- tranquilizers and antidepressant drugs to treat the emotionally distressed</p></li><li><p>New and Important Innovative Therapeutic Agents Approved by FDA</p><p>1. Efavirenz - Sustiva - to treat AIDS2. Didanosine - Videx EC - to treat AIDS3. Tenofovir - Viread - to treat AIDS4. Leuprolide acetate - Eligard prostate cancer5. Triptorelin pamoate - Trelstar - prostate cancer6. Lovastatin - Mevacor - hyperlipidemic7. Treprostinil sodium - Remodulin - pulmonary arterial hypertensive</p></li><li><p>8. Moxifloxacin HCl - Avelox - infectious disease9. Montelukast sodium - Singulair - chronic asthma10. Tegaserod maleate - Zelnorm - irritable bowel syndrome in women11. Sodium oxybate -Xyrem - cataplexy in patient with narcolepsy12. Galantamine HCl - Reminyl - dementia with Alzheimers disease13. Fondaparinux sodium - Arixtra - deep vein thrombosis14. Voriconazole - Vfend - infectious disease</p></li><li><p>SOURCES Of DRUGS</p><p> Pure organic compound</p><p> Natural or Synthetic</p><p>3. Organometallic</p></li><li><p>These remedial have their origin in essentially 3 ways</p><p> Naturally occurring materials in both plants and animalsExample: Ergot, opium, curare, cinchona</p></li><li><p>2. Synthesis of organic compounds whose structure are closely related to those naturally occurring compoundsExample: morphine, atropine, cortisone, cocaine</p></li><li><p>3. Pure synthesis in which no attempt has been made to pattern after a known naturally occurring compounds exhibiting some activityExample: antihistamine, barbiturates, diuretics, antiseptic, etc.</p></li><li><p>Sources of New Drugs</p><p>1. Reserpine - tranquilizers and hypotensive agent - isolated from Rauwolfia serpentina</p><p>2. Periwinkle or Vinca rosea - use as treatment of diabetes mellitus</p><p>3. Vinblastine and Vincristine - Vinca rosea - cancer, including acute leukemia, Hodgkins disease and lymphocytic lymphoma and other malignancies</p></li><li><p>Paclitaxel (Taxol)- Pacific yew tree - ovarian cancer</p><p>Dioscorea - Mexican yams - chemical steroid structure - cortisone and estrogen are semisynthetically produced</p><p>6. Endocrine glands of cattle, sheep, and swine - hormonal substances like thyroid, insulin, and pituitary hormone replacement therapy in the human body</p></li><li><p> Urine of pregnant mares - rich source of estrogen</p><p>8. Animals - serum, vaccines, toxins</p><p>9. Renal monkey tissue - poliomyelitis vaccines</p><p>10. Fluid of chick embryo - mumps and influenza vaccines</p></li><li><p>Duck embryo rubella (German measles)</p><p>12. Skin of Bovine calves inoculated with vaccinia virus- smallpox vaccines</p><p>13. Cell and Tissue cultures - new vaccines for diseases AIDS and cancer</p></li><li><p>14. Genetic engineering - manipulation of the helix, the spiral DNA chain of life.2 basic technologies that drive the genetic field</p><p>1. Recombinant DNA2. Monoclonal antibody production</p></li><li><p> Gene splicing - can be transplanted from higher species, such as human, into lower bacterium </p><p>to produce proteins </p><p>- human insulin, human growth hormone, hepatitis B vaccine, epoetin-alpha, and interferon are being produced in this manner.</p></li><li><p>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</p></li><li><p>In these test, the monoclonal antibody is highly sensitive to binding on one site on the human chorionic gonadotropin (HCG) molecule, a specific marker to pregnancy because in healthy women. HCG is synthesized exclusively by the placenta</p></li><li><p>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</p></li><li><p>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</p><p>- adenine and thymine (A and T respectively), cytosine and guanine (C and G) respectively) constitute the instructions on a gene. </p></li><li><p>genetic diseases, gene expression may be altered, gene sequences may be mismatched, partly missing, repeated too many times, causing cellular malfunction and disease</p><p>- 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</p></li><li><p> the first human gene therapy used was to treat adenosine deaminase (ADA) deficiency, a condition that results in abnormal functioning of the immune system.</p><p>- 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</p></li><li><p>Goal Drug - In theory, a goal drug</p><p>Would produce the specifically desired effect</p><p>Be administered by the most desired route at minimal dosage and dosing frequency</p><p>Have optimal onset and duration of activity</p><p>Exhibit no side effects</p></li><li><p> Following its desired effect would be eliminated from the body efficiently and completely</p><p> No residual side effect</p><p> It would be easily produced at low cost</p><p> Be pharmaceutically elegant</p><p>9. Physically and chemically stable under various conditions of use and storage.</p></li><li><p>Methods of Drug Discovery</p><p> 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</p></li><li><p>1. Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity</p><p> 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</p></li><li><p>2. Molecular modification</p><p>- 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</p></li><li><p>PURPOSES:Enhance its specificity for a particular body target siteIncreasing its potencyImproving its rate and extent of absorptionModifying the advantage its time-course in the bodyReducing its toxicityChanging its physical and chemical properties</p></li><li><p>3. Mechanism-based drug design</p><p>- is a molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process</p></li><li><p>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</p></li><li><p>Example of Mechanism-based drug design</p><p>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</p></li><li><p> Ranitidine - Zantac - an inhibitor of histamine at the histamine H2-receptors, including receptors on the gastric cells. Used to treat gastric ulcers</p><p> Sertraline - Zoloft - which inhibits the central nervous systems neuronal uptake of serotonin, making the drug useful in the treatment of depression.</p></li><li><p>Lead compound -is a prototype chemical compound which has a fundamental desired biologic or pharmacologic activity.</p></li><li><p>Example of Lead Compound</p><p> Cephalosporin antibiotics - additional H2 antagonists from the pioneer drug Cimetidine</p><p> Large series of antianxiety drugs derived from Benzodiazepine structure and the innovator drug chlordiazepine -Librium.</p></li><li><p>3. Most drugs exhibit activities secondary to their primary pharmacologic action. </p><p>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</p></li><li><p>Prodrugs-is a term used to described a compound that requires metabolic biotransformation following administration to yield the desired pharmacologically active compound.</p></li><li><p>Example of Prodrug</p><p>Enapril maleate Vasotec-which, after oral administration, bioactivated by hydrolysis to enaprilat, an ACE inhibitor used in the treatment of hypertension</p><p>Prodrug may be design preferentially for solubility, absorption, biostability and prolonged release</p></li><li><p>Solubility- Enabling the use of specifically desired dosage forms and routes of administration</p><p>Absorption- A drug may be made more water or lipid soluble, as desired, to facilitate absorption via the intended route of administration</p></li><li><p>Biostability- An active drug is prematurely destroyed by biochemical or enzymatic process, the design of a prodrug may protect the drug during its transport in the body</p><p>Prolonged Release- Depending on a prodrugs rate of metabolic conversion to active drug, it may provide prolonged release and extended therapeutic activity</p></li><li><p>NEW DRUG - is any that is not recognized as being safe and effective in the conditions recommended for its use among experts who are qualified by scientific training and experience.A combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered new if the change introduces a question of safety or efficacy.FDAs Definition of a New Drug</p></li><li><p>- A new dosage schedule or regimen, a new rout of administration, new dosage form all cause a drug or drug products status to new and triggers reconsideration for safety and efficacy- A drug need not be a new chemical entity to be considered new. A change in a previously approved drug products formulation or method of manufacture constitutes newness under the law, since such changes can alter the therapeutic efficacy and/or safety of a product.</p></li><li><p>NOMENCLATURE OR NAMING OF DRUGThe task of designating appropriate non-proprietary names for newly found chemical agents rests primarily with the USAN Council.</p><p>The official name for a drug is referred to as the drug nonproprietary or public name </p></li><li><p>in contrast to the proprietary or brand names or trademark names given by the specific manufacturers or distributors of the drug.</p><p>The term generic name, has been used extensively in referring to the nonproprietary names of the drugs. Brand name is registered as a trademark with the United States Patent Office</p></li><li><p>CATEGORY OR USE </p><p>In general, drugs exert their effects by one of three means:</p><p>1. By exerting a physical action such as the protective effects of ointments and lotions upon topical application</p></li><li><p> By reacting chemically outside the body cells. Example: antacids counteract excess acidity in the stomach or antibiotics to act against invading pathogenic microorganism.</p></li><li><p>3. By modifying the metabolic activity of the bodys cell. Majority of the drugs belong to the 3rd manner where brain, liver, kidney, etc. are affected</p></li><li><p>Proposals for Nonproprietary Names</p><p>1. Be short and distinctive in sound and spelling and not be such that it is easily confused with existing names</p></li><li><p>Indicate the general pharmacologic or therapeutic class into which the substance falls or the general chemical nature of the substance if the latter is associated with the specific pharmacologic activity</p><p>3. Embody the syllable or syllables characteristic of a related group of compounds</p></li><li><p>Pharmacology</p><p>pharmaco= drugs; logos = study of; is the science concerned with drugs, their sources, appearance, chemistry, actions, and uses.</p></li><li><p>The term can be expanded to include</p><p>1. Properties2. Biological and physiologic effects3. Mechanism of actions4. ADME</p></li><li><p>Pharmacodynamics = the study of the biochemical and physiologic effects of drugs and their mechanism of action</p><p>Pharmacokinetics = ADME</p><p>Clinical Pharmacology = applies pharmacologic principles to the study of the effects and actions of drugs in humans</p></li><li><p>Pharmacologic profile = In vitro cultures of cells and enzymes systems and in vivo animal models are used to define a chemicals pharmacologic profile</p><p>=...</p></li></ul>


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