New Drug Development and Approval Process

1. New Drug Development and Approval Process

2. Contents • Drug discovery and drug design • Biological characterization • Early formulation studies • The investigational New Drug (IND) Application(研究性新药申请） • The New Drug Application (NDA)

3. The Federal Food, Drug, and Cosmetic Act,as regulated through Title 21 of the U.S. Code of Federal Regulations, requires a new drug to be approved by the Food and Drug Administration(FDA) before it may be legally introduced in interstate commerce

4. To gain approval for marketing, a drug’s sponsor (e.g., a pharmaceutical company) must demonstrate, through supporting scientific evidence, that the new drug or drug product is safe and effective for its proposed use. The sponsor must also demonstrate that the various processes and controls used in producing the drug substance and in manufacturing, packaging, and labeling are properly controlled and validated to ensure that the product meets established standards

5. The process and time course from drug discovery to approval for marketing can be divided into following process: New Chemical Entity (synthesis) Prefomulation studies-define the physical and chemical properties Formulation studies-develop the initial features of the proposed pharmaceutical product or dosage form Investigational new drug application(IND)-for initial testing in humans Preclinical and Clinical studies Phase I-initial testing in humans Phase II, PhaseIII -progressive humanTrials New drug application (NDA)-seeking approval to market the new product.

6. Content of a product’s approvedlabeling-essential chemistry, pharmacology, toxicology, indications and contraindication for use, adverse effects, formulation composition, dosage, and storage requirements. Treatment IND, Orphan drug Supplemental new drug application (SNDA) Abbreviated new drug application(简化新药申请) to gain approved to market a duplicate Antibiotic drug; biologics; Medical devices

9. 1. Drug Discovery and Drug Design • Sources of new drugs • A goal drug • Methods of drug discovery • A lead compound • Prodrugs

10. 1) Sources of new drugs • New drugs may be discovered from a variety of natural sources or synthesized in the laboratory. • Plant materials have served as a reservoir of potential new drugs.

11. Reserpine （利血平）, a tranquilizer （镇定剂）and hypotensive agent, from the folklore remedy Rauwolfia serpentina（萝芙木属蛇根碱）. • Periwinkle（长春花）, or Vinca rosea, in the treatment of diabetes mellitus.

12. Vinblastine （长春碱）and vincristine （长春新碱）, from Vinca rosea, exhibited antitumor capabilities. • Paclitaxel (Taxol), from an extract of the Pacific yew （紫杉）tree, is used in the treatment of ovarian cancer.

13. After the isolation and structural identification of active plant constituents, organic chemists may recreate them by total synthesis in the laboratory. • The natural chemical could be also used as the starting material in the creation of slightly different chemical structures through molecular manipulation. The new structures, termed semisyntheticdrugs.

14. Animals have served humans in their search for drugs in a number of ways. • Hormonal substances, such as thyroid （甲状腺）extract, insulin, and pituitary（脑垂体）hormone obtained from the endocrine glands of cattle, sheep, and swine. • The use of animals in the production of various biologic products, including serums, antitoxins, and vaccines.

15. New vaccines for diseases as AIDS and cancer are being developed through the use of cell and tissue cultures. • A new era in the development of pharmaceutical products comes forth as a result of the advent of genetic engineering, the manipulation of the double helix, the spiral DNA chain of life. （药物产品发展的新时代到来由于基因工程，生命DNA链的双螺旋操作的出现。）

16. Through this process, will come more abundant and vastly purer antibiotics, vaccines, and yet unknown chemical and biological products to combat human disease. • 通过这些过程，将会出现丰富而大量的更纯的抗生素、疫苗、还有其他未知的化学和生物制品，以抵抗人类疾病。

17. There are two basic technologies that drive the genetic field of drug development • Recombinant DNA (rDNA) • Monoclonal antibody (MoAB) production

18. 2) A goal drug （目标药物） In theory, a “goal drug” • would produce the specifically desired effect, • be administered by the most desired route (generally orally) at minimal dosage and dosing frequency, • have optimal onset and duration of activity, 理论上，目标药物应能通过最理想的途径（通常为口服）以最小的剂量和给药频率给药，能产生特异的期望疗效，具有最理想的起效和持续时间，

19. exhibit no side effects, • following its desired effect would be eliminated from the body efficiently, completely, and without residual effect. • it would be easily produced at low cost, • be pharmaceutically elegant, • physically and chemically stable under various conditions of use and storage. （无副作用，并在发挥疗效后能完全有效地从体内消除，且无残留效应。它应该易于生产，费用低，制剂产品美观，在不同的使用和贮藏条件下物理和化学上稳定。）

20. 3) Methods of drug discovery • Most drugs are the result of carefully designed research programs of screening, molecular modification, andmechanism-based drug design. （大多数药物是精心设计的研究过程的结果，包括：筛选、分子修饰和基于机制的药物设计。）

21. To detect and evaluate biological activity, bioassays are used to differentiate the effect and potency of the test agent compared with controls of known action and effect. In vivo Disease-specific Animal models In vitro Cell culture

22. New methods, as high throughput screening, are capable of examining 15000 chemical compounds a week using 10-20 biological assays. • High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry.

23. To be effective, this requires a sizeable and chemically diverse collection of compounds to examine, which many pharmaceutical and chemical companies have in “chemical libraries.” （为了有效地利用它，这需要有相当大量的不同化学物质来测试，通常许多制药公司或化学品公司有“化合物库”）

24. Molecular modification involves the chemical alteration of a known and previously characterized organic compound for the purpose of enhancing its usefulness as a drug. （分子修饰涉及化学改变已知和特性明了的有机化合物以改善其作为药物的有效性。）

25. Aims for molecular modification • Enhancing its specificity for a particular body target site; • Increasing its potency; • Improving its rate and extent of absorption; • Modifying to advantage its time-course in the body; • Reducing its toxicity; • Changing its physical or chemical properties to provide pharmaceutically desired features;

26. How? Changes in • functional groups • Ring structures • Configuration （构型） （ＳＡＲ）

28. Mechanism-based drug design involves molecular modification in designing a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process. （基于机制的药物设计包括通过分子修饰设计药物，这种药物能够特异性地影响疾病过程的已知或可能的生化途径或机制。）

29. The intention is the interaction of the drug with • specific cell receptors, • enzyme systems, • the metabolic processes of pathogens or tumor cells, resulting in a blocking, disruption, or reversal of the disease process. （设计的意图是影响药物与特异性受体、酶系统、病原体或癌细胞的代谢途径的相互作用，导致疾病过程的阻滞、破坏或逆转。）

30. Molecular graphics, the use of computer graphics to represent and manipulate the structure of the drug molecule to “fit” the simulated molecular structure of the receptor site. （利用计算机绘图来描绘和操纵药物分子的结构使之“适合”于受体部位的分子设计是药物分子设计的有用的和互补的工具。）

31. Enalaprilat(依那普利拉，Vasotec)-inhibits the angiotensin-converting enzyme • Ranitidine (Zantac)-an inhibitor of histamine at the H2-receptor • Sertraline (舍曲林, Zoloft)-inhibits the central nervous system neuronal uptake of serotonin（5-羟色胺）

32. 4) A Lead Compound（先导化合物） • is a prototype（原形化学物质）chemical compound that has a fundamental desired biologic or pharmacologic activity. （先导化合物是一种具有生物学和药理学活性基本要求的原型化学物质。）

33. Although active, the lead compound may not posses all of the features desired; i.e., potency（效力）, absorbability（吸收性）, solubility, low toxicity, and so forth. • The medicinal chemist may seek to modify the lead compound’s chemical structure to achieve the desired features while reducing the undesired one.

34. Finasteride (非那雄胺, Proscar) –benign prostatic hyperplasia • Propecia (a lower recommended dosage)-male pattern baldness.

35. 5) Prodrugs • is a term used to describe a compound that requires metabolic biotransformation after administration to produce the desired pharmacologically active compound. (前体药物使之能够在给药后经体内代谢性生物转化成具有期望的药理活性化合物的化合物。）

36. The conversion of an inactive prodrug to an active compound occurs primarily through enzymatic biochemical cleavage. • Prodrugs may be designed preferentially for the following reasons. • Solubility • Absorption • Biostability • Prolonged release

37. FDA’s definition of a new drug • According to the FDA, a 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 change in a previously approved drug product’s formulation or method of manufacture constitutes newness under the law • A combination of two or more old drugs or a change in usual proportions of drugs in an established ones • A proposed new use for an established drug, a new dosage schedule or regimen, a new route of administration, or a new dosage form all cause a drug or drug product’s status to new and triggers reconsideration for safety and efficacy

38. Drug Nomenclature • 系统命名法

39. 2. Biological characterization • Pharmacology • Drug metabolism • Toxicology

40. Prospective drug substances must undergo preclinical testing for biologic activity to assess their potential as useful therapeutic agents. pharmacology Drug metabolism toxicology

41. 1) Pharmacology • embraces the physical and chemical properties, • biochemical and physiological effects • mechanisms of action, absorption, distribution, biotransformation, excretion, • useful applications of drugs.

42. Pharmacodynamicsis the study of the biochemical and physiological effects of drugs and their mechanisms of action. • Pharmacokinetics deals with the absorption, distribution, metabolism or biotransformation, and excretion of drugs.

43. Clinical pharmacology applies pharmacologic principles to the study of the effects and actions of drugs in humans.

44. Most diseases arise from • a biochemical imbalance • An abnormal proliferation of cells • An endogenous deficiency • An exogenous chemical toxin • Invasive pathogen (病原体)

45. Intricate enzymatic reactions • Structure-activity relationships (SAR) • Relationship between the quantity of drug molecules available for interaction and the capacity of the specific receptor site • Certain cells within the body are capable of binding drugs without eliciting a drug effect.

46. Cell culture Isolated animal tissues Whole animal studies Animal models of human disease

47. The primary objective of the animal studies is • to obtain basic information on the drug’s effects that may be used to predict safe and effective use in humans.

48. 2) Drug Metabolism A series of animal studies of a proposed drug’s metabolism are undertaken to determine: • the rate, primary and secondary sites, and mechanism of the drug’s metabolism in the body, • the chemistry and pharmacology of any metabolites.

49. Drugs that enter the hepatic(肝脏的) circulation after absorption from the gut, as after oral administration, are particularly exposed to rapid drug metabolism. • This transit through the liver and exposure to the hepatic enzyme system is termed the first-pass effect.

50. Drug metabolism or biotransformation frequently results in the production of one or more metabolites of the administered drug, some of which may be pharmacologically active compounds. • When metabolites are found, they are chemically and biologically characterized for activity and toxicity.