New Drug New Drug Development and Development and Approval ProcessApproval Process

New Drug New Drug Development and Development and Approval ProcessApproval Process

Contents

1. Drug discovery and drug design2. Biological characterization3. Early formulation studies4. The investigational New Drug (IND) A

pplication( 研究性新药申请）5. The New Drug Application (NDA)

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

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

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 propertiesFormulation studies-develop the initial features of the proposed pharmaceutical product or dosage formInvestigational new drug application(IND)-for initial testing in humans Preclinical and Clinical studies Phase I-initial testing in humans Phase II, Phase III -progressive humanTrials New drug application (NDA)-seeking approval to market the new product.

Content of a product’s approved labeling-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

1. Drug Discovery and Drug Design

1) Sources of new drugs

2) A goal drug

3) Methods of drug discovery

4) A lead compound

5) Prodrugs

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.

• 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.

• 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.

• 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 semisynthetic drugs.

• 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.

• 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。）

• 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。

There are two basic technologies that drive the genetic field of drug development

• Recombinant DNA (rDNA)

• Monoclonal antibody (MoAB) production

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 (g

enerally 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，

• exhibit no side effects,• following its desired effect would be eliminated fro

m 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 con

ditions 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。）

3) Methods of drug discovery

• Most drugs are the result of carefully designed research programs of screening, molecular modification, and mechanism-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。）

• 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 vitroCell culture

In vivoDisease-specific Animal models

• 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.

• 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”）

• 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。）

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;

How?

Changes in

• functional groups

• Ring structures

• Configuration （构型）

（ＳＡＲ）

• 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。）

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。）

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。）

• 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 ）

4) A Lead Compound （先导化合物）• is a prototype （原形化学物质） chemi

cal 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。）

• 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.

• Finasteride (非那雄胺 , Proscar) –benign prostatic hyperplasia

• Propecia (a lower recommended dosage)-male pattern baldness.

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。）

• 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

• FDA’s definition of a new drug• According to the FDA, a new drug is any that is not recogn

ized 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

• Drug Nomenclature• 系统命名法

2. Biological characterization

1) Pharmacology2) Drug metabolism3) Toxicology

Prospective drug substances must undergo preclinical testing for biologic activity to assess their potential as useful therapeutic agents.

pharmacology Drug metabolism

toxicology

1) Pharmacology

• embraces the physical and chemical properties,

• biochemical and physiological effects

• mechanisms of action, absorption, distribution, biotransformation, excretion,

• useful applications of drugs.

• Pharmacodynamics is 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.

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

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

• 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.

Cell culture

Isolated animal tissues

Whole animal studies

Animal models of human disease

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.

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.

• 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.

• 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.

3) Toxicology is the area of pharmacology that deals with the adverse, or undesired, effects of drugs.

• In drug development programs, preclinical drug safety evaluation or toxicity studies are undertaken to determine:

- The substance’s potential for toxicity with short-term (acute effects) or long-term use (chronic effects).

- the substance’s potential for specific organ toxicity,

- the mode, site, and degree of toxicity,- dose-response relationships, for low-high-a

nd intermediate doses over a specified time course,

- gender, reproductive, or teratogenic ( 产生畸形的 ) toxicities,

- the substance’s carcinogenic and genotoxic ( 遗传毒性的 )potential.

① Acute or short-term toxicity studies

These studies are designed to determine

• the toxic effects of a test compound

• when administered in a single dose and/or in multiple doses

• over a short period, usually a single day.

The test compound is administered at various dose levels, with toxic signs observed for

• onset （观察毒性反应的开始）• progression or reversal （发展或逆转）• severity （严重性）• mortality （死亡率）• rates of incidence （事件的发生率）

The animals are observed and compared with controls for

• eating and drinking habits, • weight change, • toxic effects, • psychomotor changes （精神变化） , • any other signs of untoward effects, us

ually over a 30 day postdose period.

② Subacute（亚急性） or subchronic（亚慢性） studies

• Animal toxicity studies of a minimum of 2 weeks duration of daily drug administration at three or more dosage levels to two animal species are required to support the initial administration of a single dose in human clinical testing.

• These studies are termed subacute or subchronic.

Chronic toxicity studies, For drugs intended to be given to

humans for a week or more, animal studies of 90 to 180 days in length must demonstrate safety.

③ Carcinogenicity studies （致癌性研究）

Carcinogenicity testing is usually a component of chronic testing ， is undertaken when the compound has shown sufficient promise as a drug to enter human clinical trials.

• Carcinogenicity studies are usually carried out in a limited number of rat and mouse strains for which there is reasonable information on spontaneous tumor incidence （自发性肿瘤形成） .

④ Reproduction studies （生殖研究）• These studies are undertaken to reveal any e

ffect of an active ingredient on mammalian reproduction. Included in these studies are

• fertility and mating behavior ( 抚养和交配行为）

• Early embryonic and pre- and post-natal development （胚胎早期、早产和产后发育）

• Multigenerational effects （多代影响）• Teratology （致畸性）

3. Early formulation studies

1) Preformulation studies

2) Initial product formulation and clinical trial materials

Physical chemical properties

Clinicaltrials

from initial to final

formulation

from pilot plant toscale-up

largescale

manufacturing

1) Preformulation studies （处方前研究）Each drug substance has intrinsic （固有的） chemical and physical characteristics that must be considered before the development of a pharmaceutical formulation

① Drug solubility• A drug substance administered by any ro

ute must possess some aqueous solubility for systemic absorption and therapeutic response.

• Poorly soluble compounds (less than 10mg/ml) may exhibit either incomplete or erratic （不稳定） absorption and thus produce a minimal response at desired dosage.

Enhanced aqueous solubility may be achieved by

• preparing more soluble derivatives of the parent compound, such as salts or esters;

• by chemical complexation;

• by reducing the drug’s particle size.

② Partition coefficientTo produce a pharmacologic response, a drug molecule must first cross a biologic membrane of protein and lipid, which acts as a lipophilic barrier to many drugs.

A drug’s partition coefficient is

• a measure of its distribution in a lipophilic/hydrophilic phase system,

• indicative of its ability to penetrate biologic multiphase systems.

（二）分配系数

• 油 / 水分配系数是分子亲脂特性的度量，在药剂学研究中主要用于预见药物对在体组织的渗透或吸收难易程度。

• 分配系数（ partition coefficient ，P ）代表药物分配在油相和水相中的比例。

P =在油相中药物的质量浓度

在水相中药物的质量浓度

③ Dissolution rate• The rate at which a drug substance

dissolves in a medium is called its dissolution rate.

• Dissolution rate data, when considered along with data on a drug’s solubility, dissolution constant, and partition coefficient, can provide an indication of the drug’s absorption potential following administration.

• For a chemical entity, its acid, base, or salt forms, as well as its physical form (e.g. particle size), may result in substantial differences in the dissolution rate.

④ Physical formThe crystal or amorphous forms and particle size of a powdered drug can affect the dissolution rate, and thus the rate and extent of absorption, for a number of drugs.

⑤ StabilityThe chemical and physical stability of a drug substance alone, and when combined with formulation components, is critical in preparing a successful pharmaceutical product.

2) initial product formulation and clinical trial materialsAn initial product is formulated

- using the information gained during the preformulation studies

- with consideration of the doses, dosage form, route of administration desired for the clinical studies and for the proposed marketed product.

• For phase 1 studies, orally administered drugs, capsules are employed containing the active ingredient alone, without pharmaceutical excipients.

• Excipients are included in the formulation for Phase 2 trials.

• Different formulations may be prepared and examined to develop the one having the desired characteristics.

• During phase 2, the final dosage form is selected and developed for Phase 3 trials.

药物制剂处方设计前工作

• 一个药物从合成到最后上市，大致经历：①药理活性的筛选；②初步药理学及分析方法研究；③处方前工作；④临床研究 ;⑤ 处方与制备工艺研究； ⑥ 制剂药理、毒理研究；⑦申报工作。

• 其中处方前工作在整个研制过程中占有重要地位。

一、任务和要求

处方前工作的主要任务：

• 处方前工作将为该药物制剂的开发提供决定性的参考价值：

① 获取新药的相关理化参数；

② 测定其动力学特征；

③ 测定与处方有关的物理性质；

④ 测定新药物与普通辅料间的相互作用。

二、文献检索• 1 、光盘检索： CA 、 IPA 、 Medline 、 Drug & Phar

macology 、中国生物医学文献光盘数据库、中国科技期刊光盘数据库等。

• 2 、网络检索： Medline 、 Rxlist 、 griffin 、 pharmacy 、 US patent 、 FDA 、中国生物科技期刊库、万方数据库、 CPA 等

• 3 、期刊检索： J Pharm Sci, Pharm Res, DDIP, J Contr Rel, Int J Pharm,

             IPA, CA, 中国药学文摘、国内药学期刊杂志等。 • 4 、书刊检索： • 5 、工具书检索： USP 、 BP 、 CP 、 PDR 、 Mardin

dale 、 Pharm Project 等。 •  6 、专利检索：

• The Investigational New Drug (IND) Application

• Under the Food, Drug, and Cosmetic Act as amended, the sponsor of a new drug is required to file with the FDA an IND before the drug may be given to human subjects.

• This is to protect the rights and safety of the subjects and to ensure that the investigational plan is sound and is designed to achieve the stated objectives

• After submission of the IND, the sponsor must delay use of the drug in human subjects for not less than 30 days from the date the FDA acknowledge receipt of the application.

• (1) Content of the IND• (2) The Clinical Protocol• (3) Pre-IND Meetings• On request, the FDA will advise a sponsor on scien

tific, technical, or formatting concerns relating to the preparation and submission of an IND

• (4) FDA Review of an IND Application• The FDA’s objectives in reviewing an IND are to p

rotect the safety and rights of the human subjects and to help ensure that the study allows the evaluation of the drug’s safety and effectiveness.

• (5) FDA Drug Classification system• Upon receipt and examination of an IND or NDA,

the FDA classifies the drug by chemical type and therapeutic potential. Page 49

• (6) Phases of a Clinical Investigation• An IND may be submitted for one or more phase

s of a clinical investigation,namely Phase 1, Phase 2, or Phase 3

• Phase 1 includes the initial introduction of an investigational drug into humans and is primarily for the purpose of assessing safety.

• Phase 1 studies are designed to determine the human pharmacology of the drug, structure-activity relationship, side effects associated with increasing doses, and if possible, early evidence of effectiveness.

• Phase 2 trials are controlled clinical studies to evaluate the effectiveness of a drug in patients with the condition for which the drug is intended and to assess side effects and risks that may be revealed. Because this phase uses patients as subjects, side effects or toxicity symptoms that were not shown in the preclinical animal studies or in Phase 1 studies with healthy volunteers may be revealed for the first time.

• Phase 3 studies may include several hundred to several thousand patients in controlled and uncontrolled trials.The objective is to determine the usefulness of the drug in an expanded patient base.

• (7) Clinical Study Controls and Designs• Phase 2 and some Phase 3 studies are controlled,

that is, the effects of the investigational drug are compared with another agent.The second agent may be a placebo (placebo control) or an active drug (positive control), a standard or comparator drug product.

• For studies that are blinded, the identities of the investigational drug and the control and controls are not revealed to certain participants to decrease bias

• In designing a clinical trial, many addition factors are considered, including the scheme of the study design and the duration of the treatment

• (8) Drug dosage and Terminology• A major part of any clinical drug is the determina

tion of a drug’s safe and effective dose. Dose and dose ranging studies are conducted during Phase 2 and concluded during Phase 3 clinical trials.

• The safe and effective dose of a drug depends on a number of factors, including characteristics of the drug substances, the dosage form and its route of administration, and a variety of patient factors including age, body weight, general health status, any pathologic conditions, and concomitant drug therapy. All of these factors and others are integral to clinical drug trials

• The dose of a drug may be described as an amount that is enough but not too much; the idea is to achieve the drug’s optimum therapeutic effect with safety but at the lowest possible dose

• The effective dose of a drug may be different for different patients.

• Usual adult dose; usual dosage range;usual pediatric dose

• The schedule of dosage, or the dosage regimen, is determined during the clinical investigation and is based largely on a drug’s inherent duration of action, its pharmacokinetics, and the characteristics of the dosage form.

• Initial dose; priming dose; loading dose;• Prophylactic dose ( 预防剂量 ); therapeutic dose

To provide systemic effects, a drug must be absorbed from its routs of administration at a suitable rate, be distributed in adequate concentration to receptor sites, and remain there for a sufficient period.

Minimum effective concentration (MEC);Minimum toxic concentration (MTC); Median effectiv

e dose; therapeutic index Some factors of patients considered in determining

a drug’s dose in clinical investigations and in medical practice include the following:

Age,Body weight, Body Surface Area, Sex, Pathologic state,Torlerance, Concomitant Drug Therapy,Time and Conditions of Administration, Dosage Form and Route of Administration

• (9)Treatment IND• A treatment IND or a treatment protocol permits t

he use of an investigational drug in the trentment of patients not enrolled in the clinical study but who have a serious or immediately life-threatening disease for which there is non satisfactory alternative therapy.

• (10) IND for an Orphan Drug• (11) Withdrawal or Termination of an IND• The New Drug Application• If the three phases of clinical testing during the IN

D period demonstrate sufficient drug safety and therapeutic effectiveness, the sponsor may file a NDA with the FDA. This filing may be proceded by a pre-NDA meeting between the sponsor and the FDA to discuss the content and format of the new drug application.

• The purpose of the NDA is to gain permission to market the drug product in the United states.

• (1) General Content of the NDA Submission

• (2) Drug Product Labeling• (a) Description of product • (b)Clinical pharmacology; • (c) Indications and usage• (d) Contraindications • (e) Warnings (f) Precautions• (g) Adverse reactions • (h) drug abuse and dependence (i) Overdosage • (j) Dosage and administration (k) How supplied

• FDA Review and Action Letters• The completed NDA is carefully reviewed by the FD

A, which decides whether to allow the sponsor to market the drug, to disallow marketing, or to require additional data before rendering a judgement.

• Phase 4 stuidies and Postmarketing Surveillance

• The receipt of marketing status for a new drug product does not necessarily end a sponsor’s investigation of the drug. Continued clinical investigations, often called Phase 4 studies.

• Annual Reports

• Supplemental, Abbreviated, and Other applications

• Supplemental New Drug Application• A sponsor of an approved NDA may make change

s in that application through the filing of a supplemental new drug application (SNDA)

• Abbreviated New Drug Application• An abbreviated new drug application (ANDA) is o

ne in which nonclinical laboratory studies and clinical investigations may be omitted, except those pertaining to the drug’s bioavailablility

• Biologics License Application

• Animal Drug Applications• Medical Devices

• International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

Questions 1. Describe the methods of drug discovery2. Define the following phrases:

- prodrugs- a lead compound- a goal drug

3. What physical and chemical properties of drug substances must be characterized during preformulation studies? Explain.

4. What biological characterization should be studied in drug development process ？

新药制剂的研究与申报

• 《药品注册管理办法》适用于在中华人民共和国境内从事药物研究和临床研究，申请药物临床研究、药品生产或者进口，以及进行相关的药品注册检验、监督管理。

一、药品注册申请• 药品注册是指依照法定程序，对拟上市销售的药品的安全性、有效性、质量可控性等进行系统评价，并作出是否同意进行药物临床研究、生产药品或者进口药品而决定的审批过程，包括对变更药品批准证明文件的申请及其附件中声明内容的审批。

• 药品注册申请包括新药申请、已有国家标准药品的申请和进口药品申请及其补充申请。

• 新药申请是指未曾在中国境内上市销售药品的注册申请。已上市药品改变剂型、改变给药途径的，按照新药管理。

• 已有国家标准药品的申请是指在国内已经生产由国家药品监督管理局颁布的标准药品注册申请。

• 进口药品申请是指在境外生产的药品在中国上市销售的注册申请。

• 补充申请是指新药申请、已有国家标准药品的申请或者进口药品申请经批准后，改变、增加或取消原批准事项或内容的注册申请。

• 审批过程中的药品注册申请、已批准的临床研究申请需进行相应变更的，以及新药技术转让、进口药品分包装、药品试行标准转正，按补充申请办理。

• 国家食品药品监督管理局主管全国药品注册管理工作，负责对药品的临床研究、药品生产和进口的审批。

• 网址： http://www.sda.gov.cn

1.未在国内外上市销售的药品① 通过合成或者半合成的方法制得的原料药及

其制剂；② 天然物质中提取或者通过发酵提取的新的有效单体及其制剂；

③ 用拆分或者合成等方法制得的已知药物中的光学异构体及其制剂；

④ 由已上市销售的多组分药物制备为较少组分的药物；

⑤ 新的复方制剂

二、新药的分类（一）化学药品注册分类

2.改变给药途径且尚未在国内外上市销售的制剂。

3.已在国外上市销售，但尚未在国内上市销售的药品

①已在国外上市销售的原料药及其制剂；②已在国外上市销售的复方制剂；③改变给药途径并已在国外上市销售的制

剂。

（一）化学药品注册分类

4.改变已上市销售盐类药物的酸根、碱基（或者金属元素），但不改变其药理作用的原料药及其制剂。

5.改变国内已上市销售药品的剂型，但不改变给药途径的制剂。

6.已有国家药品标准的原料药或者制剂。

（一）化学药品注册分类

1.未在国内上市销售的重要、天然药物中提取的有效成分及其制剂。

2.未在国内上市销售的来源于植物、动物、矿物等药用物质制成的制剂。

3. 中药材的代用品。4.未在国内上市销售的中药材新的药用部位制成

的制剂。5.未在国内上市销售的由中药、天然药物中提取

的有效部位制成的制剂。6.未在国内上市销售的由中药、天然药物制成的复方制剂。

（二）中药、天然药物注册分类

7.未在国内上市销售的由中药、天然药物制成的注射剂。

8.改变国内已上市销售药品给药途径的制剂。

9.改变国内已上市销售药品剂型的制剂。

10.改变国内已上市销售药品工艺的制剂。

11.已有国家标准的中成药和天然药物制剂。

三、申请新药需上报的项目

（一）综述资料1 、药品名称。2 、证明性文件。3 、立题目的与依据。 4 、对主要研究结果的总结及评价。5 、药品说明书样稿、起草说明及最新参

考 文献。6 、包装、标签设计样稿。

（二）药学研究资料7 、药学研究资料综述。8 、原料药生产工艺的研究资料及文献资料；制剂处方及工艺

的研究资料及文献资料。9 、确证化学结构或者组份的试验资料及文献资料。10 、质量研究工作的试验资料及文献资料。11 、药品标准草案及起草说明，并提供标准品或者对照品。12 、样品的检验报告书。13 、辅料的来源及质量标准。14 、药物稳定性研究的试验资料及文献资料。15 、直接接触药品的包装材料和容器的选择依据及质量标准

（三）药理毒理研究资料16 、药理毒理研究资料综述。17 、主要药效学试验资料及文献资料。18 、一般药理研究的试验资料及文献资料。19 、急性毒性试验资料及文献资料。20 、长期毒性试验资料及文献资料。21 、过敏性（局部、全身和光敏毒性）、溶血性和局部（血管、 皮肤、粘膜、肌肉等）刺激性等主要与局部、全身给药相关的特殊安全性试验研究和文献资料。

22 、复方制剂中多种成份药效、毒性、药代动力学相互影响的试验资料及文献资料。

23 、致突变试验资料及文献资料。24 、生殖毒性试验资料及文献资料。25 、致癌试验资料及文献资料。26 、依赖性试验资料及文献资料。27 、动物药代动力学试验资料及文献资料。

（四）临床研究资料

28 、国内外相关的临床研究资料综述。

29 、临床研究计划及研究方案。

30 、临床研究者手册。

31 、知情同意书样稿、伦理委员会批准件。

32 、临床研究报告。

四、申报新制剂的主要内容

1. 处方、制备工艺、辅料等2.稳定性试验3.溶出度或释放度试验4. 生物利用度