new drug application hardcopy

ABSTRACT

The NDA is a vehicle seeking approval to the new product after the completion of

carefully design preclinical and clinical studies. The FDA’s approval of an NDA indicates that

the body of scientific evidence submitted sufficiently demonstrating the drug or the drug

products safety efficacy for the proposed chemical indications showing adequate assurance of its

proper manufacture control and final labelling and accurately necessary information for its

proper use.

An Abbreviated New Drug Application (ANDA) is an application for generic drug

approval for an existing licensed medication or approved drug. It provides documentation on

chemistry manufacturing controls, bioavailability of the proposed product to demonstrate

biological equivalency to the product.

NEW DRUG

• A combination of two or more old drugs or a change in the usual proportions of drugs in

an established combinations product is considered new if the change introduces a

question of safety or efficacy.

• According to FDA, a new drug is any that is not recognized as being safe and effective

in the conditions recommended for it use among experts who are qualified by scientific

training and experience.

• A proposed new use for an established drug, a new dosage schedule of regimen , a new

route of administration, or a new dosage form all cause a drug or drug products status to

new and triggers reconsideration for safety and efficacy

• A change in a previously approved drug products formulation or method of manufacture

constitutes newness under the law.

NEW DRUG DEVELOPMENT PROCESS

• New chemical entity

• Pre clinical studies

• Investigational new drug application(IND)

• Clinical trials

• New drug application.

• Post marketing surveillance

Investigational New Drug Application (INDA):

Current Federal law requires that a drug be the subject of an

approved marketing application before it is transported or distributed across state lines. Because

a sponsor will probably want to ship the investigational drug to clinical investigators in many

states, it must seek an exemption from that legal requirement. The IND is the means through

which the sponsor technically obtains this exemption from the FDA.

During a new drug's early preclinical development, the

sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans,

and if the compound exhibits pharmacological activity that justifies commercial development.

When a product is identified as a viable candidate for further development, the sponsor then

focuses on collecting the data and information necessary to establish that the product will not

expose humans to unreasonable risks when used in limited, early-stage clinical studies.

FDA's role in the development of a new drug begins when the

drug's sponsor (usually the manufacturer or potential marketer) having screened the new

molecule for pharmacological activity and acute toxicity potential in animals, wants to test its

diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status

under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific

requirements of the drug regulatory system.

There are three IND types:

An Investigator IND is submitted by a physician who both initiates and conducts an

investigation, and under whose immediate direction the investigational drug is

administered or dispensed. A physician might submit a research IND to propose studying

an unapproved drug, or an approved product for a new indication or in a new patient

population.

Emergency Use IND allows the FDA to authorize use of an experimental drug in an

emergency situation that does not allow time for submission of an IND in accordance

with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet

the criteria of an existing study protocol, or if an approved study protocol does not exist.

Treatment IND is submitted for experimental drugs showing promise in clinical testing

for serious or immediately life-threatening conditions while the final clinical work is

conducted and the FDA review takes place.

There are two IND categories:

Commercial

Research (non-commercial)

The IND application must contain information in three broad areas:

Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment

as to whether the product is reasonably safe for initial testing in humans. Also included

are any previous experience with the drug in humans (often foreign use).

Manufacturing Information - Information pertaining to the composition, manufacturer,

stability, and controls used for manufacturing the drug substance and the drug product.

This information is assessed to ensure that the company can adequately produce and

supply consistent batches of the drug.

Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical

studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.

Also, information on the qualifications of clinical investigators--professionals (generally

physicians) who oversee the administration of the experimental compound--to assess

whether they are qualified to fulfill their clinical trial duties. Finally, commitments to

obtain informed consent from the research subjects, to obtain review of the study by an

institutional review board (IRB), and to adhere to the investigational new drug

regulations.

CONTENT OF THE IND:

The content of the IND is as specified in the code of federal regulations and is submitted under a

cover sheet (form FDA-1571).

Requirements:

• Sponsor’s information.

• Investigation monitors information.

• Review evaluation body information.

• Contract research organization.

• Phase identity.

• Introductory statement and general investigation plan.

• Description of investigational plan.

• History of previous human experience.

• Chemistry, manufacture and control information

• Pharmacology and toxicology information.

• Previously investigated drug information component.

• Clinical protocol.

• Commitment.

• Investigator brochure.

• Commitment undertaking.

PRE IND MEETINGS:

On request FDA will advice sponsors on scientific technical of formatting concerns

Relating to the preparation and submission of IND.

It includes

• Advice on adequacy of data to support an investigational plan.

• Design of clinical trial.

• Filing of NDA.

FLOW CHART:

New Drug Application (N D A):

Introduction:

Introduction The new drug application (N D A) is a critical component in the drug

approval process. The NDA contains Clinical and non clinical test data and analyses, Drug

chemistry information, and Descriptions of manufacturing procedures. An NDA consists of

thousands of pages of information to be reviewed by FDA teams composed of highly qualified

individuals with expertise in their respective technical fields.

Usually, six different teams are responsible for reviewing an NDA. The teams are

organized by technical reviewing responsibilities: Clinical Pharmacology/toxicology Chemistry

Statistics Biopharmaceutical and Microbiology. Introduction

The FDA has established guidelines for formatting, assembling, and submitting the

NDA. Failure to follow these guidelines can result in deficiencies that could Delay review,

require an amended application, or Result in a refusal to File. Introduction

Most of the FDA guidelines regarding NDAs were written and implemented in

early 1987. NDA shares many common elements with the Common Technical Document (CTD)

developed by the ICH Introduction

Assembling Applications for Submission:

Assembling Applications for Submission, the FDA requires drug

sponsors to submit multiple copies of the NDA The archival copy The review copy The field

copy In 1997 the FDA’s Center for Drug Evaluation and Research (CDER) published guidelines

that allow sponsors to submit NDAs electronically instead of on paper.

The Archival Copy:

The Archival Copy Contains all sections of the NDA, including The

cover letter, Form FDA-356h (Application to Market a New Drug, Biologic, or an Antibiotic for

Human Use), The administrative sections, Comprehensive NDA index, and All technical

sections. It must contain four copies of the Labeling section. It must contain three additional

copies of the CMC and Methods Validation Package in a separate binder. The archival copy is

the only copy that contains the Case Report Tabulation and Case Report Forms.

The Review Copy: The Review Copy Intended for reviewers in the corresponding technical

disciplines. In addition to the appropriate technical section, each review copy also includes ,the

cover letter, Form FDA-356h, The administrative sections, Comprehensive NDA index

Individual table of contents, The Labeling section, and The Application Summary.

The Field Copy: The Field Copy required since 1993 for use by FDA inspectors during

pre approval facilities inspections. It includes the Cover letter and Form FDA-356h, the

administrative sections, the comprehensive NDA index Individual table of contents, The

Labeling section, The Application Summary, and CMC and Methods Validation Package.

NDA CONTENTS: The NDA may have as many as 20 different sections in addition to

the Form FDA-356h itself. The specific contents of the NDA will depend on the Nature of the

drug and The information available at the time of submission. The application Form FDA-356h

serves as Checklist as well as Certification that the sponsor agrees to comply with a range of

legal and regulatory requirements. NDA includes

CONTENTS:

1: Index NDA Section

2: Labeling NDA Section

3: Application Summary NDA Section

4: Chemistry, Manufacturing, and Controls (CMC) NDA Section

5: Nonclinical Pharmacology and Toxicology NDA Section

6: Human Pharmacokinetics and Bioavailability NDA Section

7: Microbiology NDA Section

8: Clinical Data NDA Section

9: Safety Update Reports.

10: Statistics NDA Section

11: Case Report Form Tabulations NDA Section

12: Case Report Forms (CRFs) NDA Section

13: Patent Information NDA Section

14: Patent Certification NDA Section

15: Establishment Description NDA Section

16: Debarment certificate NDA Section

17: Field copy certification NDA Section

18: User fee coversheet NDA Section

19: Financial Disclosure NDA Section

20: Other/ Pediatrics NDA CONTENTS

NDA Section 1: Index: The NDA index is a comprehensive table of contents that enables

the reviewers to find specific information in this massive document quickly. The NDA index

should follow immediately after the Form FDA-356h and the administrative items. It must show

the location of every section in the archival NDA by volume and by page number.

It should guide reviewers the data in the technical sections, the summary, and the supporting

documents , each separately bound technical section should also contain a copy of the overall

NDA index in addition to its own table of contents based on the index.

NDA Section 2: Labeling: The labeling section must include all draft labeling that is

intended for use on The product container, Cartons or packages, The proposed package insert.

The draft product labeling include the following sections

1. Description

2. Clinical Pharmacology

3. Indications and Usage

4. Contraindications

5. Warnings

6. Precautions

7. Adverse Reactions

8. Drug Abuse and Dependence

9. Overdosage

10. Dosage and Administration

11. How Supplied (primary and secondary packages)

NDA Section 3: Application Summary:

The application summary is an abbreviated version of the entire application. This

overview is one of the few elements of the application that all reviewers receive, and it should

give them a clear idea of the drug and its application. The summary usually comprises 50 to 200

pages

The application summary is an abbreviated version of the entire application. This

overview is one of the few elements of the application that all reviewers receive, and it should

give them a clear idea of the drug and its application. The summary usually comprises 50 to 200

pages.

Application Summary For each section of the labeling, include annotations

referring to information in the summary and technical sections of the application that support the

inclusion of each statement in the labeling with respect to Animal pharmacology and/or animal

toxicology, Clinical studies, Integrated Summary of Safety (ISS) and Integrated Summary of

Effectiveness (ISE) Safety (ISS) and Integrated Summary of Effectiveness (ISE) Pharmacologic

class Scientific rationale Intended use Potential clinical benefits Application Summary Foreign

marketing history

The summary must include a list of any countries in which the drug is or was

marketed, along with the dates when it was marketed, if they are known. It must also include a

list of any countries in which the drug has been withdrawn from marketing for any reason

relating to safety or efficacy or in which an application has been rejected.

NDA Section 4: Chemistry, Manufacturing, and Controls (CMC)

The first technical section of the NDA It includes information on The

composition, Manufacturing, and Specifications of the drug substance and the drug product. The

three main elements are Chemistry, manufacturing and controls information, Samples Methods

validation package.

The CMC information must include Description of the drug substance or active

ingredient, Its stability Physical and chemical characteristics, Provide the names/designations of

the drug substance, including: Generic/common name Chemical name (IUPAC/USAN/CAS)

Code(s) (CAS/internal)

CMC Provide a structural overview, including: Molecular structure Empirical

formula Molecular weight Elemental composition. The description of the drug substance’s

physical and chemical characteristics should include: Appearance, including color, crystalline

form, and odor Melting/boiling point Refractive index, viscosity, and specific gravity

Polymorphs, including modifications (forms) and relative kinetic/ thermodynamic stabilities

The physical and chemical characteristics should also include Solubility,

Ionization constants, and Partition coefficients at various pHs. Solubility in common organic

solvents as well as in various aqueous media Water 0.1 N HCl 0.02 N HCl SGF without pepsin

Water buffered to various acidic/neutral/basic pHs

CMC Provide a reference standard (RS) to elucidate the drug substance’s

chemical structure, including Preparation method, Test methods, Test results as shown by a

certificate of analysis (C.O.A). Provide proof that the reference standard was adequately tested

and characterize the spectra completely.

It Provides structural elucidation using a reference standard as applicable.

Measures might include X-ray (in the case of absolute configuration or polymorphism)

UV/visible spectrum FTIR spectrum 1H NMR/13C NMR spectrum Low-resolution/high-

resolution mass spectrum Elemental analysis

The CMC information must also include the Names, addresses and functions of

each site where the drug substance is manufactured or tested. The description of the drug

substance manufacturing methods must include Synthesis scheme Synthesis description Typical

executed manufacturing record Compilation of and analytical controls for starting materials;

Reagents, Solvents Catalysts, and Intermediates Suppliers for starting materials

The discussion of drug substance analytical controls should include the

following: Specifications Methods Rationale for methods/specifications Method validations

Batch analytical data (including impurity profiles cross-referenced with toxicology studies)

Sampling plan

It Provides information on drug substance stability, including:

Ambient/accelerated stability data Retest dating highly stressed (e.g., acid, base, reflux) data

Provide a listing of all inactive ingredients. For compendial (e.g., UPS/NF) inactive ingredients,

reference the appropriate current compendial monographs and provide more precise

specifications as necessary.

CMC For noncompendial ingredients that fall under 21 CFR such as D&C and

FD&C dyes, reference the appropriate section of 21 CFR and provide any additional

specifications beyond the scope of the CFR. For noncompendial items that are not regulated by

21 CFR, provide appropriate analytical specifications and methods.

It Provides information on the drug product manufacturing methods: Summary

and schematics of manufacturing procedure Master batch record for proposed marketed products,

including actual operating conditions, type and size of equipment, and in process controls and

tests Executed batch record

The section on drug product packaging must include: Summary of

container/closure system(s) Listing of packaging components and component/resin suppliers

Specifications for each packaging component DMF authorization letters Description of the

packaging process Test methods (as appropriate) Developmental data that confirms the

suitability of the packaging. This includes water vapor permeation data for plastic containers/

closures and compatibility testing for solutions, suspensions, emulsions, etc.

The drug product stability information will differ slightly from the drug

substance stability information. Unstressed/stressed stability data Statistical analysis to establish

consistency of data Expiration dating Post approval stability commitment/protocol

CMC For an NDA, provide a list of all drug product investigational

formulations used in clinical studies, along with the quantitative composition of each

formulation. Every NDA must include an environmental assessment (EA) The EA, also called

the environmental impact analysis report, includes an analysis of the manufacturing process and

ultimate use of the drug product as well as a discussion of how the process and the drug product

may affect the environment.

The final component of the CMC technical section is the methods validation

package. The package must comprise: Specifications and test methods for each component used

in the drug product Specifications and methods for the drug product Validation of test methods

Names and addresses of component suppliers Names and addresses of the suppliers of the

container closure system.

NDA Section 5: Nonclinical Pharmacology and Toxicology:

The second technical section of the NDA provides a description of all

animal and in vitro studies with the drug. Include a narrative summary of notable findings in all

studies and a discussion of notable findings across the various studies.

It provides individual study reports, including Pharmacology, Toxicology,

and ADME studies. For the pharmacology studies, following data is required 1. Effects related to

the therapeutic indication, such as the pharmacodynamic ED 50 in dose-ranging studies and the

mechanism of action (if known) 2. Secondary pharmacological actions in order of clinical

importance as possible adverse effects or as ancillary therapeutic effects 3. Interactions with

other drugs NDA Section 5: Nonclinical Pharmacology and Toxicology

The Toxicology information must include information on Acute toxicity,

Multidose toxicity (including sub chronic, chronic, and carcinogenicity) Special toxicity studies,

as well as Reproduction studies and mutagenicity studies. NDA Section 5: Nonclinical

Pharmacology and Toxicology. It Presents toxicology data by intended route of administration in

the following order: 1. Oral 2. Intravenous 3. Intramuscular 4. Interperitoneal 5. Subcutaneous 6.

Inhalation 7. Topical 8. Other in vivo 9.In vitro NDA Section 5: Nonclinical Pharmacology and

Toxicology

For acute toxicity studies, present the animal study data in the following

order: 1. Mouse 2. Rat 3. Hamster 4. Other rodent(s) 5. Rabbit 6. Dog 7. Monkey 8. Other

nonrodent mammal(s) 9. Nonmammals NDA Section 5: Nonclinical Pharmacology and

Toxicology. It Presents the ADME data in the following order: 1. Absorption 2. Distribution

(protein binding, tissue distribution, accumulation) 3. Metabolism (enzyme induction or

inhibition) 4. Excretion (serum half-life, Key etc) NDA Section 5: Nonclinical Pharmacology

and Toxicology

NDA Section 6: Human Pharmacokinetics and Bioavailability: This technical section includes data from Phase I safety and tolerance

studies in healthy volunteers and ADME studies. It should include a table of PK parameters,

giving the values for the major parameters (mean and % cv) such as • Peak concentration (Cmax)

• Area under the curve (AUC) • Time to reach peak concentration (tmax) • Elimination constant

(Ke) • Distribution volume (Vd) • Plasma and renal clearance • Urinary excretion

It should include a list of all formulations used in clinical trials and in in

vivo bioavailability and PK studies. The analytical methods used must be summarized in each in

vivo biopharmaceutical study. Include detailed information, such as Sensitivity Linearity

Specificity and Reproducibility of the analytical test methods used in each study

It Provides dissolution data on each strength and dosage form for which

an approval is sought. Include a comparative dissolution study with the lot in the in vivo

biopharmaceutical study. Include summary of the product’s Dissolution performance Dissolution

method and Dissolution specifications, this technical section must include individual study

reports from five types of biopharmaceutical studies as described below: Pilot or background

studies Bioavailability/bioequivalence Pharmacokinetic studies other in vivo studies In vitro

studies

Pilot or background studies:

Pilot or background studies Pilot or background studies are carried

out in a small number of subjects to provide preliminary assessment of ADME information. It

acts as a guide to the design of early clinical trials and definitive kinetic studies.

Bioavailability/bioequivalence:

Bioavailability/bioequivalence Bioavailability studies define the

rate and extent of absorption relative to a reference dosage form, such as IV, solution, or

suspension. Bioequivalence studies compare pharmaceutical alternatives to establish equivalent

extents and, where necessary, equivalent rates of absorption. Dosage strength equivalence studies

show that equivalent doses of different dosage forms deliver the same amount of drug. For

example, three doses of 100 milligrams (mg) is equivalent to a single 300 mg tablet.

Pharmacokinetic studies:

Pharmacokinetic studies Designed to define the drug’s time course

and, where appropriate, major metabolite concentrations in the blood and other body

compartments. With these studies, it is critical to demonstrate the rate of drug absorption and

delivery to systemic circulation and the rate of elimination of the drug through metabolic or

excretory processes. Dose dependent changes in kinetic parameters are very important.

Pharmacokinetic studies Other information from PK studies may

include the influence of demographic characteristics such as age, gender, or race certain disease

states (e.g., cirrhosis) external factors such as meals or other drugs. Include information on

studies that show drug binding to biological constituents such as Plasma protein or red blood

cells Studies performed in special patient populations (e.g., Steroid-dependent patients), and

Studies performed under conditions of therapeutic use.

In vivo studies: In vivo studies include any bioavailability studies that employ

pharmacological or clinical measurements or endpoints in humans or animals. In addition,

chemical analysis of body fluids may be used when appropriate.

In vitro studies: In vitro studies In vitro studies should include studies designed to

define the release rate of a drug substance from the dosage form. Such studies are conducted in

order to characterize a dosage form and to assure consistent batch-to-batch behavior. Other in

vitro studies may be conducted for further characterization of the drug moiety (e.g., protein

binding).

NDA Section 7: Microbiology: Microbiology required for anti infective drug products.

Antimicrobial drugs differ from other classes of drugs in that they are designed to affect

microbial physiology rather than patient physiology. In vitro and in vivo studies are critical in

establishing the new drug’s effectiveness, especially if the microorganism has the potential to

develop, or has developed, resistance to other antimicrobial drugs. This section requires the

following technical information and data: 1. A complete description of the biochemical basis of

the drug’s action on microbial physiology. 2. The drug’s antimicrobial spectrum. Include results

of in vitro studies demonstrating the concentrations of the drug that are required for effective use.

3. Describe any known mechanisms of resistance to the drug and provide information or data of

any known epidemiologic studies demonstrating prevalence to resistance factors. 4. Clinical

microbiology laboratory methods, such as in vitro sensitivity discs, necessary to evaluate

effective use of the drug.

NDA Section 8: Clinical Data:

This technical section of the NDA comprises ten elements. The

document’s largest and most complex section. List of investigators and list of INDs and NDAs

Background/overview of clinical investigations Clinical pharmacology section Controlled

clinical trials Uncontrolled clinical trials other studies and information section Integrated

summary of effectiveness data Integrated summary of safety information Drug abuse and over

dosage information Integrated summary of benefits and risks of the drug.

List of investigators and list of INDs and NDAs:

List of investigators and list of INDs and NDAs the list of

investigators should include all investigators who have used any dosage form. Alphabetize the

list and note each investigator’s address, the type of study, the study identifier, and its location in

the NDA. Provide a list of all known INDs under which the drug, in any dosage form, has been

studied.

Background/overview of clinical investigations:

Background/overview of clinical investigations Describe the general

approach and rationale used in developing the clinical data. Explain how information about the

drug derived from clinical pharmacology studies led to critical features of the clinical studies.

Support the basis for the design features of the clinical trials, such as number of patients,

duration, selection criteria, and controls.

Clinical pharmacology:

Clinical pharmacology should include ADME studies,

pharmacodynamic dose range, and dose response studies, and any other studies of the drug’s

action. The format and order of presentation is as follows: 1. Table of all studies grouped by

study type. Provide the investigators, study numbers, start date, and location of the report in the

NDA. 2. For each group of studies, a brief synopsis of each study 3. An overall summary of the

clinical pharmacology data

Controlled clinical trials:

Controlled clinical trials provide the following material in the order

presented below: 1. A table of all studies 2. Full clinical trial reports of all controlled studies in

the following order: Completed studies ongoing studies with interim results Incomplete or

discontinued studies 3. Full reports of dose-comparison concurrent control studies, followed by

those for “no- treatment” concurrent control, active control studies, and historical control studies

Uncontrolled clinical trials:

Uncontrolled clinical trials they may be used to provide support for

controlled studies and to provide critical safety information. This section should include a table

of all studies. Group full reports of studies according to completeness and availability of Case

Report Forms (CRFs).

Other studies and information:

Other studies and information include a description and analysis of

any additional information that the applicant has obtained from any source, foreign or domestic,

that is relevant to evaluating the product’s safety and effectiveness. It should include information

on commercial marketing experience and foreign regulatory actions, including: List of countries

in which the drug has been approved Details of any rejected registrations Copies of approved

labeling (package inserts) from major regions such as Europe, Canada, Australia, New Zealand,

and Japan Any other reports from the literature not provided elsewhere in the NDA

Integrated summary of effectiveness:

Integrated summary of effectiveness Demonstrate substantial

evidence of effectiveness for each claimed indication. It should also include a summary of

evidence supporting the dosage and administration section of the labeling, including the dosage

and dose interval recommended.

Integrated summary of safety information:

Integrated summary of safety information incorporate safety data

from all sources, including pertinent animal data, Clinical studies, and foreign marketing

experience. Describe the demographics and other characteristics of the entire drug exposed

population and also of logical groups of studies.

NDA Section 9: Safety Update Reports:

A pending application must be updated when new safety data

becomes available that could affect any of the following: Statements in draft labeling

Contraindications Warnings Precautions Adverse events. Safety update reports are not to be used

to submit any new final reports that may impact FDA review time unless the FDA agrees at the

pre-NDA meeting that it will accept the reports in this manner. Safety updates are submitted 4

months (120 days) after the initial application, following the receipt of an approval letter and at

any other time that the FDA requests such an update.

NDA Section 10: Statistics:

This technical section includes descriptions and documentation of

the statistical analyses performed to evaluation the controlled clinical trials and other safety

information. It must include copies of: All controlled clinical trial reports integrated efficacy and

safety summaries integrated summary of risks and benefits.

NDA Section 11: Case Report Form Tabulations:

This section must include complete tabulations for each patient

from every adequately or well-controlled Phase II and Phase III efficacy study, and from every

Phase I clinical pharmacology study. It also must include tabulations of safety data from all

clinical studies.

NDA Section 12: Case Report Forms (CRFs):

It is necessary to include the complete CRF for each patient who

died during a clinical study and for any patients who were dropped from the study the report

must be submitted regardless of whether the AE is considered to be related to the study drug,

even if the patient was receiving a placebo or comparative drug. Additional CRFs must be

provided at the request of the FDA.

The NDA in CTD Format:

The NDA in CTD Format ICH has developed a Common

Technical Document to streamline regulatory submissions in Europe, the U.S. and Japan. CTD is

an information format that contains clinical, nonclinical, and manufacturing technical data. The

CTD format features well-defined modules, with a highly specific structure and numbering of

sections within the modules. It makes a clear distinction between subjective information sections

and objective information sections.

FLOWCHART:

Abbreviated New Drug Application (ANDA):

An Abbreviated New Drug Application (ANDA) contains

data which when submitted to FDA's Center for Drug Evaluation and Research, Office of

Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once

approved, an applicant may manufacture and market the generic drug product to provide a safe,

effective, low cost alternative to the American public.

A generic drug product is one that is comparable to an

innovator drug product in dosage form, strength, route of administration, quality, performance

characteristics and intended use. All approved products, both innovator and generic, are listed in

FDA's Approved Drug Products with Therapeutic Equivalence Evaluation (Orange Book).

Generic drug applications are termed "abbreviated" because

they are generally not required to include preclinical (animal) and clinical (human) data to

establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate

that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One

way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to

reach the bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of absorption, or

bioavailability, of the generic drug, which they can then compare to that of the innovator drug.

The generic version must deliver the same amount of active ingredients into a patient's

bloodstream in the same amount of time as the innovator drug.

Using bioequivalence as the basis for approving generic copies

of drug products was established by the "Drug Price Competition and Patent Term Restoration

Act of 1984," also known as the Waxman-Hatch Act. This Act expedites the availability of less

costly generic drugs by permitting FDA to approve applications to market generic versions of

brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the

brand-name companies can apply for up to five additional years longer patent protection for the

new medicines they developed to make up for time lost while their products were going through

FDA's approval process. Brand-name drugs are subject to the same bioequivalence tests as

generics upon reformulation. For more information on generic drug bioequivalence

requirements, please see the chapter entitled "FDA Ensures Equivalence of Generic Drugs" in

"From Test Tube to Patient: Improving Health Through Human Drugs."

The Office of Generic Drugs provides additional information to

generic drug developers, focusing on how CDER determines the safety and bioequivalence of

generic drug products prior to approval for marketing. Generic drug application reviewers focus

on bioequivalence data, chemistry and microbiology data, requests for plant inspection, and drug

labeling information.

FLOWCHART:

DRUGS APPROVED BY FDA IN THE YEAR 2010

Cardiology/Vascular Diseases

Pradaxa (dabigatran etexilate mesylate); Boehringer Ingeleheim; For the risk reduction of stroke and embolism due to atrial fibrillation, Approved October 2010

Tekamlo (aliskiren + amlodipine); Novartis; For the treatment of hypertension, Approved August 2010

Tribenzor (olmesartan medoxomil + amlodipine + hydrochlorothiazide); Daiichi Sankyo; For the treatment of hypertension, Approved July 2010

Dermatology/Plastic Surgery

Veltin (clindamycin phosphate and tretinoin); Stiefel; For the treatment of acne vulgaris, Approved July 2010

Zyclara (imiquimod); Graceway; For the treatment of actinic keratoses of the face and scalp, Approved March 2010

Endocrinology

Prolia (denosumab); Amgen; For the treatment of postmenopausal women with osteoporosis at high risk for fracture, Approved June 2010

Victoza (liraglutide); Novo Nordisk; For the treatment of type 2 diabetes mellitus, Approved January 2010

Gastroenterology

Herceptin (trastuzumab); Genentech; For the treatment of gastric cancer, Approved October 2010

Pancreaze (pancrelipase); Johnson & Johnson; For the treatment of exocrine pancreatic insufficiency, Approved April of 2010

Vimovo (naproxen + esomeprazole); AstraZeneca; For the treatment of arthritis in patients at risk for NSAID-associated ulcers, Approved April 2010

Zuplenz (ondansetron oral soluble film); Strativa Pharmaceuticals; For the prevention of post-operative, chemotherapy and radiotherapy induced nausea and vomiting, Approved July 2010

Hematology

Vpriv (velaglucerase alfa for injection); Shire; For the treatment of type 1 Gaucher disease, Approved March 2010

http://www.centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=1091












Immunology/Infectious Diseases

Cayston (aztreonam for inhalation solution); Gilead Sciences; For the treatment of cystic fibrosis patients with Pseudomonas aeruginosa, Approved February 2010

Menveo (meningitis vaccine); Novartis; For the active immunization to prevent invasive meningococcal disease, Approved February 2010

Oravig (miconazole); Strativa Pharmaceuticals; oropharyngeal candidiasis, Approved April 2010

Prevnar 13 (Pneumococcal 13-valent Conjugate Vaccine); Wyeth; For the active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae, Approved February 2010

Zortress (everolimus); Novartis; For the prevention of organ rejection following kidney transplant, Approved May 2010

Zymaxid (gatifloxacin ophthalmic solution); Allergan; For the treatment of bacterial conjunctivitis, Approved May 2010

Musculoskeletal

Actemra (tocilizumab); Genentech; For the treatment of rheumatoid arthritis, Approved January 2010

Ampyra (dalfampridine); Acorda; For the improvement of walking in patients with multiple sclerosis, Approved January 2010

Botox (onabotulinumtoxinA); Allergan; For the treatment of upper limb spasticity, Approved March 2010

Gilenya (fingolimod); Novartis; For the treatment of relapsing multiple sclerosis, Approved September 2010

Krystexxa (pegloticase); Savient Pharma; For the treatment of chronic gout (hyperuricemia), Approved September 2010



Xeomin (incobotulinumtoxinA); Merz Pharmaceutical; For the treatment of cervical dystonia and blepharospasm, Approved July 2010

Xiaflex (collagenase clostridium histolyticum); Auxilium Pharmaceuticals; For the treatment of Dupuytren’s contracture, Approved February 2010

Nephrology/Urology
















Carbaglu (carglumic acid); Recordati; For the treatment of hyperammonemia, Approved March 2010

Jalyn (dutasteride + tamsulosin); GlaxoSmithKline; For the treatment of benign prostatic hyperplasia, Approved June 2010

Jevtana (cabazitaxel); sanofi aventis; For the treatment of prostate cancer, Approved June 2010

Provenge (sipuleucel-T); Dendreon; For the treatment of hormone refractory prostate cancer, Approved May 2010

Xifaxan (rifaximin); Salix; For the treatment of hepatic encephalopathy, Approved March 2010

Zortress (everolimus); Novartis; For the prevention of organ rejection following kidney transplant, Approved May 2010

Neurology

Ampyra (dalfampridine); Acorda; For the improvement of walking in patients with multiple sclerosis, Approved January 2010

Botox (onabotulinumtoxinA); Allergan; For the treatment of upper limb spasticity, Approved March 2010

Botox (onabotulinumtoxinA); Allergan; For the treatment of chronic migraine, Approved October 2010

Carbaglu (carglumic acid); Recordati; For the treatment of hyperammonemia, Approved March 2010

Cuvposa (glycopyrrolate); Shionogi; For the treatment of chronic severe drooling in pediatrics with neurologic conditions, Approved July 2010

Exalgo (hydromorphone hydrochloride) extended release; Alza; For the management of moderate to severe pain, Approved March 2010

Kapvay (clonidine hydrochloride); Shionogi Pharma; For the treatment of attention deficit hyperactivity disorder, Approved October 2010

Silenor (doxepin); Somaxon Pharma; For the treatment of insomnia, Approved March 2010

Sprix (ketorolac tromethamine); Roxro Pharma; For the treatment of moderate to severe pain, Approved May 2010

Vivitrol (naltrexone for extended-release injectable suspension); Alkermes; For the prevention of relapse to opioid dependence, Approved October 2010

Vpriv (velaglucerase alfa for injection); Shire; For the treatment of type 1 Gaucher disease, Approved March 2010

Xifaxan (rifaximin); Salix; For the treatment of hepatic encephalopathy, Approved March 2010

Obstetrics/Gynecology



















ella (ulipristal acetate); HRA Pharma; For the emergency prevention of contraception, Approved August 2010

Natazia (estradiol valerate + dienogest); Bayer; For the prevention of contraception, Approved May 2010


Oncology

Herceptin (trastuzumab); Genentech; For the treatment of gastric cancer, Approved October 2010

Jevtana (cabazitaxel); sanofi aventis; For the treatment of prostate cancer, Approved June 2010

Provenge (sipuleucel-T); Dendreon; For the treatment of hormone refractory prostate cancer, Approved May 2010


Ophthalmology

Zymaxid (gatifloxacin ophthalmic solution); Allergan; For the treatment of bacterial conjunctivitis, Approved May 2010

Otolaryngology

Oravig (miconazole); Strativa Pharmaceuticals; oropharyngeal candidiasis, Approved April 2010

Pediatrics/Neonatology

Cuvposa (glycopyrrolate); Shionogi; For the treatment of chronic severe drooling in pediatrics with neurologic conditions, Approved July 2010

Dulera (mometasone furoate + formoterol fumarate dihydrate); Merck; For the treatment of asthma, Approved June 2010

Kapvay (clonidine hydrochloride); Shionogi Pharma; For the treatment of attention deficit hyperactivity disorder, Approved October 2010

Veltin (clindamycin phosphate and tretinoin); Stiefel; For the treatment of acne vulgaris, Approved July 2010

Pharmacology/Toxicology















Psychiatry/Psychology

Oleptro (trazodone hydrochloride); Labopharm; For the treatment of major depressive disorder, Approved February 2010

Vivitrol (naltrexone for extended-release injectable suspension); Alkermes; For the prevention of relapse to opioid dependence, Approved October 2010

Pulmonary/Respiratory Diseases

Cayston (aztreonam for inhalation solution); Gilead Sciences; For the treatment of cystic fibrosis patients with Pseudomonas aeruginosa, Approved February 2010

Dulera (mometasone furoate + formoterol fumarate dihydrate); Merck; For the treatment of asthma, Approved June 2010

Rheumatology

Actemra (tocilizumab); Genentech; For the treatment of rheumatoid arthritis, Approved January 2010

Krystexxa (pegloticase); Savient Pharma; For the treatment of chronic gout (hyperuricemia), Approved September 2010


Trauma/Emergency Medicine











Conclusion:

Advances in the field of Genomics and Bioinformatics will help in the

identification of potential drug targets especially related to disease targets in the future. New

drugs for the genetic disorders such as Huntington’s disease, Alzheimer’s disease, cancer and

several polygenic diseases will become available. It is estimated that there are about 100 diseases

for which new drugs are required in the near future, which may provide about 10,000 different

new target sites for new drug discovery. Therefore, future is brimming with opportunity and

challenging in identifying the critical targets ad designing of safe and effective drugs that interact

with these targets.

REFERENCE:

• Ansel’s Pharmaceutical Dosage Forms & Drug Delivery Systems.

• Industrial Pharmacy By Lachhman Liebermann.

• www.innovation .org .com

• www.fda.gov.in

• www.sciencemag.org

• www. drug s.com/ new - drug - application s

• www.authorstream.com

• www.novartis.com/research/drug-discovery

http://www.authorstream.com/

http://www.drugs.com/new-drug-applications









http://www.sciencemag.org/

http://www.fda.gov.in/

new drug application hardcopy

Documents