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An NDA (New drug application) is application submitted to US FDA for permission to market a new drug product in the world . WHAT ARE THE GOALS OF NDA ? Whether the drug is safe and effective in its propose use(s), and whether the benefits of the drug outweigh the risks. Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain. Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity. WHAT IS NDA

NDA Classifications  :

CDER(center for drug evaluations and research )classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses New Molecular Entity New Salt of Previously Approved Drug (not a new molecular entity) New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) New Combination of Two or More Drugs New Indication (claim) for Already Marketed Drug (includes switch in marketing status from prescription to OTC) NDA Classifications


The Food and Drug Administration (FDA) receives new drug applications (NDAs) from sponsors, typically pharmaceutical companies, and reviews these applications for scientific evidence pertaining to the safety and efficacy of drugs. Based on its assessments, the FDA determines whether drugs can be marketed in the United States. For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug or therapy has been the subject of an approved NDA before US commercialization. The Prescription Drug User Fee Act (PDUFA), enacted in 1992, authorized FDA to collect user fees from sponsors to help speed up the review of NDAs. It also established time goals for FDA’s reviews. In 1997, the FDA Modernization Act reauthorized user fees for another 5 years. It shortened the time goals and called for FDA to work more collaboratively with sponsors. In June 2002, the Public Health Security and Bioterrorism Preparedness Act of 2002 once again reauthorized user fees. The part of this Act addressing user fees is referred to as PDUFA III. BACK GROUND HISTORY OF NDA


Preclinical Research Investigational New Drug (IND) Application Phase 1 Trials Phase II Trials Phase III Trials New Drug Application (NDA) Approval FDA Approval: The sponsor has received final product approval by the FDA to sell and market a Product. STEPS INVOLVED IN NDA APPROVAL


The purpose of an NDA from the FDA’s perspective is to ensure that the new drug meets the criteria to be “safe and effective.” FDA looks to the new drug’s efficacy as a measure of its safety. It weighs the risks vs. benefits of approving the drug for use in the U.S. market. The FDA is required to review an application within 180 days of filing. At the end of that time, the agency is required to respond with an “action letter . ” There are three kinds of action letters. An Approval Letter An Approvable Letter A Non-Approvable Letter NDA FILING PROCESS AND APPROVAL


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. To help speed the process of reviewing such complex document with multiple sections, it is important that the data to be presented is clear and consistent. The FDA has established guidelines for formatting assembling and submission of NDA. Failure to follow these guidelines may result in deficiencies that could delay review , require an amended application, or result in a Refusal to File. NDA ORGANIASATION:

FDA Guidelines :

Most of the FDA guidelines regarding NDAs were written and implemented in early 1987. The guidelines address format, assembly, submission, and content of the overall NDA. Additional guidelines address format and content of specific sections within the NDA. A list of the current FDA guidelines with their most recent revision dates follows: Guideline on Formatting, Assembling, and Submitting New Drug and Antibiotic Applications, February 1987 Guideline for the Format and Content of the Summary for New Drug and Antibiotic Applications, February 1987 Guideline for the Format and Content of the Nonclinical/Pharmacology/Toxicology Section of an Application, February 1987 Guideline for the Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application, February 1987 Guideline for the Format and Content of the Microbiology Section of an Application, February 1987 FDA Guidelines

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Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, July 1987 Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application, February 1987 Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, February 1987 Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products, February 1987 Guideline for Submitting Samples and Analytical Data for Methods Validation, February 1987 Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics, February 1987 (new draft proposed July 1997) Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics, February 1987

Assembling Applications for Submission   :

The FDA requires drug sponsors to submit multiple copies of the NDA 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 review copy The Field copy Assembling Applications for Submission


The NDA may have as many as 20 different sections in addition to the Form FDA-356h itself. To a certain degree, the specific contents of the NDA will depend on the nature of the drug and the information available at the time of submission. The components of the application, however, are uniform . NDA section 1 : Index NDA Section 2: Labeling NDA section 3: Application summary NDA Section4: Chemistry Manufacturing And Controls (CMC ) NDA Section5: Non Clinical Pharmacology And Toxicology NDA Section6: Human Pharmacokinetics And Bioavailability NDA Section7: Microbiology NDA Section8: Clinical Data NDA Section9: Safety Update Reports NDA Section10: Statistics NDA CONTENTS

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NDASection11: Case Report Tabulation NDA Section12: Case Report Forms (CRF’s) NDASection13: Patent Information NDA Section14: Patent Certification NDA Section15: Establishment Description (If Available) NDA Section16: Debarment Certification NDA section 17: Field Copy Certification NDA Section18: User Fee Cover Sheet (Form Fda - 3397) NDA Section19: Financial Disclosure (Form Fda-3454, Form Fda-3455) NDA Section20: Other/Pediatric Use

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 should guide reviewers to 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 1: 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, including the proposed package insert. As noted above, the NDA must have four copies of the draft labeling. One copy should be bound into the archival copy. Copies should also be placed in the review copies of the clinical, chemistry, and pharmacology sections. NDA Section 2: Labeling

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. It must include : Pharmacologic class, scientific rationale ended use, and potential clinical benefits. Foreign marketing history. Chemistry, manufacturing, and controls summary. Nonclinical pharmacology and toxicology summary Human pharmacokinetics and bioavailability (HPKB) summary. Microbiology summary Clinical data summary and results of statistical analys is. NDA Section 3: Application Summary

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

The first technical section of the NDA is the chemistry section. It includes information on the composition, manufacture, and specifications of the drug substance and the drug product. The three main elements are (1) chemistry, manufacturing and controls information, (2) samples and, (3) methods validation package. The CMC information must include a description of the drug substance or active ingredient, including its stability and physical and chemical characteristics, and provide the names/designations of the drug substance, including: Generic /common name Chemical name(IUPAC/USAN/CAS) Codes(CAS/internal) Samples. In addition to the chemistry, manufacturing and controls information, the CMC technical section must include a commitment to submit samples to FDA laboratories for testing and validation of analytical methods. Actual samples are submitted only upon FDA request. If samples are requested, submit the drug product, the drug substance, and the reference standards. NDA Section 4 Chemistry, Manufacturing, and Controls (CMC)

NDA Section 5: Nonclinical Pharmacology and Toxicology :

The second technical section of the NDA provides a description or summaryof all animal and in vitro studies with the drug. The table of contents should clearly identify all studies not previously submitted to the IND. Include a narrative summary of notable findings in all studies and a discussion of notable findings across the various studies. This discussion might include intra- and interspecies differences or similarities. Provide a tabular display of data, and cross-references to individual study reports. Provide individual study reports, including pharmacology, toxicology, and ADME studies. For the pharmacology studies, present data as follows: 1. Effects related to the therapeutic indication, such as the pharmacodynamic ED50 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 therapeutic effects 3 interactions with other drugs The toxicology information must include information on acute toxicity, multi dose toxicity (including sub chronic, chronic, and carcinogenicity) and special toxicity studies, as well as reproduction studies and mutagen city studies 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. The first element in this section is a tabulated summary of studies showing all in vivo biopharmaceutics studies performed. List them in descending order of importance. Include a summary of data and overall conclusions. This summary should address all bioavailability and pharmacokinetic data and conclusions. It should include a table of PK parameters, giving the values for the major parameters such as: Peak concentration ( Cmax ) • Area under the curve (AUC) • Time to reach peak concentration ( tmax ) • Plasma and renal clearance • Elimination constant • Distribution volume ( Vd ) • Urinary excretion NDA Section 6: Human Pharmacokinetics and Bioavailability

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Provide 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 bio pharmaceutic study. Pharmacokinetic studies are designed to define the drug’s time course and, where appropriate, major metabolite concentrations in the blood and other body compartments. 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 in animals may be used when appropriate. 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.

NDA Section 7: Microbiology   :

The microbiology technical section is only required for anti infective drug products. 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 pro- vide 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 7: Microbiology

NDA Section 8: Clinical Data :

This technical section of the NDA comprises ten elements. The document’s largest and most complex section, the clinical data and analyses are key to the FDA’s understanding of the new drug’s safety and effectiveness . The first element in this section is a list of investigators and list of INDs and NDAs. The next element is the background/overview of clinical investigations. This narrative should describe the general approach and rationale used in developing the clinical data. Address the reason for selecting areas of special interest, such as demographics, gender or drug interactions, and discuss any effectiveness or safety issues raised by other drugs in the same pharmacologic or therapeutic class. The clinical pharmacology section should include : For the controlled clinical trials section: Uncontrolled clinical trials: Ordinarily the integrated summary of benefits and risks of the drug recapitulates the evidence for effectiveness and safety . NDA Section 8: Clinical Data

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 9: Safety Update Reports

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 10: Statistics

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. Routine submission of data from uncontrolled studies is not required. Note that data listings are most often placed with the final reports in each section rather than with the CRF tab NDA Section 11: Case Report Form Tabulations

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 due to an adverse event, 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 . NDA Section 12: Case Report Forms (CRFs)

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. I Use of the CTD format benefits both regulatory agencies and the pharmaceutical industry. In addition to enhancing reviews, the CTD’s use of common elements facilitates communications between the agencies and the applicants and simplifies the exchange of information between regulatory authorities. The document also provides a common basis for continuous improvement of Good Regulatory Practices. The NDA in CTD Format


An Abbreviated New Drug Application (ANDA) is specifically designed for an approval of a generic drug product. When data within an ANDA are submitted to the Food and Drug Administration’s Center for Drug Evaluation and Research (CDER), Office of Generic Drugs, the applications are reviewed and approved from that division . A generic drug must be a drug product that is comparable to an innovator drug product in dosage form, strength, and route of administration, quality, performance characteristic, and intended use . BACKGROUND HISTORY In 1970 FDA established the ANDA as a mechanism for the review and approval of generic versions. Before 1978, generic product applicants were required to submit complete safety and efficacy through clinical trials. Post 1978, applicants were required to submit published reports of such trials documenting safety and efficacy. Neither of these approaches was considered satisfactory and so originated Hatch Waxman Act on 1984. ABBREVIATED NEW DRUG APPLICATION (ANDA)

Hatch-Waxman Act :

Commonly known as “Drug Price Competition & Patent Term Restoration Act” of 1984. “The Hatch-Waxman Act is an act dealing with the approval of generic drugs and associated conditions for getting their approval from FDA, market exclusivity, rights of exclusivity, patent term extension and Orange Book Listing.” General Provisions of the Act 1. Maintaining list of patents which would be infringed. 2. Only Bioavailability studies and not clinical trials needed for approval. 3. Para I, II, III and IV certifications. 4. Data exclusivity period for New Molecular Entities. 5. Extension of the original patent term. Hatch-Waxman Act

Recent additions to the Hatch-Waxman Act :

Under the “Medicare Prescription Drug and Modernization Act”, 2003: Non-extension of the 30-month period. Time limit for informing patent owner. Provision for allowing declaratory judgment. Benefit of exclusivity for several ANDAs filed on same day allowed. Recent additions to the Hatch-Waxman Act



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Indian pharma secure approval for 88 ANDAs from US FDA in first half of 2012 : DRL's received 9 approvals from US FDA during the first half ended June 2012. Aurobindo Pharma received 9 approvals from US FDA during the first half ended June 2012. It filed 30 ANDAs in USA during the year ended March 2012 and its cumulative filings reached at 239. Ranbaxy Laboratories , a Rs.9,958 crore leading pharma major, has received two ANDA approvals for pantoprazole sodium and morphine sulfate during the first half ended June 2012. Glenmark Pharmaceuticals and its US based subsidiary Glenmark Generics Inc., continued to maintained the product filing in highly regulated market. In the FY12, Glenmark was granted approval of 14 ANDAs. Lupin's R&D expenditure increased to Rs.523 crore during the year ended March 2012 from Rs.483 crore , a growth of 8.3 per cent. It filed 25 ANDAs during the year and its cumulative ANDA filings with the US FDA rose to 173 with the company having received 64 approvals . RECENT (ANDA ) APPROVALS

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Indian companies are stepping up investment in R&D during last couple of years to grab more market share in the highly regulated markets like US, Europe and Japan. The higher number of approvals from highly regulated markets will help to spread market presence in the lucrative markets and it will help to encash upcoming opportunities with the expiration of patents.


1. 2.FDA Regulatory Affairs , A Guide For Prescription Of Drugs Medical Devices And Biologics Edited By DOUGLAS J .PISANO DAVID MANTUS CRC Press. 3 .Strauss, S, Food and Drug Administration: An Overview, Strauss Federal Drug Laws and Examination Review, 5th ed., Technomic Publishing Co., Lancaster, PA, 1999, p. 323. 4 .The Orphan Drug Act of 1982, PL 97-414. 5.The Orphan Drug Amendments of 1985, PL 99-91. 6.Pinna, K. and Pines, W., The Drugs/Biologics Approval Process, A Practical Guide To Food and Drug Law and Regulation, FDLI, Washington, D.C., 1998, pp. 102–103. Fed Reg , V. 64(18), January 28, 1999. 7 .Pinna , K., and Pines, W., The Drugs/Biologics Approval Process, A Practical Guide To Food and Drug Law and Regulation, FDLI, Washington, D.C., 1998, p. 103. REFERENCES

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