The document discusses the process for product registration and drug approval in the United States. All new drug products must complete a registration process with the FDA to ensure safety and efficacy. This involves submitting a New Drug Application (NDA) containing clinical and manufacturing data and information. The NDA goes through a review process by FDA teams with expertise in technical areas. The review determines if the drug is approved for marketing in the United States.

1. Product Registration and Drug Approval
Process in United States

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CONTENT
 Back ground for product registration in the united
states
 Introduction
 The New Drug Application (NDA) Clasification
 Format and content of NDA
 NDA content
 NDA and review process
 Generic drug product registration and review process
(ANDA)
 Post-Approval activities for NDA and ANDA
 Other considerations for NDA and ANDA
 Pre-Approval inspection

3. Background for product registration in the United States
 All new drug products must be registered and
approved by the regulatory agency governing the
intended market before the products can be
introduced into the market.
 The registration process is to ensure the quality, safety,
and efficacy of drug products.
 The requirements for the development and
registration of new drug products in the United states
are defined in the Federal Food Drug and Cosmetic
Act (FD&C Act) and the regulations promulgated by
the FDA.

4. Introduction
 The new drug application (N D A) is a critical
component in the drug approval process. The NDA
contains Clinical and nonclinical 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.

5.  NDAs and ANDAs are submitted to FDA
 FDA has complex organisation for review and approval of
NDAs and ANDAs.
 Review and approval are conducted by CDER(Center for
Drug Evaluation and Research )
 Which reports directly to the office of commissioner of
FDA
 Within CDER there are number of offices organized under
the office of center director.

8. Format and content of NDA
1. Index
2. Summary
3. Chemistry, Manufacturing and Control
4. Samples, Methods Validation Package and Labeling
5. Nonclinical Pharmacology and Toxicology
6. Human Pharmacokinetics and Bioavailability
7. Microbiology ( for anti-microbial drugs only)
8. Clinical Data
9. Safety Update report ( typically submitted 120 days after
the NDA’s submission )
10. Statistical
11. Case Report Tabulations

9. 11.Case Report Tabulations
12.Case Report Forms
13. Patent Information
14. Patent Certification
15. Establishment description
16. Debarment certification
17. Field copy certification
18. User fee cover sheet
19. Financial information
20. Other

10. NDA CONTENTS
 Section 1: Overall NDA index:-
It Provides a guide through the entire application for the
FDA reviewers. The index must clearly describe the
contents and location of each section by volume and page
number.
 Section 2: Labeling
It must include all draft labeling that is intended for use on
the product container, cartons or packages, including the
proposed package insert.

11. 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
Application Summary 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)

12. Section 4: Chemistry, manufacturing and controls
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,
Method validation, package.
Section 5: Nonclinical pharmacology and toxicology
Provide individual study reports, including pharmacology,
toxicology, ADME studies.
Effects related to the therapeutic indication, such as the
pharmacodynamics ED50 in dose- ranging studies and the
mechanism of action
Interactions with other drugs (or cross-reference the location of the
information in any of the above subsection)

13.  Section 6: Human Pharmacokinetics and
bioavailability
Includes data from Phase I safety and tolerance studies in
healthy volunteers. Element in the section tabulated summary of
studies showing all in vivo biopharmaceutics studies performed
•Summary of analytical method used in in vivo biopharmaceutic study
•Pilot or background studies
•Bioavailability or bioequivalence studies
•Pharmacokinetic studies
•In vitro studies
Section 7: Microbiology
Includes data for anti infective drug products.
requires the following technical information and data:-
•A complete description of the biochemical basis of the drug action on
microbial physiology
•The drugs antimicrobial spectrum
•Describe any known mechanism of resistance to the drug and provide
information/data of any known epidemiologic studies demonstrating
prevalence to resistance factor
•Clinical microbiology laboratory methods

14. Section 8: Clinical data
Includes.
 Background or overview of clinical investigations
 Clinical pharmacology
 Controlled clinical trials
 Uncontrolled clinical trials
 Other studies and information
 Integrated summary of effectiveness data
 Integrated summary of safety information
 Drug abuse and overdose information
 Integrated summary of benefits and risks of drug

15. Section 9: Safety data
Statements in draft labeling
Contraindications
Warnings
Precautions
Adverse events
Section 10: Statistical data
All controlled clinical trial reports
Integrated efficacy and safety summaries
Integrated summary of risks and benefits

16. Section 11: Case report tabulation
include complete tabulation for each patient from every adequately are
well controlled phase II and Phase III efficacy, clinical pharmacology
study. It also tabulation of safety data from all clinical studies.
Section 12: Case report forms
include the complete CRF for each patient who died during a
clinical study or 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.

17.  13: Patent information (Form 3542a)
 14: Patent certification
 15: Establishment description (for biologics only)
 16: Debarment certification
 17: Field copy certification
 18: User fee cover sheet (Form FDA-3397)
FDA charges a fee for the review of an original NDA, and certain other
NDA submissions. These fees vary according to their type and the need to
review clinical data.

18.  19: Financial disclosure (Form FDA 3454, form FDA-3455)
 20: Other/pediatric use
 The FDA requires drug sponsors to submit multiple copies of the NDA
The archival copy
The review copy
The field copy

19.  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 Archival Copy

20. 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.

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Preclinical Studies
Synthesis and purification of the new drug
Pharmacology of the new drug:
 Pharmacokinetics: absorption, distribution, metabolism, excretion,
half-life
 Pharmacodynamics: mechanism of action and estimates of
therapeutic effects
 Toxicology including carcinogenicity, mutagenicity, and
teratogenicity
Efficacy studies on animals

22. The NDA in CTD Format
 ICH (International Council for Harmonisation)has
developed a Common Technical Document to streamline
regulatory submissions in U.S. .
 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.

23. NDA Review Process
TIMING
Within 45 days after receipt of the NDA, the reviewing
division will meet, and determine if the application is
fileable.
If the application is to be filed, then a review plan is
established for that NDA, its review priority depending on
the importance of the drug
If not fileable, a refuse to file (RTF) letter is sent to the
sponsor.

24.  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.

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.

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
 NDA starts with FDA form 356h which provides listing of 20 sections.
 The Form 356h is completed and signed by the sponsor or the sponsors
authorized US agent, who resides or maintains a business site in the United
states.

25. NDA Review Process

26. Post-Approval Activities For NDA and ANDA
Annual reports:
 Sponsors of NDA or ANDA must submit an annual report each year, within 60
days of the anniversary date of US Approval of the application, to the FDA
division responsible for reviewing the application.
 The report is required to contain in the order listed:
 Form FDA 2252( Tramittal of periodic reports for drugs for human use)
 Summary
 Distribution data
 Labelling
 CMC changes
 Non clinical laboratory studies
 Clinical data
 Status reports of post-marketing study commitments
 Status of other post-marketing studies
 Log of outstanding regulatory business (optional)

27. Other considerations for NDA and ANDA
 Supplemental Applications
 Establishment registration and drug listing requirements for foreign
establishments.
Pre-Approval Inspection
The purpose of PAI is to verify the authenticity of data submitted in the
applications, and to evaluate the cGMP compliance of the applicant.

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