The document outlines the process and requirements for Non-Clinical Drug Development and New Drug Application (NDA) in the United States. It details the objectives of the NDA, its contents, regulatory guidelines, phases of clinical trials, and data required for FDA submission. The document serves as a comprehensive guide for drug sponsors to ensure compliance with FDA standards for safety, efficacy, and manufacturing quality.

1. S.GOKULAKRISHNAN
M.Pharm (Pharmaceutics) – I Year,
Department of Pharmaceutics,
College of Pharmacy,
Mother Theresa Post Graduate and Research Institute of Health Sciences,
Puducherry.
NON CLINICAL DRUG DEVELOPMENT
-NEW DRUG APPLICATION
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 1

2. OBJECTIVES
Provide enough information to permit FDA reviewers to establish the
following:
 Safety & effectiveness of drug.
 Benefits overweigh risks.
 Is the drug’s proposed labelling (package insert) appropriate, and what
should it contain?
 Are the methods used in manufacturing (Good Manufacturing Practice,
GMP) the drug and the controls used to maintain the drug’s quality
adequate to preserve the drug’s identity,,strength,quality and purity
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 2

3. NEW DRUG APPLICATION
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 has been the subject of an approved NDA
before U.S. commercialization.
The data gathered during the animal studies and human clinical
trials of an Investigational New Drug (IND) becomes part of the
NDA.
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 3

4. 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 product 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
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 4

5. NDA CONTENTS
 Introduction
 Brief description of the drug and the therapeutic class to which it belongs
 Chemical and pharmaceutical information
 Animal Pharmacolog
 Animal Toxicology
 Human/Clinical Pharmacology phase I
 Therapeutic exploratory trials (Phase II)
 Therapeutic confirmatory trials (Phase III)
 Special Studies
Geriatrics, pediatrics, pregnant or nursing women
 Regulatory status in other countries
 Prescribing information
 Samples and Testing Protocol/sGOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 5

6. WHEN TO GET APPROVAL FROM NDA
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 6

7. CLINICAL TRAIL PHASES
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 7

8. REVIEW OF NDA PROCESS
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 8

9. DATA REQUIRED TO BE SUBMITTED WITH APPLICATION
FOR PERMISSION TO MARKET A NEW DRUG
1)INTRODUCTION
 Brief introduction of the drug and the therapeutic class it belongs.
2) CHEMICAL AND PHARMACEUTICAL INFORMATION
 Information of active ingredients eg; Generic name.
 Physiochemical Data eg; Chemical name , structure , emperical Formula , mol wt.
 Physical properties eg; Solubility , Rotation, Partition coefficient, Dissociation constant.
 Analytiacal data eg;Elemental Analysis,Mass,NMR,IR,UV spectra,Polymorphic
identification.
 Complete Monograph Specification including eg; quantification of impurities,
Enantiomeric purity,Assay.
 Dosage form and its composition.
 Specification of active and inactive ingredients.
 Outline of the method of the manufacture of the active ingredient.
 Stability Data.
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 9

10. 3.ANIMAL PHARMACOLOGY
 Summary
 Specific pharmacological actions.
 General pharmacological actions.
 Follow up and Supplemental safety pharmacological studies
 pharmaacokinetics: absorption,distribution,metabolism,excretion.
4.ANIMAL TOXICOLOGY
 Genral aspects
 Systemic toxicity studies
 Male fertility studies
 female Reproduction and developmental studies
 local toxicity
 Allergenicity/Hyper sensitivity
 Genotoxicity
 Carcinogenicity GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 10

11. 5.HUMAN/CLINICAL PHARMACOLOGY
(PHASE I)
 Summary
 Specific Pharmacological effects.
 General Phamacological effects
 Pharmacokinetics,absorption,distribution,metabolism,excretion
 Pharmacodynamics/early measurement of drug activity
6.THERAPEUTIC EXPLORATORY TRIALS
(PHASE II)
 Summary
 Study reports
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12. 7.THERAPEUTIC CONFIRMATORY TRIALS
(PHASE III)
 Summary
 Individual study reports with listing of sites and Investigators.
8.SPECIAL STUDIES
 Summary
 Bio-availability/Bio-equivalence
 Other Studies eg; geriatrics,paediatrics,pregnant or nursing woman
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 12

13. 9.REGULATORY STATUS IN OTHER
COUNTRIES
 Countries where the drug is marketed Approved
 Approved as IND
 Withdrawn if any with reasons.
 Restrictions on use, if any, in countries where
marketed.
 Free sale certificate or certificate of analysis, as
appropriate.
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14. NDA CONTENT AND FORMAT
REQUIREMENTS
 NDA must provide all relevant data and information
that a sponsor has collected during the product's
research and development.
 The FDA has numerous guidelines that relate to
NDA content and format issues. These guidelines
can be obtained from CDER's Drug Information
Branch (DIB).
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15. NDA CONTENTS
SECTION 1: OVERALL NDA INDEX
 The NDA index is a comprehensive table of contents
that enables the reviewers to find specific
information in this massive document quickly.
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.GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 15

16. SECTION 3: APPLICATION SUMMARY
 Proposed annotated package insert
 Pharmacology class, scientific rational, intended use, and potential
clinical benefits
 Foreign marketing history
 Chemistry, Manufacturing and control summary
 Nonclinical pharmacology and toxicology summary
 Human pharmacokinetics and bioavailability summary
 Microbiology summary
 Clinical data summary and results of statistical analysis
 Discussion of benefit/risk relationship
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17. SECTION 4: CHEMISTRY, MANUFACTURING AND
CONTROLS
 Chemistry, manufacturing and control information
 Samples
 Methods 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 pharmacodynamic
ED50 in dose- ranging studies and the mechanism of act ion (if known)
 Interactions with other drugs (or cross-reference the location of the
information in any of the above subsectionGOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 17

18. SECTION 6: HUMAN PHARMACOKINETICS AND
BIOAVAILABILITY
o 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
 Bioavailibility or bioequivalence studies
 Pharmacokinetic studies
 In vitro studies
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19. SECTION 7: MICROBIOLOGY
o Includes 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
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20. SECTION 8: CLINICAL DATA
Includes.
 List of investigators and list of INDs and NDAs
 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 drugGOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 20

21. 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 benefitsGOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 21

22. 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.
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23. oApplication itself consists of a cover letter and a completed form
FDA-356h along with several other supporting items as
appropriate
 Item 13: Patent information
 Item 14: Patent certification
 Item 15: Establishment description
 Item 16: Debarment certification
 Item 17: Field copy certification
 Item 18: User fee cover sheet (Form FDA-3397)
 Item 19: Financial disclosure (Form FDA 3454, form FDA-3455)
 Item 20: Other/pediatric use
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24. GENERAL REQUIREMENTS
 The new (present) NDA regulations require that an
application be submitted in two copies :
1.ARCHIVAL COPY
 Serves as a permanent record of the submission.
2.REVIEW COPY
 The review copy is made up of a number of separate
technical volumes, each tailored to the needs of the
disciplines involved in the review.
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25.  Both the archival and review copies are submitted in
hard copy, the regulations permit an application to
submit the archival copy as microfiche.
 The NDA application form (FORM NDA 356 h)
consist of Twelve items (including index) deals with
the safety and efficacy features of drug product, two
are concerned with patent information.
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26. GUIDANCE DOCUMENTS FOR NDAs
 These documents are prepared for FDA review staff and
applicants/sponsors to provide guidelines to the
processing, content, and evaluation/approval of
applications.
 CDER gives guidance documents to help prepare NDAs
 CDER - Centre for Drug Evaluation and Research
 Drug Registration & Licensing System
 ICSR-Individual Case Safety system Reporting
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27.  Bioavailability and bioequivalence studies for Orally
administered drug products- General considerations.
 Formatting, assembling and submitting new drug and
antibiotic application.
 Format and content of Chemistry, Manufacturing and
Control section of an application.
 Format and content of Microbiology section of an
application.
 Format and content of Clinical and Statistical section of an
application.
 Container closure system for packing human drugs and
biologics. GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 27

28.  Submitting documentation for the Stability of human drugs
and biologics.
 Format and content of human pharmacokinetics and
bioavailability section of an application.
 Providing clinical evidence of effectiveness for human
drug and biological products.
 NDAs- Impurities in drug substances.
 Drug Master Files (DMF).
 Required specifications for FDA’s IND, NDA and ANDA
drug master file binders.
 Refusal to file.
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29. ASSEMBLING APPLICATIONS FOR
SUBMISSION
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30. ARCHIVAL COPY
 The cover letter
 Form FDA- 356h
 The Administrative sections
 Comprehensive NDA index
 Four copies of labeling section
 Three copies of CMC, Methods validation package
 Case report tabulations & Case report forms
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31. REVIEW COPY
 Appropriate technical section
 The cover letter
 Form FDA- 356h
 The Administrative section
 Comprehensive NDA- index
 The labeling section
 The application summary
GOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 31

32. FIELD COPY
 Since 1993, use by FDA inspectors
 Cover letter
 Form FDA-356h
 The administrative sections
 The comprehensive NDA index
 An individual table of contents
 The Labeling section
 The Application Summary
 The CMC and Methods Validation PackageGOKULAKRISHNAN NON CLINICAL DRUG DEVELOPMENT 32

33. FDA APPROVAL PROCESS
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34. FAST TRACK APPROVAL
Drugs For
 Serious diseases
 Fill an unmet medical need
 Must be requested by the drug company
 FDA- 60 Days-Review- Decision
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35. ACCELERATED APPROVAL
 In 1992 FDA instituted the Accelerated Approval
regulation.
 Based on a Surrogate endpoint, not on clinical outcome.
 A surrogate endpoint is a marker- a laboratory
measurement, or physical sign - that is used in clinical
trials as an indirect or substitute measurement that
represents a clinically meaningful outcome, such as
survival or symptom improvement.
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36. PRIORITY REVIEW
 A Priority Review designation is given to drugs that offer
major advances in treatment.
 The goal for completing a Priority Review is six months.
 It can given for Drugs use to Serious/ Nonserious diseases.
 Standard Review is applied to a drug that offers a
most, only minor improvement over existing
marketed therapies (Ten months for Approval).
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37. REFERENCES
 www.fda.gov/cder/handbook/ndabox.htm
 www.fda.gov
 www.phrma.org
 www.fda.gov/cder/about/history/time1.html
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38. 38GOKULAKRISHNAN NON CLINICAL DRUG